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AKI doubles risk of death for those with acute pancreatitis
CHICAGO – Acute kidney injury (AKI) doubles the risk of death among patients hospitalized for acute pancreatitis, Kalpit Devani, MD, reported at the annual Digestive Disease Week®.
This severe complication of acute pancreatitis also significantly increases the length of stay and drives up hospital costs, said Dr. Devani of East Tennessee State University, Johnson City. Fortunately, although the risks associated with it remain high, death from AKI in the setting of acute pancreatitis has decreased significantly, from a high of 17% in 2002 to 6.4% in 2012, Dr. Devani determined in his database review.
“Increasing awareness and prompt diagnosis of AKI could be the reason for the increasing trend of prevalence of AKI in acute pancreatitis patients,” he said in an interview. “Decreasing mortality can be related to adherence to recent advances in the management approach of acute pancreatitis, such as early (within 24 hours) and aggressive intravenous hydration and early enteral feeding.”
Dr. Devani examined these trends in data extracted from the National Inpatient Sample, 2002-2012. During that 10-year period, almost 3.5 million adults were hospitalized for acute pancreatitis. These patients were a mean of 53 years old, and half were women. Their mean length of stay was just over 5 days, at a mean cost of about $12,000. Of these, 273,687 (7.9%) also developed AKI.
There were some significant differences between those who did and did not develop AKI. AKI patients were significantly older (61 vs. 53 years), and less likely to be women (43% vs. 51%). They had a higher Charlson Comorbidity Index score (1.49 vs. 0.84). They were also significantly more likely to develop a number of complications, including systemic inflammatory response syndrome (2% vs. 0.4%), septic shock (6% vs. 0.3%), sepsis (8.7% vs. 1.4%), acute respiratory failure (18% vs. 2%), and electrolyte disorder (72% vs. 30%).
Not surprisingly, their length of stay was significantly longer (10 vs. 5 days), as was hospitalization cost ($25,923 vs. $10,889). Mortality was much higher, at almost 9% vs. 0.7%.
In a propensity matching analysis, Dr. Devani matched 53,000 pairs of acute pancreatitis patients with and without AKI. This determined that those with AKI faced a doubling in the risk of in-hospital mortality.
He also examined temporal trends with regard to the complication. The rate of diagnosed AKI in hospitalized acute pancreatitis cases rose dramatically, from 4% in 2002 to 11.6% in 2012. However, mortality in acute pancreatitis patients decreased among both those with AKI (17%-6%) and those without (1%-0.4%).
The mean length of stay in patients with AKI and pancreatitis likewise fell, from 14.8 to 8.6 days. Not surprisingly, total hospitalization cost for these patients fell as well ($42,975-$20,716).
Among pancreatitis patients without AKI, length of stay and costs declined, although not as dramatically as they did among AKI patients (6-5 days; $13,654-$10,895).
Dr. Devani had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Acute kidney injury (AKI) doubles the risk of death among patients hospitalized for acute pancreatitis, Kalpit Devani, MD, reported at the annual Digestive Disease Week®.
This severe complication of acute pancreatitis also significantly increases the length of stay and drives up hospital costs, said Dr. Devani of East Tennessee State University, Johnson City. Fortunately, although the risks associated with it remain high, death from AKI in the setting of acute pancreatitis has decreased significantly, from a high of 17% in 2002 to 6.4% in 2012, Dr. Devani determined in his database review.
“Increasing awareness and prompt diagnosis of AKI could be the reason for the increasing trend of prevalence of AKI in acute pancreatitis patients,” he said in an interview. “Decreasing mortality can be related to adherence to recent advances in the management approach of acute pancreatitis, such as early (within 24 hours) and aggressive intravenous hydration and early enteral feeding.”
Dr. Devani examined these trends in data extracted from the National Inpatient Sample, 2002-2012. During that 10-year period, almost 3.5 million adults were hospitalized for acute pancreatitis. These patients were a mean of 53 years old, and half were women. Their mean length of stay was just over 5 days, at a mean cost of about $12,000. Of these, 273,687 (7.9%) also developed AKI.
There were some significant differences between those who did and did not develop AKI. AKI patients were significantly older (61 vs. 53 years), and less likely to be women (43% vs. 51%). They had a higher Charlson Comorbidity Index score (1.49 vs. 0.84). They were also significantly more likely to develop a number of complications, including systemic inflammatory response syndrome (2% vs. 0.4%), septic shock (6% vs. 0.3%), sepsis (8.7% vs. 1.4%), acute respiratory failure (18% vs. 2%), and electrolyte disorder (72% vs. 30%).
Not surprisingly, their length of stay was significantly longer (10 vs. 5 days), as was hospitalization cost ($25,923 vs. $10,889). Mortality was much higher, at almost 9% vs. 0.7%.
In a propensity matching analysis, Dr. Devani matched 53,000 pairs of acute pancreatitis patients with and without AKI. This determined that those with AKI faced a doubling in the risk of in-hospital mortality.
He also examined temporal trends with regard to the complication. The rate of diagnosed AKI in hospitalized acute pancreatitis cases rose dramatically, from 4% in 2002 to 11.6% in 2012. However, mortality in acute pancreatitis patients decreased among both those with AKI (17%-6%) and those without (1%-0.4%).
The mean length of stay in patients with AKI and pancreatitis likewise fell, from 14.8 to 8.6 days. Not surprisingly, total hospitalization cost for these patients fell as well ($42,975-$20,716).
Among pancreatitis patients without AKI, length of stay and costs declined, although not as dramatically as they did among AKI patients (6-5 days; $13,654-$10,895).
Dr. Devani had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Acute kidney injury (AKI) doubles the risk of death among patients hospitalized for acute pancreatitis, Kalpit Devani, MD, reported at the annual Digestive Disease Week®.
This severe complication of acute pancreatitis also significantly increases the length of stay and drives up hospital costs, said Dr. Devani of East Tennessee State University, Johnson City. Fortunately, although the risks associated with it remain high, death from AKI in the setting of acute pancreatitis has decreased significantly, from a high of 17% in 2002 to 6.4% in 2012, Dr. Devani determined in his database review.
“Increasing awareness and prompt diagnosis of AKI could be the reason for the increasing trend of prevalence of AKI in acute pancreatitis patients,” he said in an interview. “Decreasing mortality can be related to adherence to recent advances in the management approach of acute pancreatitis, such as early (within 24 hours) and aggressive intravenous hydration and early enteral feeding.”
Dr. Devani examined these trends in data extracted from the National Inpatient Sample, 2002-2012. During that 10-year period, almost 3.5 million adults were hospitalized for acute pancreatitis. These patients were a mean of 53 years old, and half were women. Their mean length of stay was just over 5 days, at a mean cost of about $12,000. Of these, 273,687 (7.9%) also developed AKI.
There were some significant differences between those who did and did not develop AKI. AKI patients were significantly older (61 vs. 53 years), and less likely to be women (43% vs. 51%). They had a higher Charlson Comorbidity Index score (1.49 vs. 0.84). They were also significantly more likely to develop a number of complications, including systemic inflammatory response syndrome (2% vs. 0.4%), septic shock (6% vs. 0.3%), sepsis (8.7% vs. 1.4%), acute respiratory failure (18% vs. 2%), and electrolyte disorder (72% vs. 30%).
Not surprisingly, their length of stay was significantly longer (10 vs. 5 days), as was hospitalization cost ($25,923 vs. $10,889). Mortality was much higher, at almost 9% vs. 0.7%.
In a propensity matching analysis, Dr. Devani matched 53,000 pairs of acute pancreatitis patients with and without AKI. This determined that those with AKI faced a doubling in the risk of in-hospital mortality.
He also examined temporal trends with regard to the complication. The rate of diagnosed AKI in hospitalized acute pancreatitis cases rose dramatically, from 4% in 2002 to 11.6% in 2012. However, mortality in acute pancreatitis patients decreased among both those with AKI (17%-6%) and those without (1%-0.4%).
The mean length of stay in patients with AKI and pancreatitis likewise fell, from 14.8 to 8.6 days. Not surprisingly, total hospitalization cost for these patients fell as well ($42,975-$20,716).
Among pancreatitis patients without AKI, length of stay and costs declined, although not as dramatically as they did among AKI patients (6-5 days; $13,654-$10,895).
Dr. Devani had no financial disclosures.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: Mortality among those with AKI was 9% vs. 0.7% among those without. After controlling for confounders, the risk of death was doubled.
Data source: A 10-year National Inpatient Sample database review comprising 3.5 million patients with pancreatitis.
Disclosures: Dr. Devani had no financial disclosures.
Recurrent acute pancreatitis significantly impairs both mental and physical quality of life
CHICAGO – Despite its intermittent and unpredictable nature, recurrent acute pancreatitis exacts a significant toll on patients’ physical and mental quality of life.
It is well-known that patients with chronic pancreatitis suffer physically and emotionally. However, the same understanding has not been engendered for those who experience recurrent acute pancreatitis (RAP), Gregory A. Cote, MD, said at the annual Digestive Disease Week®. Sporadic episodes of acute pancreatitis may cause persistent declines in quality of life.
“RAP clearly leads to a significant reduction in physical and mental quality of life, despite its erratic and sporadic nature,” Dr. Cote said. “Smoking and self-reported disability are very important drivers of these reductions, and a concomitant diagnosis of diabetes exacerbates that even further.”
To explore RAP’s impact on mental and physical quality of life, Dr. Cote examined data from three related cross-sectional North American Pancreatitis Studies (NAPS): the NAPS2, NAPS2-CV (Continuation and Validation), and NAPS2-AS (Ancillary Study).
These studies comprised 2,619 subjects who were enrolled at 27 U.S. sites from 2000 to 2014. Both patients and their physicians completed detailed baseline questionnaires that included personal and family history, risk factors, symptoms, and the 12-Item Short Form Health Survey (SF-12), a detailed quality of life measure.
A score of 50 is the mean for the U.S. general population, and a difference of 3 points or more is considered clinically relevant, Dr. Cote noted.
He parsed the cohort into three groups: those with RAP (508), those with chronic pancreatitis (1,086), and a reference group of healthy controls who were also in the database (1,025).
Some significant between-group differences were immediately obvious, Dr. Cote said. Patients with RAP were significantly younger than both chronic pancreatitis patients (CP) and controls (45 vs. 51 and 49 years, respectively). They also experienced their first bout of acute pancreatitis sooner than CP patients became symptomatic (40 vs. 44 years). Gender was a factor as well: CP patients were more often men (55% vs. 46%).
The pattern of alcohol use between the groups was difficult to interpret, he said. About one-quarter of RAP patients abstained, another fourth were light drinkers, and another fourth moderate drinkers – 12% drank heavily and 7% very heavily. In contrast, frequent drinking was more common among CP patients, with 12% reporting that they drank heavily and 33% very heavily.
CP patients were significantly more likely to be smokers, with 75% reporting current or past tobacco use, compared with 55% of RAP patients. More RAP patients reported never smoking (44% vs. 25%).
RAP patients fell between CP patients and controls in terms of medical comorbidities, including diabetes, renal disease or kidney failure, heart disease, and liver disease.
On the SF-12 physical component section, RAP patients scored a mean of 41 points – significantly worse than controls (51) but significantly better than CP patients (37). The findings were similar for the mental component score: RAP patients scored a mean of 45, compared with 52 in controls and 43 in CP patients.
Dr. Cote performed a multivariate analysis that controlled for age, sex, tobacco and alcohol use, and diabetes. Again, he found that, compared with controls, RAP was associated with significantly reduced scores on both the physical and mental components (mean 8.5 and 6.5 points, respectively).
“The magnitude of reduction was even greater for chronic pancreatitis, with an 11-point reduction on the physical component score and a 7.6-point reduction on the mental component score.
He then sought to identify which clinical characteristics most contributed to this impact on quality of life.
On the physical component score, several were significant, including female sex, which was associated with a 4.4-point decrease; prior pancreatic surgery (–3.3); endocrine insufficiency (–4.6); past smoking (–2.5); current smoking (–3.6); and self-reported physical disability (–9.5).
The mental component score breakdown echoed some of these. Self-reported disability exerted the largest impact, bringing the mental score down by a mean of 5.4 points. Other significant factors were smoking less than a pack a day (–2.5) and smoking more than a pack a day (–4.6). Any suspicion of chronic pancreatitis by the treating physician was associated with a 2.9-point decrease on the score.
“Our findings stress that this is not a disease that can be followed conservatively. We have to investigate interventions that will attenuate it, not only because these patients may go on to develop chronic pancreatitis but because, in their current state, most are experiencing significant reductions in their quality of life.”
Dr Cote had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Despite its intermittent and unpredictable nature, recurrent acute pancreatitis exacts a significant toll on patients’ physical and mental quality of life.
It is well-known that patients with chronic pancreatitis suffer physically and emotionally. However, the same understanding has not been engendered for those who experience recurrent acute pancreatitis (RAP), Gregory A. Cote, MD, said at the annual Digestive Disease Week®. Sporadic episodes of acute pancreatitis may cause persistent declines in quality of life.
“RAP clearly leads to a significant reduction in physical and mental quality of life, despite its erratic and sporadic nature,” Dr. Cote said. “Smoking and self-reported disability are very important drivers of these reductions, and a concomitant diagnosis of diabetes exacerbates that even further.”
To explore RAP’s impact on mental and physical quality of life, Dr. Cote examined data from three related cross-sectional North American Pancreatitis Studies (NAPS): the NAPS2, NAPS2-CV (Continuation and Validation), and NAPS2-AS (Ancillary Study).
These studies comprised 2,619 subjects who were enrolled at 27 U.S. sites from 2000 to 2014. Both patients and their physicians completed detailed baseline questionnaires that included personal and family history, risk factors, symptoms, and the 12-Item Short Form Health Survey (SF-12), a detailed quality of life measure.
A score of 50 is the mean for the U.S. general population, and a difference of 3 points or more is considered clinically relevant, Dr. Cote noted.
He parsed the cohort into three groups: those with RAP (508), those with chronic pancreatitis (1,086), and a reference group of healthy controls who were also in the database (1,025).
Some significant between-group differences were immediately obvious, Dr. Cote said. Patients with RAP were significantly younger than both chronic pancreatitis patients (CP) and controls (45 vs. 51 and 49 years, respectively). They also experienced their first bout of acute pancreatitis sooner than CP patients became symptomatic (40 vs. 44 years). Gender was a factor as well: CP patients were more often men (55% vs. 46%).
The pattern of alcohol use between the groups was difficult to interpret, he said. About one-quarter of RAP patients abstained, another fourth were light drinkers, and another fourth moderate drinkers – 12% drank heavily and 7% very heavily. In contrast, frequent drinking was more common among CP patients, with 12% reporting that they drank heavily and 33% very heavily.
CP patients were significantly more likely to be smokers, with 75% reporting current or past tobacco use, compared with 55% of RAP patients. More RAP patients reported never smoking (44% vs. 25%).
RAP patients fell between CP patients and controls in terms of medical comorbidities, including diabetes, renal disease or kidney failure, heart disease, and liver disease.
On the SF-12 physical component section, RAP patients scored a mean of 41 points – significantly worse than controls (51) but significantly better than CP patients (37). The findings were similar for the mental component score: RAP patients scored a mean of 45, compared with 52 in controls and 43 in CP patients.
Dr. Cote performed a multivariate analysis that controlled for age, sex, tobacco and alcohol use, and diabetes. Again, he found that, compared with controls, RAP was associated with significantly reduced scores on both the physical and mental components (mean 8.5 and 6.5 points, respectively).
“The magnitude of reduction was even greater for chronic pancreatitis, with an 11-point reduction on the physical component score and a 7.6-point reduction on the mental component score.
He then sought to identify which clinical characteristics most contributed to this impact on quality of life.
On the physical component score, several were significant, including female sex, which was associated with a 4.4-point decrease; prior pancreatic surgery (–3.3); endocrine insufficiency (–4.6); past smoking (–2.5); current smoking (–3.6); and self-reported physical disability (–9.5).
The mental component score breakdown echoed some of these. Self-reported disability exerted the largest impact, bringing the mental score down by a mean of 5.4 points. Other significant factors were smoking less than a pack a day (–2.5) and smoking more than a pack a day (–4.6). Any suspicion of chronic pancreatitis by the treating physician was associated with a 2.9-point decrease on the score.
“Our findings stress that this is not a disease that can be followed conservatively. We have to investigate interventions that will attenuate it, not only because these patients may go on to develop chronic pancreatitis but because, in their current state, most are experiencing significant reductions in their quality of life.”
Dr Cote had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Despite its intermittent and unpredictable nature, recurrent acute pancreatitis exacts a significant toll on patients’ physical and mental quality of life.
It is well-known that patients with chronic pancreatitis suffer physically and emotionally. However, the same understanding has not been engendered for those who experience recurrent acute pancreatitis (RAP), Gregory A. Cote, MD, said at the annual Digestive Disease Week®. Sporadic episodes of acute pancreatitis may cause persistent declines in quality of life.
“RAP clearly leads to a significant reduction in physical and mental quality of life, despite its erratic and sporadic nature,” Dr. Cote said. “Smoking and self-reported disability are very important drivers of these reductions, and a concomitant diagnosis of diabetes exacerbates that even further.”
To explore RAP’s impact on mental and physical quality of life, Dr. Cote examined data from three related cross-sectional North American Pancreatitis Studies (NAPS): the NAPS2, NAPS2-CV (Continuation and Validation), and NAPS2-AS (Ancillary Study).
These studies comprised 2,619 subjects who were enrolled at 27 U.S. sites from 2000 to 2014. Both patients and their physicians completed detailed baseline questionnaires that included personal and family history, risk factors, symptoms, and the 12-Item Short Form Health Survey (SF-12), a detailed quality of life measure.
A score of 50 is the mean for the U.S. general population, and a difference of 3 points or more is considered clinically relevant, Dr. Cote noted.
He parsed the cohort into three groups: those with RAP (508), those with chronic pancreatitis (1,086), and a reference group of healthy controls who were also in the database (1,025).
Some significant between-group differences were immediately obvious, Dr. Cote said. Patients with RAP were significantly younger than both chronic pancreatitis patients (CP) and controls (45 vs. 51 and 49 years, respectively). They also experienced their first bout of acute pancreatitis sooner than CP patients became symptomatic (40 vs. 44 years). Gender was a factor as well: CP patients were more often men (55% vs. 46%).
The pattern of alcohol use between the groups was difficult to interpret, he said. About one-quarter of RAP patients abstained, another fourth were light drinkers, and another fourth moderate drinkers – 12% drank heavily and 7% very heavily. In contrast, frequent drinking was more common among CP patients, with 12% reporting that they drank heavily and 33% very heavily.
CP patients were significantly more likely to be smokers, with 75% reporting current or past tobacco use, compared with 55% of RAP patients. More RAP patients reported never smoking (44% vs. 25%).
RAP patients fell between CP patients and controls in terms of medical comorbidities, including diabetes, renal disease or kidney failure, heart disease, and liver disease.
On the SF-12 physical component section, RAP patients scored a mean of 41 points – significantly worse than controls (51) but significantly better than CP patients (37). The findings were similar for the mental component score: RAP patients scored a mean of 45, compared with 52 in controls and 43 in CP patients.
Dr. Cote performed a multivariate analysis that controlled for age, sex, tobacco and alcohol use, and diabetes. Again, he found that, compared with controls, RAP was associated with significantly reduced scores on both the physical and mental components (mean 8.5 and 6.5 points, respectively).
“The magnitude of reduction was even greater for chronic pancreatitis, with an 11-point reduction on the physical component score and a 7.6-point reduction on the mental component score.
He then sought to identify which clinical characteristics most contributed to this impact on quality of life.
On the physical component score, several were significant, including female sex, which was associated with a 4.4-point decrease; prior pancreatic surgery (–3.3); endocrine insufficiency (–4.6); past smoking (–2.5); current smoking (–3.6); and self-reported physical disability (–9.5).
The mental component score breakdown echoed some of these. Self-reported disability exerted the largest impact, bringing the mental score down by a mean of 5.4 points. Other significant factors were smoking less than a pack a day (–2.5) and smoking more than a pack a day (–4.6). Any suspicion of chronic pancreatitis by the treating physician was associated with a 2.9-point decrease on the score.
“Our findings stress that this is not a disease that can be followed conservatively. We have to investigate interventions that will attenuate it, not only because these patients may go on to develop chronic pancreatitis but because, in their current state, most are experiencing significant reductions in their quality of life.”
Dr Cote had no financial disclosures.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: On a physical QOL scale, patients scored a mean of 41 points – 10 points lower than controls. The mental QOL score was 7 points lower.
Data source: The database review comprised 2,619 subjects.
Disclosures: Dr. Cote had no financial disclosures.
Open-capsule technique improves AIE
CHICAGO – A thrice-daily regimen of open-capsule budesonide has the potential to manage a rare and severe illness – adult autoimmune enteropathy (AIE) – according to Ayush Sharma, MD.
Most patients who received the treatment responded to it, with about half experiencing a complete cessation of the chronic diarrhea that is the clinical hallmark of adult autoimmune enteropathy, Dr. Sharma said at the annual Digestive Disease Week®.
“AIE is a very rare disease, with only about 50 cases reported in the literature,” said Dr. Sharma. But part of its rarity may result from misdiagnosis. AIE is frequently mistaken for severe treatment-refractory celiac disease. Both are clinically characterized by refractory diarrhea, malabsorption of nutrients, and anorexia. However, unlike celiac disease, which is caused by genetic gluten intolerance and limited to the large intestine, AIE is a pangastrointestinal disorder that also involves the pancreas and liver. On histology, the small intestine displays often complete villous atrophy. AIE also has a very specific immune marker: gut epithelial cell antibodies, which attack enterocytes and goblet cells. These cells are often completely absent as the disease progresses.
AIE has typically been treated with immunosuppressive therapy, including corticosteroids and azathioprine. Resistant cases have been treated with adalimumab, infliximab, and tacrolimus, which are moderately successful. Because it’s an autoimmune disorder, patients need long-term maintenance therapy, which exposes them to all the risks associated with these powerful medicines.
Recently, physicians at the Mayo Clinic have adopted Dr. Murray’s open-capsule budesonide regimen as an AIE treatment. It employs three daily doses of 3-mg enteric-coated budesonide capsules, which are consumed in three different ways:
- Morning dose: Open the capsule, empty the contents in applesauce, grind between the teeth, and swallow with water.
- Afternoon dose: Open the capsule, empty the contents in applesauce, and swallow without chewing.
- Evening dose: Swallow the whole capsule.
Dr. Sharma presented a retrospective analysis comparing patient characteristics and treatment response among 43 patients with treatment-refractory celiac disease (RCD) and 26 with AIE. Patients were treated at the Mayo Clinic in Rochester from 2001 to 2016.
AIE patients were younger than RCD patients (44 vs. 57 years) and, more often, male (62% vs. 28%). They were more likely to report diarrhea (100% vs. 70%), weight loss (84% vs. 69%), and fatigue (50% vs. 14%), and to be on total parenteral nutrition (35% vs. 7%).
A large proportion (69%) had tried a gluten-free diet, but none responded to it. Gut epithelial cell antibodies were often present (82% of AIE patients vs. 12.5% of RCD patients). AIE patients more often had hypoalbuminemia (64% vs. 16%). Nearly half (46%) showed complete villous atrophy, compared with 30% of those with RCD. However, they showed intraepithelial lymphocytes less often than did those with RCD (54% vs. 91%).
Patients in both the AIE and RCD cohorts were initially treated with other drugs, including azathioprine (27% and 35%, respectively) and systemic corticosteroids (96% and 14%). Only three of the AIE patients responded well to these. Additionally, about a quarter of each cohort had already taken a course of enteric-coated budesonide, but none had responded to it. All patients except the three responders were given a trial of open-capsule budesonide.
Clinical response was defined as complete cessation of diarrhea after treatment. Partial response was an improvement in stool frequency or weight gain but not complete resolution. After subtracting the numbers lost to follow-up and the patients who responded to initial therapy, clinical outcomes were available for 17 AIE patients and 37 RCD patients (about 85% of each group).
Almost half of those with AIE (8; 47%) and a majority of those with RCD (25; 68%) experienced a complete response to open-capsule budesonide. A partial response occurred in seven of those with AIE (41%) and nine of those with RCD (24%). Only two patients with AIE and three with RCD failed to respond to the regimen.
“We were very happy to see that 89% of our AIE patients responded to open-label budesonide,” Dr. Sharma said. “We need prospective clinical trials of this treatment. Open-label budesonide may be useful as an initial treatment in AIE, with the benefit of a safer therapeutic profile than systemic steroids.”
Dr. Sharma had no relevant financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – A thrice-daily regimen of open-capsule budesonide has the potential to manage a rare and severe illness – adult autoimmune enteropathy (AIE) – according to Ayush Sharma, MD.
Most patients who received the treatment responded to it, with about half experiencing a complete cessation of the chronic diarrhea that is the clinical hallmark of adult autoimmune enteropathy, Dr. Sharma said at the annual Digestive Disease Week®.
“AIE is a very rare disease, with only about 50 cases reported in the literature,” said Dr. Sharma. But part of its rarity may result from misdiagnosis. AIE is frequently mistaken for severe treatment-refractory celiac disease. Both are clinically characterized by refractory diarrhea, malabsorption of nutrients, and anorexia. However, unlike celiac disease, which is caused by genetic gluten intolerance and limited to the large intestine, AIE is a pangastrointestinal disorder that also involves the pancreas and liver. On histology, the small intestine displays often complete villous atrophy. AIE also has a very specific immune marker: gut epithelial cell antibodies, which attack enterocytes and goblet cells. These cells are often completely absent as the disease progresses.
AIE has typically been treated with immunosuppressive therapy, including corticosteroids and azathioprine. Resistant cases have been treated with adalimumab, infliximab, and tacrolimus, which are moderately successful. Because it’s an autoimmune disorder, patients need long-term maintenance therapy, which exposes them to all the risks associated with these powerful medicines.
Recently, physicians at the Mayo Clinic have adopted Dr. Murray’s open-capsule budesonide regimen as an AIE treatment. It employs three daily doses of 3-mg enteric-coated budesonide capsules, which are consumed in three different ways:
- Morning dose: Open the capsule, empty the contents in applesauce, grind between the teeth, and swallow with water.
- Afternoon dose: Open the capsule, empty the contents in applesauce, and swallow without chewing.
- Evening dose: Swallow the whole capsule.
Dr. Sharma presented a retrospective analysis comparing patient characteristics and treatment response among 43 patients with treatment-refractory celiac disease (RCD) and 26 with AIE. Patients were treated at the Mayo Clinic in Rochester from 2001 to 2016.
AIE patients were younger than RCD patients (44 vs. 57 years) and, more often, male (62% vs. 28%). They were more likely to report diarrhea (100% vs. 70%), weight loss (84% vs. 69%), and fatigue (50% vs. 14%), and to be on total parenteral nutrition (35% vs. 7%).
A large proportion (69%) had tried a gluten-free diet, but none responded to it. Gut epithelial cell antibodies were often present (82% of AIE patients vs. 12.5% of RCD patients). AIE patients more often had hypoalbuminemia (64% vs. 16%). Nearly half (46%) showed complete villous atrophy, compared with 30% of those with RCD. However, they showed intraepithelial lymphocytes less often than did those with RCD (54% vs. 91%).
Patients in both the AIE and RCD cohorts were initially treated with other drugs, including azathioprine (27% and 35%, respectively) and systemic corticosteroids (96% and 14%). Only three of the AIE patients responded well to these. Additionally, about a quarter of each cohort had already taken a course of enteric-coated budesonide, but none had responded to it. All patients except the three responders were given a trial of open-capsule budesonide.
Clinical response was defined as complete cessation of diarrhea after treatment. Partial response was an improvement in stool frequency or weight gain but not complete resolution. After subtracting the numbers lost to follow-up and the patients who responded to initial therapy, clinical outcomes were available for 17 AIE patients and 37 RCD patients (about 85% of each group).
Almost half of those with AIE (8; 47%) and a majority of those with RCD (25; 68%) experienced a complete response to open-capsule budesonide. A partial response occurred in seven of those with AIE (41%) and nine of those with RCD (24%). Only two patients with AIE and three with RCD failed to respond to the regimen.
“We were very happy to see that 89% of our AIE patients responded to open-label budesonide,” Dr. Sharma said. “We need prospective clinical trials of this treatment. Open-label budesonide may be useful as an initial treatment in AIE, with the benefit of a safer therapeutic profile than systemic steroids.”
Dr. Sharma had no relevant financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – A thrice-daily regimen of open-capsule budesonide has the potential to manage a rare and severe illness – adult autoimmune enteropathy (AIE) – according to Ayush Sharma, MD.
Most patients who received the treatment responded to it, with about half experiencing a complete cessation of the chronic diarrhea that is the clinical hallmark of adult autoimmune enteropathy, Dr. Sharma said at the annual Digestive Disease Week®.
“AIE is a very rare disease, with only about 50 cases reported in the literature,” said Dr. Sharma. But part of its rarity may result from misdiagnosis. AIE is frequently mistaken for severe treatment-refractory celiac disease. Both are clinically characterized by refractory diarrhea, malabsorption of nutrients, and anorexia. However, unlike celiac disease, which is caused by genetic gluten intolerance and limited to the large intestine, AIE is a pangastrointestinal disorder that also involves the pancreas and liver. On histology, the small intestine displays often complete villous atrophy. AIE also has a very specific immune marker: gut epithelial cell antibodies, which attack enterocytes and goblet cells. These cells are often completely absent as the disease progresses.
AIE has typically been treated with immunosuppressive therapy, including corticosteroids and azathioprine. Resistant cases have been treated with adalimumab, infliximab, and tacrolimus, which are moderately successful. Because it’s an autoimmune disorder, patients need long-term maintenance therapy, which exposes them to all the risks associated with these powerful medicines.
Recently, physicians at the Mayo Clinic have adopted Dr. Murray’s open-capsule budesonide regimen as an AIE treatment. It employs three daily doses of 3-mg enteric-coated budesonide capsules, which are consumed in three different ways:
- Morning dose: Open the capsule, empty the contents in applesauce, grind between the teeth, and swallow with water.
- Afternoon dose: Open the capsule, empty the contents in applesauce, and swallow without chewing.
- Evening dose: Swallow the whole capsule.
Dr. Sharma presented a retrospective analysis comparing patient characteristics and treatment response among 43 patients with treatment-refractory celiac disease (RCD) and 26 with AIE. Patients were treated at the Mayo Clinic in Rochester from 2001 to 2016.
AIE patients were younger than RCD patients (44 vs. 57 years) and, more often, male (62% vs. 28%). They were more likely to report diarrhea (100% vs. 70%), weight loss (84% vs. 69%), and fatigue (50% vs. 14%), and to be on total parenteral nutrition (35% vs. 7%).
A large proportion (69%) had tried a gluten-free diet, but none responded to it. Gut epithelial cell antibodies were often present (82% of AIE patients vs. 12.5% of RCD patients). AIE patients more often had hypoalbuminemia (64% vs. 16%). Nearly half (46%) showed complete villous atrophy, compared with 30% of those with RCD. However, they showed intraepithelial lymphocytes less often than did those with RCD (54% vs. 91%).
Patients in both the AIE and RCD cohorts were initially treated with other drugs, including azathioprine (27% and 35%, respectively) and systemic corticosteroids (96% and 14%). Only three of the AIE patients responded well to these. Additionally, about a quarter of each cohort had already taken a course of enteric-coated budesonide, but none had responded to it. All patients except the three responders were given a trial of open-capsule budesonide.
Clinical response was defined as complete cessation of diarrhea after treatment. Partial response was an improvement in stool frequency or weight gain but not complete resolution. After subtracting the numbers lost to follow-up and the patients who responded to initial therapy, clinical outcomes were available for 17 AIE patients and 37 RCD patients (about 85% of each group).
Almost half of those with AIE (8; 47%) and a majority of those with RCD (25; 68%) experienced a complete response to open-capsule budesonide. A partial response occurred in seven of those with AIE (41%) and nine of those with RCD (24%). Only two patients with AIE and three with RCD failed to respond to the regimen.
“We were very happy to see that 89% of our AIE patients responded to open-label budesonide,” Dr. Sharma said. “We need prospective clinical trials of this treatment. Open-label budesonide may be useful as an initial treatment in AIE, with the benefit of a safer therapeutic profile than systemic steroids.”
Dr. Sharma had no relevant financial disclosures.
[email protected]
On Twitter @alz_gal
Key clinical point:
Major finding: Most patients (89%) experienced complete or partial remission after treatment.
Data source: A retrospective study comparing 26 patients with adult autoimmune enteropathy and 43 with treatment-refractory celiac disease.
Disclosures: Dr. Sharma had no relevant financial disclosures.
Plecanatide improves bowel function, abdominal pain
CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.
Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week®.
During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.
“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”
The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.
Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.
Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.
The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).
The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.
Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.
In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.
Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.
Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.
One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.
The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.
Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.
Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.
[email protected]
On Twitter @alz_gal
CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.
Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week®.
During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.
“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”
The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.
Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.
Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.
The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).
The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.
Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.
In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.
Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.
Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.
One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.
The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.
Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.
Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.
[email protected]
On Twitter @alz_gal
CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.
Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week®.
During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.
“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”
The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.
Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.
Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.
The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).
The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.
Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.
In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.
Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.
Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.
One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.
The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.
Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.
Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.
[email protected]
On Twitter @alz_gal
Key clinical point:
Major finding: In study -04, the placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.
Data source: The studies enrolled almost 2,200 patients.
Disclosures: Synergy Pharmaceuticals sponsored the trials. Dr. Fogel has no financial interest in the company or in plecanatide.
FDA: Some blood lead tests have reported falsely low levels since 2014
The Food and Drug Administration is recommending repeat lead testing of young children and at-risk women who were tested via a venous blood sample. The recommendation was issued May 17 after the agency discovered a probable 3-year history of inaccurate tests by the nation’s largest lead test distributor.
The tests should be repeated with a capillary sample in children younger than 6 years of age as of May 17, and all pregnant or breastfeeding women who had a lead level of 10 mcg/dL or lower in a venous blood draw tested with any system made by Magellan Diagnostics, FDA representatives said during at a press briefing.
“We do have evidence of a problem with falsely lower lead reading with venous blood,” said Dr. Shuren, director of the FDA Center for Devices and Radiological Health. “Based on the information we have now, we don’t know how often we see this inaccuracy in samples, or how much lower it is. There is a wide variation and a small amount of data. We need to do further testing to see how big the problem is and the root cause. However, we do have enough data to be confident that we don’t have the problem in capillary blood.”
The warning includes all tests run on four of Magellan Diagnostics’ lead testing systems: LeadCare; LeadCare II; LeadCare Plus; and LeadCare Ultra. All LeadCare systems can be used with blood from a finger or heel stick, including the LeadCare II system – one found in many doctors’ offices and clinics. In addition, some laboratories offer other methods of lead testing, which are not now believed to be affected.
At this point, Magellan isn’t required to pay for any retesting. Tim Hill, acting director of the Center for Medicaid and CHIP Services, who was also on the call, confirmed that retesting will be covered for Medicaid and CHIP recipients. Patients with private insurance will have to contact their insurance companies to ascertain coverage, he said.
“Our first priority is to be sure folks get retested through our programs,” Mr. Hill said during the briefing. “We don’t want reimbursement to hold up the retesting. My understanding is that talks with Magellan with regard to their liability are ongoing.”
Regulators discovered the extent of the problem in March, after Magellan submitted a 510(k) premarket notification for a new iteration of its point-of-care test, FDA spokesperson Tara Goodin said in an interview. The new product was based on a kit approved in 2013, so all tests run on venous blood since then are in question.
During the data review, FDA discovered that customers began complaining to Magellan about inaccurate results on venous blood in 2014. Magellan issued three customer notifications letters (primarily to laboratories) alerting them to testing inaccuracies and recommending mitigations designed to address them. These customer notifications were issued on Nov. 24, 2014; Nov. 4, 2016; and April 28, 2017. In these, the company indicated that about 2.5% of patients whose tests were below the level of medical concern could actually have enough lead to warrant intervention. Magellan suggested that the problem could be solved by holding all samples for 24 hours before mixing them with the reagent – a step the company said would reduce risk of a misread to zero.
Regulators disagreed, Ms. Goodin said.
“Based on available information, the FDA believes that Magellan should have determined that the risk of an inaccurate test result and the number of people that could be adversely affected was much higher than they estimated and that their mitigation might not be adequate to address the increased risk. Instead, the company submitted a malfunction report in 2015 related to an observed increased frequency of falsely low test results in the LeadCare Ultra system that the firm indicated it first identified through the August 2014 complaint.”
In the malfunction report, the company characterized this issue as a Class III recall, which the FDA defines as a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.
The scope of the problem became apparent only after Magellan submitted its 510(k) paperwork in March, Ms. Goodin said.
“After reviewing initial data available from Magellan on these inaccuracies and their mitigations, the FDA was unable to identify the root cause of the inaccuracies, the frequency and extent of the inaccuracies, or to confirm that the mitigations are effective. While the FDA’s investigation is in its early stages, we did not want to delay warning health care professionals and laboratories about the risk of testing inaccuracies and encouraging parents and at-risk adults to follow the CDC’s recommendations.”
As soon as FDA identified the issue as a potential public health risk, it began working with the Centers for Medicare & Medicaid Services to issue recommendations for laboratories, health care professionals, and at-risk individuals.
“The FDA prioritized communicating to the public about this issue but is also aggressively investigating this issue to determine the cause of the inaccurate results and will provide updates as more is learned,” Ms. Goodin said. “This includes reviewing data provided by the company, requesting additional information from Magellan regarding the issue, and inspecting the company’s facility. The FDA has also requested an independent analysis of the test. We are aggressively investigating this issue and have already sent staff to inspect Magellan’s facility.”
Phone calls to Magellan for clarification on its mitigation procedures, the potential impact on customers, and the history of the LeadCare series’ approvals were not returned at press time, and the company had no prepared statement. A safety communication was posted to its website.
Since 2014, Magellan has run 8 million blood lead tests. Based on the company’s 2.5% estimate of misreads, 200,000 patients tested with the kit could have dangerously high blood lead levels. Currently, the FDA has no official estimate of how many tests were run on venous blood, how many of those returned inaccurate results, or even what caused the tests to read out with falsely low levels, Dr. Shuren said.
“We are investigating the cause, however when [Magellan’s prior test kits] came on the market, there was data supporting their accuracy. The root cause of this, we don’t know. It may not be specific to the test; it may have to do with the tubes, the reactions with chemicals, the way it’s processed. We are looking into all [of] these.”
On Twitter @Alz_gal
The Food and Drug Administration is recommending repeat lead testing of young children and at-risk women who were tested via a venous blood sample. The recommendation was issued May 17 after the agency discovered a probable 3-year history of inaccurate tests by the nation’s largest lead test distributor.
The tests should be repeated with a capillary sample in children younger than 6 years of age as of May 17, and all pregnant or breastfeeding women who had a lead level of 10 mcg/dL or lower in a venous blood draw tested with any system made by Magellan Diagnostics, FDA representatives said during at a press briefing.
“We do have evidence of a problem with falsely lower lead reading with venous blood,” said Dr. Shuren, director of the FDA Center for Devices and Radiological Health. “Based on the information we have now, we don’t know how often we see this inaccuracy in samples, or how much lower it is. There is a wide variation and a small amount of data. We need to do further testing to see how big the problem is and the root cause. However, we do have enough data to be confident that we don’t have the problem in capillary blood.”
The warning includes all tests run on four of Magellan Diagnostics’ lead testing systems: LeadCare; LeadCare II; LeadCare Plus; and LeadCare Ultra. All LeadCare systems can be used with blood from a finger or heel stick, including the LeadCare II system – one found in many doctors’ offices and clinics. In addition, some laboratories offer other methods of lead testing, which are not now believed to be affected.
At this point, Magellan isn’t required to pay for any retesting. Tim Hill, acting director of the Center for Medicaid and CHIP Services, who was also on the call, confirmed that retesting will be covered for Medicaid and CHIP recipients. Patients with private insurance will have to contact their insurance companies to ascertain coverage, he said.
“Our first priority is to be sure folks get retested through our programs,” Mr. Hill said during the briefing. “We don’t want reimbursement to hold up the retesting. My understanding is that talks with Magellan with regard to their liability are ongoing.”
Regulators discovered the extent of the problem in March, after Magellan submitted a 510(k) premarket notification for a new iteration of its point-of-care test, FDA spokesperson Tara Goodin said in an interview. The new product was based on a kit approved in 2013, so all tests run on venous blood since then are in question.
During the data review, FDA discovered that customers began complaining to Magellan about inaccurate results on venous blood in 2014. Magellan issued three customer notifications letters (primarily to laboratories) alerting them to testing inaccuracies and recommending mitigations designed to address them. These customer notifications were issued on Nov. 24, 2014; Nov. 4, 2016; and April 28, 2017. In these, the company indicated that about 2.5% of patients whose tests were below the level of medical concern could actually have enough lead to warrant intervention. Magellan suggested that the problem could be solved by holding all samples for 24 hours before mixing them with the reagent – a step the company said would reduce risk of a misread to zero.
Regulators disagreed, Ms. Goodin said.
“Based on available information, the FDA believes that Magellan should have determined that the risk of an inaccurate test result and the number of people that could be adversely affected was much higher than they estimated and that their mitigation might not be adequate to address the increased risk. Instead, the company submitted a malfunction report in 2015 related to an observed increased frequency of falsely low test results in the LeadCare Ultra system that the firm indicated it first identified through the August 2014 complaint.”
In the malfunction report, the company characterized this issue as a Class III recall, which the FDA defines as a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.
The scope of the problem became apparent only after Magellan submitted its 510(k) paperwork in March, Ms. Goodin said.
“After reviewing initial data available from Magellan on these inaccuracies and their mitigations, the FDA was unable to identify the root cause of the inaccuracies, the frequency and extent of the inaccuracies, or to confirm that the mitigations are effective. While the FDA’s investigation is in its early stages, we did not want to delay warning health care professionals and laboratories about the risk of testing inaccuracies and encouraging parents and at-risk adults to follow the CDC’s recommendations.”
As soon as FDA identified the issue as a potential public health risk, it began working with the Centers for Medicare & Medicaid Services to issue recommendations for laboratories, health care professionals, and at-risk individuals.
“The FDA prioritized communicating to the public about this issue but is also aggressively investigating this issue to determine the cause of the inaccurate results and will provide updates as more is learned,” Ms. Goodin said. “This includes reviewing data provided by the company, requesting additional information from Magellan regarding the issue, and inspecting the company’s facility. The FDA has also requested an independent analysis of the test. We are aggressively investigating this issue and have already sent staff to inspect Magellan’s facility.”
Phone calls to Magellan for clarification on its mitigation procedures, the potential impact on customers, and the history of the LeadCare series’ approvals were not returned at press time, and the company had no prepared statement. A safety communication was posted to its website.
Since 2014, Magellan has run 8 million blood lead tests. Based on the company’s 2.5% estimate of misreads, 200,000 patients tested with the kit could have dangerously high blood lead levels. Currently, the FDA has no official estimate of how many tests were run on venous blood, how many of those returned inaccurate results, or even what caused the tests to read out with falsely low levels, Dr. Shuren said.
“We are investigating the cause, however when [Magellan’s prior test kits] came on the market, there was data supporting their accuracy. The root cause of this, we don’t know. It may not be specific to the test; it may have to do with the tubes, the reactions with chemicals, the way it’s processed. We are looking into all [of] these.”
On Twitter @Alz_gal
The Food and Drug Administration is recommending repeat lead testing of young children and at-risk women who were tested via a venous blood sample. The recommendation was issued May 17 after the agency discovered a probable 3-year history of inaccurate tests by the nation’s largest lead test distributor.
The tests should be repeated with a capillary sample in children younger than 6 years of age as of May 17, and all pregnant or breastfeeding women who had a lead level of 10 mcg/dL or lower in a venous blood draw tested with any system made by Magellan Diagnostics, FDA representatives said during at a press briefing.
“We do have evidence of a problem with falsely lower lead reading with venous blood,” said Dr. Shuren, director of the FDA Center for Devices and Radiological Health. “Based on the information we have now, we don’t know how often we see this inaccuracy in samples, or how much lower it is. There is a wide variation and a small amount of data. We need to do further testing to see how big the problem is and the root cause. However, we do have enough data to be confident that we don’t have the problem in capillary blood.”
The warning includes all tests run on four of Magellan Diagnostics’ lead testing systems: LeadCare; LeadCare II; LeadCare Plus; and LeadCare Ultra. All LeadCare systems can be used with blood from a finger or heel stick, including the LeadCare II system – one found in many doctors’ offices and clinics. In addition, some laboratories offer other methods of lead testing, which are not now believed to be affected.
At this point, Magellan isn’t required to pay for any retesting. Tim Hill, acting director of the Center for Medicaid and CHIP Services, who was also on the call, confirmed that retesting will be covered for Medicaid and CHIP recipients. Patients with private insurance will have to contact their insurance companies to ascertain coverage, he said.
“Our first priority is to be sure folks get retested through our programs,” Mr. Hill said during the briefing. “We don’t want reimbursement to hold up the retesting. My understanding is that talks with Magellan with regard to their liability are ongoing.”
Regulators discovered the extent of the problem in March, after Magellan submitted a 510(k) premarket notification for a new iteration of its point-of-care test, FDA spokesperson Tara Goodin said in an interview. The new product was based on a kit approved in 2013, so all tests run on venous blood since then are in question.
During the data review, FDA discovered that customers began complaining to Magellan about inaccurate results on venous blood in 2014. Magellan issued three customer notifications letters (primarily to laboratories) alerting them to testing inaccuracies and recommending mitigations designed to address them. These customer notifications were issued on Nov. 24, 2014; Nov. 4, 2016; and April 28, 2017. In these, the company indicated that about 2.5% of patients whose tests were below the level of medical concern could actually have enough lead to warrant intervention. Magellan suggested that the problem could be solved by holding all samples for 24 hours before mixing them with the reagent – a step the company said would reduce risk of a misread to zero.
Regulators disagreed, Ms. Goodin said.
“Based on available information, the FDA believes that Magellan should have determined that the risk of an inaccurate test result and the number of people that could be adversely affected was much higher than they estimated and that their mitigation might not be adequate to address the increased risk. Instead, the company submitted a malfunction report in 2015 related to an observed increased frequency of falsely low test results in the LeadCare Ultra system that the firm indicated it first identified through the August 2014 complaint.”
In the malfunction report, the company characterized this issue as a Class III recall, which the FDA defines as a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.
The scope of the problem became apparent only after Magellan submitted its 510(k) paperwork in March, Ms. Goodin said.
“After reviewing initial data available from Magellan on these inaccuracies and their mitigations, the FDA was unable to identify the root cause of the inaccuracies, the frequency and extent of the inaccuracies, or to confirm that the mitigations are effective. While the FDA’s investigation is in its early stages, we did not want to delay warning health care professionals and laboratories about the risk of testing inaccuracies and encouraging parents and at-risk adults to follow the CDC’s recommendations.”
As soon as FDA identified the issue as a potential public health risk, it began working with the Centers for Medicare & Medicaid Services to issue recommendations for laboratories, health care professionals, and at-risk individuals.
“The FDA prioritized communicating to the public about this issue but is also aggressively investigating this issue to determine the cause of the inaccurate results and will provide updates as more is learned,” Ms. Goodin said. “This includes reviewing data provided by the company, requesting additional information from Magellan regarding the issue, and inspecting the company’s facility. The FDA has also requested an independent analysis of the test. We are aggressively investigating this issue and have already sent staff to inspect Magellan’s facility.”
Phone calls to Magellan for clarification on its mitigation procedures, the potential impact on customers, and the history of the LeadCare series’ approvals were not returned at press time, and the company had no prepared statement. A safety communication was posted to its website.
Since 2014, Magellan has run 8 million blood lead tests. Based on the company’s 2.5% estimate of misreads, 200,000 patients tested with the kit could have dangerously high blood lead levels. Currently, the FDA has no official estimate of how many tests were run on venous blood, how many of those returned inaccurate results, or even what caused the tests to read out with falsely low levels, Dr. Shuren said.
“We are investigating the cause, however when [Magellan’s prior test kits] came on the market, there was data supporting their accuracy. The root cause of this, we don’t know. It may not be specific to the test; it may have to do with the tubes, the reactions with chemicals, the way it’s processed. We are looking into all [of] these.”
On Twitter @Alz_gal
JAK-1 inhibitor upadacitinib advances to phase III for refractory Crohn’s
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: Several doses achieved statistically significant effects in endoscopic and clinical response. About 30% of patients taking a higher dose achieved steroid-free remission.
Data source: The phase II dose-ranging study comprised 220 patients.
Disclosures: AbbVie is developing the drug and sponsored the study. Dr. Sandborn is a consultant for the company.
VIDEO: LINX magnetic band beats omeprazole for GERD regurgitation
CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week®.
In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.
“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”
The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.
This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.
The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.
These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.
The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.
Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).
An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.
When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.
There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.
Dr. Bell disclosed that he is a consultant for TORAX.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @Alz_gal
CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week®.
In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.
“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”
The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.
This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.
The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.
These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.
The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.
Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).
An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.
When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.
There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.
Dr. Bell disclosed that he is a consultant for TORAX.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @Alz_gal
CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week®.
In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.
“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”
The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.
This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.
The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.
These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.
The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.
Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).
An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.
When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.
There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.
Dr. Bell disclosed that he is a consultant for TORAX.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @Alz_gal
AT DDW 2017
Key clinical point:
Major finding: Symptoms resolved in 93% of patients, compared to 9% of those who took the proton pump inhibitor.
Data source: An ongoing randomized study of 150 patients; Dr. Bell reported 6-month outcomes on 80.
Disclosures: Dr. Bell is a consultant for TORAX Medical, which developed and manufactures the device.
For vertebral osteomyelitis, early switch to oral antibiotics is feasible
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
[email protected]
On Twitter @Alz_gal
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
[email protected]
On Twitter @Alz_gal
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
[email protected]
On Twitter @Alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: There were two treatment failures attributable to the antibiotic regimen, and two deaths that were not, for a total treatment success rate of 95%.
Data source: A retrospective cohort comprising 82 patients.
Disclosures: Dr. Lemaignen had no financial disclosures.
Ribaxamase prevented C. difficile infections by protecting microbiome
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
[email protected]
On Twitter @alz_gal
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
[email protected]
On Twitter @alz_gal
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
[email protected]
On Twitter @alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: Ribaxamase reduced C. difficile infections by 71%, relative to a placebo.
Data source: The study randomized 412 patients to either placebo or ribaxamase in addition to their therapeutic antibiotics.
Disclosures: Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
Topical imiquimod boosted response to intradermal hepatitis B vaccine
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
[email protected]
On Twitter @alz_gal
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
[email protected]
On Twitter @alz_gal
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
[email protected]
On Twitter @alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: By 1 month, seroprotection was significantly higher in the imiquimod group than in those who got an intradermal vaccination without imiquimod and those who had an intramuscular injection only (60% vs. 50% and 38%, respectively).
Data source: The four-armed randomized study comprised 69 patients on hemodialysis or peritoneal dialysis.
Disclosures: Dr. Hung has served on advisory boards for Pfizer and Gilead Sciences.