An estimated 1-1.8 million sport-related concussions (SRC) occur per year in patients younger than 18 years of age. Concussion is defined as “a traumatically induced transient disturbance of brain function.” More than 50% of concussions among high school youth are not related to organized sports and between 2% and 15% of athletes in organized sports will sustain a concussion during a season of play.

©s-c-s/Thinkstock

In its position statement on concussion in sports, the American Medical Society for Sports Medicine recommends that student athletes receive specific evaluations, which will be described in this article. The guidelines include recommendations for imaging, treatment, and decision making regarding when as well as whether to return to play. Here is a brief summary of those recommendations.


Preseason: Preseason evaluation includes a preparticipation physical evaluation and discussion of concussion history as well as risk factors associated with prolonged concussion recovery. Neurocognitive tests are available for baseline evaluation. While these may assist with diagnosis and return-to-play decisions, there can be considerable variation in an individual’s baseline score as well as the possibility of changes in that baseline over time. Because of this potential for variability, these tests are not required or accepted as the standard of care.

Sideline assessment: Familiarity with the athlete is the best way to detect subtle changes in personality or performance. Looking at symptoms is still the most sensitive way to diagnose a concussion. Loss of consciousness, seizure, tonic posturing, lack of motor coordination, confusion, amnesia, difficulty with balance, or any cognitive difficulty should prompt removal from play for possible concussion. Once a potential injury is identified, how the athlete responds to the elements of orientation, memory, concentration, speech pattern, and balance should be evaluated. If an athlete has a probable or definite concussion, the athlete needs to be removed from play and cannot return to same-day play, and a more detailed evaluation needs to be done.

Office assessment: It is not unusual for symptoms and testing to normalize by the time an office visit occurs. If this is the case, the visit should focus on recommendations for safe return to school and sport. A standard office evaluation should include taking a history with details of the mechanism of injury and preexisting conditions – such as depression and prior concussion – that can affect concussion recovery. The history should focus on detecting symptoms that typically cause impairment from concussion: headache, ocular-vestibular issues leading to problems with balance, and cognitive issues with difficulty concentrating and remembering, as well as fatigue and mood issues such as anxiety, irritability, and depression. The physical exam should include assessment of ocular and vestibular function, gait, and balance in addition to a neurological exam.

Imaging: Head CT or MRI are rarely indicated. Intracranial bleeds are rare in the context of SRC but can occur. If there is concern for a bleed, then CT scan is the imaging test of choice. MRI may have value for evaluation for atypical or prolonged recovery.

Recovery time: The large majority (80%-90%) of concussed older adolescents and adults return to preinjury levels of function within 2 weeks; in younger athletes, clinical recovery may take up to 4 weeks. The best predictor of recovery from SRC is the number and severity of symptoms.

Treatment: For decades, cognitive and physical rest has been the standard of treatment. However, this is no longer the “gold standard” as it has been shown that strict rest (“cocoon therapy”) after SRC slows recovery and leads to an increased chance of prolonged symptoms. Current consensus guidelines support 24-48 hours of symptom-limited rest, both cognitive and physical, followed by a gradual increase in activity, staying below symptom-exacerbation thresholds. Activity, along with good sleep hygiene, appears to be helpful in facilitating recovery from SRC. In athletes with persistent post concussive symptoms that continue beyond the expected recovery time frame, activities of daily living, school, and exercise that do not significantly exacerbate symptoms are recommended.

Return to learning/play: A concussion can cause temporary deficits in attention, cognitive processing, short-term memory, and executive functioning. School personnel should be informed of the injury and assist in employing an individualized return to learn plan, including academic accommodations. Ultimately, return to sports activities should follow a successful return to the classroom. Return to play involves a stepwise increase in physical demands/activity without symptoms before a student is allowed to participate in full contact play.

Concussion-related risks: Continuing to participate in sports before resolution of concussion can worsen and prolong symptoms of SRC. Returning too early after concussion, before full recovery, increases the risk of recurrent SRC. During the initial post-injury period, returning to sports too early increases the risk for a rare but devastating possibility of second impact syndrome that can be a life-threatening repeat head injury. Studies of long-term mental health diagnoses are conflicting and inconsistent. Chronic traumatic encephalopathy has been described in athletes with a long history of concussions and repetitive sub-symptom head impacts. The degree of exposure needed appears to be variable and dependent on the individual.

Disqualification from play: Because each athlete is individually assessed after SRC, there are no evidence-based studies indicating how many concussions are “safe” for an athlete to have in a lifetime. The decision to stop playing sports is both serious and difficult for most athletes and requires shared decision making between clinician, the athlete, and the athlete’s parents. Factors to consider when determining if disqualification from play is warranted include:

• The total number of concussions experienced by a patient.
• Whether a patient has sustained subsequent concussions with progressively less forceful blows to the head.
• If a patient has sustained multiple concussions,whether the time to complete a full recovery after each concussion event increased.

The bottom line: “Cocoon therapy” is no longer recommended. Consensus guidelines endorse 24-48 hours of symptom-limited cognitive and physical rest followed by a gradual increase in activity, including noncontact physical activity that does not provoke symptoms.

Dr. Belogorodsky is a second-year resident and Dr. Fidler is an associate director in the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

Reference

Harmon KG et al. American Medical Society for Sports Medicine position statement on concussion in sport. Br J Sports Med. 2019;53:213-25.

An estimated 1-1.8 million sport-related concussions (SRC) occur per year in patients younger than 18 years of age. Concussion is defined as “a traumatically induced transient disturbance of brain function.” More than 50% of concussions among high school youth are not related to organized sports and between 2% and 15% of athletes in organized sports will sustain a concussion during a season of play.

©s-c-s/Thinkstock

In its position statement on concussion in sports, the American Medical Society for Sports Medicine recommends that student athletes receive specific evaluations, which will be described in this article. The guidelines include recommendations for imaging, treatment, and decision making regarding when as well as whether to return to play. Here is a brief summary of those recommendations.


Preseason: Preseason evaluation includes a preparticipation physical evaluation and discussion of concussion history as well as risk factors associated with prolonged concussion recovery. Neurocognitive tests are available for baseline evaluation. While these may assist with diagnosis and return-to-play decisions, there can be considerable variation in an individual’s baseline score as well as the possibility of changes in that baseline over time. Because of this potential for variability, these tests are not required or accepted as the standard of care.

Sideline assessment: Familiarity with the athlete is the best way to detect subtle changes in personality or performance. Looking at symptoms is still the most sensitive way to diagnose a concussion. Loss of consciousness, seizure, tonic posturing, lack of motor coordination, confusion, amnesia, difficulty with balance, or any cognitive difficulty should prompt removal from play for possible concussion. Once a potential injury is identified, how the athlete responds to the elements of orientation, memory, concentration, speech pattern, and balance should be evaluated. If an athlete has a probable or definite concussion, the athlete needs to be removed from play and cannot return to same-day play, and a more detailed evaluation needs to be done.

Office assessment: It is not unusual for symptoms and testing to normalize by the time an office visit occurs. If this is the case, the visit should focus on recommendations for safe return to school and sport. A standard office evaluation should include taking a history with details of the mechanism of injury and preexisting conditions – such as depression and prior concussion – that can affect concussion recovery. The history should focus on detecting symptoms that typically cause impairment from concussion: headache, ocular-vestibular issues leading to problems with balance, and cognitive issues with difficulty concentrating and remembering, as well as fatigue and mood issues such as anxiety, irritability, and depression. The physical exam should include assessment of ocular and vestibular function, gait, and balance in addition to a neurological exam.

Imaging: Head CT or MRI are rarely indicated. Intracranial bleeds are rare in the context of SRC but can occur. If there is concern for a bleed, then CT scan is the imaging test of choice. MRI may have value for evaluation for atypical or prolonged recovery.

Recovery time: The large majority (80%-90%) of concussed older adolescents and adults return to preinjury levels of function within 2 weeks; in younger athletes, clinical recovery may take up to 4 weeks. The best predictor of recovery from SRC is the number and severity of symptoms.

Treatment: For decades, cognitive and physical rest has been the standard of treatment. However, this is no longer the “gold standard” as it has been shown that strict rest (“cocoon therapy”) after SRC slows recovery and leads to an increased chance of prolonged symptoms. Current consensus guidelines support 24-48 hours of symptom-limited rest, both cognitive and physical, followed by a gradual increase in activity, staying below symptom-exacerbation thresholds. Activity, along with good sleep hygiene, appears to be helpful in facilitating recovery from SRC. In athletes with persistent post concussive symptoms that continue beyond the expected recovery time frame, activities of daily living, school, and exercise that do not significantly exacerbate symptoms are recommended.

Return to learning/play: A concussion can cause temporary deficits in attention, cognitive processing, short-term memory, and executive functioning. School personnel should be informed of the injury and assist in employing an individualized return to learn plan, including academic accommodations. Ultimately, return to sports activities should follow a successful return to the classroom. Return to play involves a stepwise increase in physical demands/activity without symptoms before a student is allowed to participate in full contact play.

Concussion-related risks: Continuing to participate in sports before resolution of concussion can worsen and prolong symptoms of SRC. Returning too early after concussion, before full recovery, increases the risk of recurrent SRC. During the initial post-injury period, returning to sports too early increases the risk for a rare but devastating possibility of second impact syndrome that can be a life-threatening repeat head injury. Studies of long-term mental health diagnoses are conflicting and inconsistent. Chronic traumatic encephalopathy has been described in athletes with a long history of concussions and repetitive sub-symptom head impacts. The degree of exposure needed appears to be variable and dependent on the individual.

Disqualification from play: Because each athlete is individually assessed after SRC, there are no evidence-based studies indicating how many concussions are “safe” for an athlete to have in a lifetime. The decision to stop playing sports is both serious and difficult for most athletes and requires shared decision making between clinician, the athlete, and the athlete’s parents. Factors to consider when determining if disqualification from play is warranted include:

• The total number of concussions experienced by a patient.
• Whether a patient has sustained subsequent concussions with progressively less forceful blows to the head.
• If a patient has sustained multiple concussions,whether the time to complete a full recovery after each concussion event increased.

The bottom line: “Cocoon therapy” is no longer recommended. Consensus guidelines endorse 24-48 hours of symptom-limited cognitive and physical rest followed by a gradual increase in activity, including noncontact physical activity that does not provoke symptoms.

Dr. Belogorodsky is a second-year resident and Dr. Fidler is an associate director in the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

Reference

Harmon KG et al. American Medical Society for Sports Medicine position statement on concussion in sport. Br J Sports Med. 2019;53:213-25.

An estimated 1-1.8 million sport-related concussions (SRC) occur per year in patients younger than 18 years of age. Concussion is defined as “a traumatically induced transient disturbance of brain function.” More than 50% of concussions among high school youth are not related to organized sports and between 2% and 15% of athletes in organized sports will sustain a concussion during a season of play.

©s-c-s/Thinkstock

In its position statement on concussion in sports, the American Medical Society for Sports Medicine recommends that student athletes receive specific evaluations, which will be described in this article. The guidelines include recommendations for imaging, treatment, and decision making regarding when as well as whether to return to play. Here is a brief summary of those recommendations.


Preseason: Preseason evaluation includes a preparticipation physical evaluation and discussion of concussion history as well as risk factors associated with prolonged concussion recovery. Neurocognitive tests are available for baseline evaluation. While these may assist with diagnosis and return-to-play decisions, there can be considerable variation in an individual’s baseline score as well as the possibility of changes in that baseline over time. Because of this potential for variability, these tests are not required or accepted as the standard of care.

Sideline assessment: Familiarity with the athlete is the best way to detect subtle changes in personality or performance. Looking at symptoms is still the most sensitive way to diagnose a concussion. Loss of consciousness, seizure, tonic posturing, lack of motor coordination, confusion, amnesia, difficulty with balance, or any cognitive difficulty should prompt removal from play for possible concussion. Once a potential injury is identified, how the athlete responds to the elements of orientation, memory, concentration, speech pattern, and balance should be evaluated. If an athlete has a probable or definite concussion, the athlete needs to be removed from play and cannot return to same-day play, and a more detailed evaluation needs to be done.

Office assessment: It is not unusual for symptoms and testing to normalize by the time an office visit occurs. If this is the case, the visit should focus on recommendations for safe return to school and sport. A standard office evaluation should include taking a history with details of the mechanism of injury and preexisting conditions – such as depression and prior concussion – that can affect concussion recovery. The history should focus on detecting symptoms that typically cause impairment from concussion: headache, ocular-vestibular issues leading to problems with balance, and cognitive issues with difficulty concentrating and remembering, as well as fatigue and mood issues such as anxiety, irritability, and depression. The physical exam should include assessment of ocular and vestibular function, gait, and balance in addition to a neurological exam.

Imaging: Head CT or MRI are rarely indicated. Intracranial bleeds are rare in the context of SRC but can occur. If there is concern for a bleed, then CT scan is the imaging test of choice. MRI may have value for evaluation for atypical or prolonged recovery.

Recovery time: The large majority (80%-90%) of concussed older adolescents and adults return to preinjury levels of function within 2 weeks; in younger athletes, clinical recovery may take up to 4 weeks. The best predictor of recovery from SRC is the number and severity of symptoms.

Treatment: For decades, cognitive and physical rest has been the standard of treatment. However, this is no longer the “gold standard” as it has been shown that strict rest (“cocoon therapy”) after SRC slows recovery and leads to an increased chance of prolonged symptoms. Current consensus guidelines support 24-48 hours of symptom-limited rest, both cognitive and physical, followed by a gradual increase in activity, staying below symptom-exacerbation thresholds. Activity, along with good sleep hygiene, appears to be helpful in facilitating recovery from SRC. In athletes with persistent post concussive symptoms that continue beyond the expected recovery time frame, activities of daily living, school, and exercise that do not significantly exacerbate symptoms are recommended.

Return to learning/play: A concussion can cause temporary deficits in attention, cognitive processing, short-term memory, and executive functioning. School personnel should be informed of the injury and assist in employing an individualized return to learn plan, including academic accommodations. Ultimately, return to sports activities should follow a successful return to the classroom. Return to play involves a stepwise increase in physical demands/activity without symptoms before a student is allowed to participate in full contact play.

Concussion-related risks: Continuing to participate in sports before resolution of concussion can worsen and prolong symptoms of SRC. Returning too early after concussion, before full recovery, increases the risk of recurrent SRC. During the initial post-injury period, returning to sports too early increases the risk for a rare but devastating possibility of second impact syndrome that can be a life-threatening repeat head injury. Studies of long-term mental health diagnoses are conflicting and inconsistent. Chronic traumatic encephalopathy has been described in athletes with a long history of concussions and repetitive sub-symptom head impacts. The degree of exposure needed appears to be variable and dependent on the individual.

Disqualification from play: Because each athlete is individually assessed after SRC, there are no evidence-based studies indicating how many concussions are “safe” for an athlete to have in a lifetime. The decision to stop playing sports is both serious and difficult for most athletes and requires shared decision making between clinician, the athlete, and the athlete’s parents. Factors to consider when determining if disqualification from play is warranted include:

• The total number of concussions experienced by a patient.
• Whether a patient has sustained subsequent concussions with progressively less forceful blows to the head.
• If a patient has sustained multiple concussions,whether the time to complete a full recovery after each concussion event increased.

The bottom line: “Cocoon therapy” is no longer recommended. Consensus guidelines endorse 24-48 hours of symptom-limited cognitive and physical rest followed by a gradual increase in activity, including noncontact physical activity that does not provoke symptoms.

Dr. Belogorodsky is a second-year resident and Dr. Fidler is an associate director in the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

Reference

Harmon KG et al. American Medical Society for Sports Medicine position statement on concussion in sport. Br J Sports Med. 2019;53:213-25.

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]

When influenza season arrives, conventional morbidity and mortality statistics, health care encounters, and laboratory data might not “fully reflect the disruption caused to the social and economic life of the community,” say CDC researchers. That is the reason that the National Institute for Occupational Safety and Health (NIOSH) monitors health-related workplace absenteeism every month, and why the World Health Organization (WHO) uses those data to help determine the impact of influenza season worldwide.

The workplace is a prime area for transmission—people share workspace and equipment and interact with one another closely. Estimates of influenza attack rates for working-aged adults can be as high as 14.3% in a given influenza season, the CDC says.

According to NIOSH, absenteeism rose sharply in the 2017-2018 season, to a level significantly higher than that of the average during the previous 5 seasons. In October, 1.7% of workers were absent due to health issues. That figure began climbing in November, peaking in January at 3.0%, significantly exceeding the epidemic threshold. Absenteeism declined steadily after that to a low of 1.4%, then began rising again in August and September.

Male workers, people aged 45 to 64 years, and those working in certain occupations (including management, business, and repair services) were more likely to be out.

Regional absenteeism peaks corresponded to concurrent peaks in influenza-like illness (ILI) activity in those regions. The researchers say this is in line with a longtime recognition that health-related workplace absenteeism correlates well with the presence of ILI, which is why absenteeism data are used as a nonspecific indicator of ILI in the community. During the 2009-2010 influenza A (H1N1) pandemic, for instance, peak workplace absenteeism correlated with the highest occurrence of both ILI and influenza-positive laboratory tests, according to NIOSH.

The associations between ILI, absenteeism, and demographic characteristics are complex, the researchers say, and mediated by factors such as vaccination coverage and access to paid sick leave.

The usual recommendations—vaccination, covering coughs and sneezes, handwashing, and routinely cleaning frequently touched surfaces—are the most effective ways to prevent transmission, the researchers note. During a pandemic, other measures may be needed, such as “social distancing” in workplaces.

NIOSH makes absenteeism surveillance results available (https://www.cdc.gov/niosh/topics/absences/default.html). The researchers suggest that employers might wish to consult them when developing prevention messages.

When influenza season arrives, conventional morbidity and mortality statistics, health care encounters, and laboratory data might not “fully reflect the disruption caused to the social and economic life of the community,” say CDC researchers. That is the reason that the National Institute for Occupational Safety and Health (NIOSH) monitors health-related workplace absenteeism every month, and why the World Health Organization (WHO) uses those data to help determine the impact of influenza season worldwide.

The workplace is a prime area for transmission—people share workspace and equipment and interact with one another closely. Estimates of influenza attack rates for working-aged adults can be as high as 14.3% in a given influenza season, the CDC says.

According to NIOSH, absenteeism rose sharply in the 2017-2018 season, to a level significantly higher than that of the average during the previous 5 seasons. In October, 1.7% of workers were absent due to health issues. That figure began climbing in November, peaking in January at 3.0%, significantly exceeding the epidemic threshold. Absenteeism declined steadily after that to a low of 1.4%, then began rising again in August and September.

Male workers, people aged 45 to 64 years, and those working in certain occupations (including management, business, and repair services) were more likely to be out.

Regional absenteeism peaks corresponded to concurrent peaks in influenza-like illness (ILI) activity in those regions. The researchers say this is in line with a longtime recognition that health-related workplace absenteeism correlates well with the presence of ILI, which is why absenteeism data are used as a nonspecific indicator of ILI in the community. During the 2009-2010 influenza A (H1N1) pandemic, for instance, peak workplace absenteeism correlated with the highest occurrence of both ILI and influenza-positive laboratory tests, according to NIOSH.

The associations between ILI, absenteeism, and demographic characteristics are complex, the researchers say, and mediated by factors such as vaccination coverage and access to paid sick leave.

The usual recommendations—vaccination, covering coughs and sneezes, handwashing, and routinely cleaning frequently touched surfaces—are the most effective ways to prevent transmission, the researchers note. During a pandemic, other measures may be needed, such as “social distancing” in workplaces.

NIOSH makes absenteeism surveillance results available (https://www.cdc.gov/niosh/topics/absences/default.html). The researchers suggest that employers might wish to consult them when developing prevention messages.

When influenza season arrives, conventional morbidity and mortality statistics, health care encounters, and laboratory data might not “fully reflect the disruption caused to the social and economic life of the community,” say CDC researchers. That is the reason that the National Institute for Occupational Safety and Health (NIOSH) monitors health-related workplace absenteeism every month, and why the World Health Organization (WHO) uses those data to help determine the impact of influenza season worldwide.

The workplace is a prime area for transmission—people share workspace and equipment and interact with one another closely. Estimates of influenza attack rates for working-aged adults can be as high as 14.3% in a given influenza season, the CDC says.

According to NIOSH, absenteeism rose sharply in the 2017-2018 season, to a level significantly higher than that of the average during the previous 5 seasons. In October, 1.7% of workers were absent due to health issues. That figure began climbing in November, peaking in January at 3.0%, significantly exceeding the epidemic threshold. Absenteeism declined steadily after that to a low of 1.4%, then began rising again in August and September.

Male workers, people aged 45 to 64 years, and those working in certain occupations (including management, business, and repair services) were more likely to be out.

Regional absenteeism peaks corresponded to concurrent peaks in influenza-like illness (ILI) activity in those regions. The researchers say this is in line with a longtime recognition that health-related workplace absenteeism correlates well with the presence of ILI, which is why absenteeism data are used as a nonspecific indicator of ILI in the community. During the 2009-2010 influenza A (H1N1) pandemic, for instance, peak workplace absenteeism correlated with the highest occurrence of both ILI and influenza-positive laboratory tests, according to NIOSH.

The associations between ILI, absenteeism, and demographic characteristics are complex, the researchers say, and mediated by factors such as vaccination coverage and access to paid sick leave.

The usual recommendations—vaccination, covering coughs and sneezes, handwashing, and routinely cleaning frequently touched surfaces—are the most effective ways to prevent transmission, the researchers note. During a pandemic, other measures may be needed, such as “social distancing” in workplaces.

NIOSH makes absenteeism surveillance results available (https://www.cdc.gov/niosh/topics/absences/default.html). The researchers suggest that employers might wish to consult them when developing prevention messages.

The skin biopsy confirmed toxic epidermal necrolysis (TEN), possibly secondary to one of the antibiotics he’d been given upon hospital admission. The health care team suspected that the patient had Stevens-Johns Syndrome when he sought care and that it had evolved into TEN. Both diseases are life-threatening and require intensive in-hospital care.

TEN is part of a spectrum of disorders that includes erythema multiforme (< 10% of the body surface is involved); SJS/TEN (10%-30% involvement with erythematous or pruritic macules, widespread blisters on the trunk and face, and erosions of ≥ 1 mucous membranes); and TEN (> 30% involvement).

Drugs most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. Fifty percent of SJS/TEN cases have no identifiable cause. Not all SJS is secondary to drug exposure, but it is the job of the clinician to investigate this cause and stop any suspicious medications.

In this case, trimethoprim/sulfamethoxazole was discontinued immediately and the patient was transferred to a burn unit and given intravenous gamma-globulin 1 g/kg for 3 days. Fortunately, the patient survived with intensive supportive care in the burn unit. The exfoliation of > 30% of the skin is like a large secondary burn, and a burn unit is the optimal location for lifesaving measures.

‌

Photo courtesy of Robert T. Gilson, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The skin biopsy confirmed toxic epidermal necrolysis (TEN), possibly secondary to one of the antibiotics he’d been given upon hospital admission. The health care team suspected that the patient had Stevens-Johns Syndrome when he sought care and that it had evolved into TEN. Both diseases are life-threatening and require intensive in-hospital care.

TEN is part of a spectrum of disorders that includes erythema multiforme (< 10% of the body surface is involved); SJS/TEN (10%-30% involvement with erythematous or pruritic macules, widespread blisters on the trunk and face, and erosions of ≥ 1 mucous membranes); and TEN (> 30% involvement).

Drugs most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. Fifty percent of SJS/TEN cases have no identifiable cause. Not all SJS is secondary to drug exposure, but it is the job of the clinician to investigate this cause and stop any suspicious medications.

In this case, trimethoprim/sulfamethoxazole was discontinued immediately and the patient was transferred to a burn unit and given intravenous gamma-globulin 1 g/kg for 3 days. Fortunately, the patient survived with intensive supportive care in the burn unit. The exfoliation of > 30% of the skin is like a large secondary burn, and a burn unit is the optimal location for lifesaving measures.

‌

Photo courtesy of Robert T. Gilson, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The skin biopsy confirmed toxic epidermal necrolysis (TEN), possibly secondary to one of the antibiotics he’d been given upon hospital admission. The health care team suspected that the patient had Stevens-Johns Syndrome when he sought care and that it had evolved into TEN. Both diseases are life-threatening and require intensive in-hospital care.

TEN is part of a spectrum of disorders that includes erythema multiforme (< 10% of the body surface is involved); SJS/TEN (10%-30% involvement with erythematous or pruritic macules, widespread blisters on the trunk and face, and erosions of ≥ 1 mucous membranes); and TEN (> 30% involvement).

Drugs most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. Fifty percent of SJS/TEN cases have no identifiable cause. Not all SJS is secondary to drug exposure, but it is the job of the clinician to investigate this cause and stop any suspicious medications.

In this case, trimethoprim/sulfamethoxazole was discontinued immediately and the patient was transferred to a burn unit and given intravenous gamma-globulin 1 g/kg for 3 days. Fortunately, the patient survived with intensive supportive care in the burn unit. The exfoliation of > 30% of the skin is like a large secondary burn, and a burn unit is the optimal location for lifesaving measures.

‌

Photo courtesy of Robert T. Gilson, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.

gorodenkoff/iStock/Getty Images Plus

This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.

It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.

The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.

The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.

This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.

The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).

FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.

“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”

Dr. Brody reported having no relevant disclosures.

[email protected]

The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.

gorodenkoff/iStock/Getty Images Plus

This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.

It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.

The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.

The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.

This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.

The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).

FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.

“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”

Dr. Brody reported having no relevant disclosures.

[email protected]

The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.

gorodenkoff/iStock/Getty Images Plus

This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.

It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.

The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.

The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.

This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.

The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).

FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.

“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”

Dr. Brody reported having no relevant disclosures.

[email protected]

PHILADELPHIA – People with moderately high levels of riboflavin consumption from food – two to three times the recommended dietary allowance – had a significantly lower prevalence of a recent severe or migraine headache in a study of more than 3,600 younger U.S. adults.

Adults 20-50 years old who consumed 2.07-2.87 mg riboflavin (vitamin B₂) in food a day based on a 24-hour recall questionnaire had an adjusted, statistically significant 27% reduced prevalence of a recent severe or migraine headache, compared with people in the lowest quartile of dietary riboflavin intake, 1.45 mg/day or less, Margaret Slavin, Ph.D., said at the annual meeting of the American Headache Society. Foods particularly high in riboflavin include eggs, milk, and meat.

Dietary riboflavin intakes greater than 2.87 mg/day were not linked to a difference in the prevalence of a recent history of severe or migraine headache, compared with lowest-quartile consumption. Additionally, riboflavin intake from supplements alone at any level of consumption also showed no statistically significant link with the prevalence of a recent, severe headache, said Dr. Slavin, a nutrition and food studies researcher at George Mason University in Fairfax, Va.

The “vast majority” of people in the study had a riboflavin intake that at least matched the U.S. recommended dietary allowance (RDA),1.3 mg/ day for men and 1.1 mg/day for women), “but it’s possible that people with migraine headaches need more riboflavin,” Dr. Slavin suggested. Professional societies in the United States (Neurology. 2012 Apr;78[17]: 1346-53) and Canada (Can J Neurol Sci. 2012 Mar;39[Suppl 2]S8-S28) have gone on record with some level of recommendation for a daily riboflavin supplement of 400 mg to prevent migraine headaches, she said.

A U.S. guideline that included riboflavin has been “retired” because of an issue unrelated to riboflavin, according to the Neurology website.

The new study ran data collected in the biennial National Health and Nutrition Examination Survey (NHANES), specifically the surveys from 2001-2002 and 2003-2004. The combined data included 5,528 adults 20-50 years old, and 3,634 with complete data and without an excluding condition such as pregnancy, diabetes, or menopause. Among the study participants 884 reported having “severe headaches or migraines,” during the 3 months preceding the survey and the remaining 2,750 people served as controls. People who reported recent severe headache or migraine overall had a significantly lower average amount of vitamin B2 in their diet than did the controls, but the two subgroups showed no significant differences in their levels of riboflavin intake from supplements, or from both diet and supplements combined.

The researchers calculated odds ratios for people having severe headaches or migraines relative to their riboflavin-intake quartile, and they adjusted the findings for age, sex, body mass index, and alcohol intake.

Further analysis that looked at total riboflavin intake, from both food and supplements, showed that the two middle quartiles for this metric, with a combined riboflavin intake of 1.6-3.8 mg/day, had a significantly reduced prevalence of recent severe or migraine headaches, compared with the lowest-intake quartile, with an odds ratio that roughly matched the dietary riboflavin analysis.

Dr. Slavin has received research funding from the Egg Nutrition Center, the Maryland Soybean Board, the McCormick Science Institute, and PepsiCo.

[email protected]

SOURCE: Slavin M. Headache. 2019 June;59[S1]:1-208, Abstract LBOR04.

PHILADELPHIA – People with moderately high levels of riboflavin consumption from food – two to three times the recommended dietary allowance – had a significantly lower prevalence of a recent severe or migraine headache in a study of more than 3,600 younger U.S. adults.

Adults 20-50 years old who consumed 2.07-2.87 mg riboflavin (vitamin B₂) in food a day based on a 24-hour recall questionnaire had an adjusted, statistically significant 27% reduced prevalence of a recent severe or migraine headache, compared with people in the lowest quartile of dietary riboflavin intake, 1.45 mg/day or less, Margaret Slavin, Ph.D., said at the annual meeting of the American Headache Society. Foods particularly high in riboflavin include eggs, milk, and meat.

Dietary riboflavin intakes greater than 2.87 mg/day were not linked to a difference in the prevalence of a recent history of severe or migraine headache, compared with lowest-quartile consumption. Additionally, riboflavin intake from supplements alone at any level of consumption also showed no statistically significant link with the prevalence of a recent, severe headache, said Dr. Slavin, a nutrition and food studies researcher at George Mason University in Fairfax, Va.

The “vast majority” of people in the study had a riboflavin intake that at least matched the U.S. recommended dietary allowance (RDA),1.3 mg/ day for men and 1.1 mg/day for women), “but it’s possible that people with migraine headaches need more riboflavin,” Dr. Slavin suggested. Professional societies in the United States (Neurology. 2012 Apr;78[17]: 1346-53) and Canada (Can J Neurol Sci. 2012 Mar;39[Suppl 2]S8-S28) have gone on record with some level of recommendation for a daily riboflavin supplement of 400 mg to prevent migraine headaches, she said.

A U.S. guideline that included riboflavin has been “retired” because of an issue unrelated to riboflavin, according to the Neurology website.

The new study ran data collected in the biennial National Health and Nutrition Examination Survey (NHANES), specifically the surveys from 2001-2002 and 2003-2004. The combined data included 5,528 adults 20-50 years old, and 3,634 with complete data and without an excluding condition such as pregnancy, diabetes, or menopause. Among the study participants 884 reported having “severe headaches or migraines,” during the 3 months preceding the survey and the remaining 2,750 people served as controls. People who reported recent severe headache or migraine overall had a significantly lower average amount of vitamin B2 in their diet than did the controls, but the two subgroups showed no significant differences in their levels of riboflavin intake from supplements, or from both diet and supplements combined.

The researchers calculated odds ratios for people having severe headaches or migraines relative to their riboflavin-intake quartile, and they adjusted the findings for age, sex, body mass index, and alcohol intake.

Further analysis that looked at total riboflavin intake, from both food and supplements, showed that the two middle quartiles for this metric, with a combined riboflavin intake of 1.6-3.8 mg/day, had a significantly reduced prevalence of recent severe or migraine headaches, compared with the lowest-intake quartile, with an odds ratio that roughly matched the dietary riboflavin analysis.

Dr. Slavin has received research funding from the Egg Nutrition Center, the Maryland Soybean Board, the McCormick Science Institute, and PepsiCo.

[email protected]

SOURCE: Slavin M. Headache. 2019 June;59[S1]:1-208, Abstract LBOR04.

PHILADELPHIA – People with moderately high levels of riboflavin consumption from food – two to three times the recommended dietary allowance – had a significantly lower prevalence of a recent severe or migraine headache in a study of more than 3,600 younger U.S. adults.

Adults 20-50 years old who consumed 2.07-2.87 mg riboflavin (vitamin B₂) in food a day based on a 24-hour recall questionnaire had an adjusted, statistically significant 27% reduced prevalence of a recent severe or migraine headache, compared with people in the lowest quartile of dietary riboflavin intake, 1.45 mg/day or less, Margaret Slavin, Ph.D., said at the annual meeting of the American Headache Society. Foods particularly high in riboflavin include eggs, milk, and meat.

Dietary riboflavin intakes greater than 2.87 mg/day were not linked to a difference in the prevalence of a recent history of severe or migraine headache, compared with lowest-quartile consumption. Additionally, riboflavin intake from supplements alone at any level of consumption also showed no statistically significant link with the prevalence of a recent, severe headache, said Dr. Slavin, a nutrition and food studies researcher at George Mason University in Fairfax, Va.

The “vast majority” of people in the study had a riboflavin intake that at least matched the U.S. recommended dietary allowance (RDA),1.3 mg/ day for men and 1.1 mg/day for women), “but it’s possible that people with migraine headaches need more riboflavin,” Dr. Slavin suggested. Professional societies in the United States (Neurology. 2012 Apr;78[17]: 1346-53) and Canada (Can J Neurol Sci. 2012 Mar;39[Suppl 2]S8-S28) have gone on record with some level of recommendation for a daily riboflavin supplement of 400 mg to prevent migraine headaches, she said.

A U.S. guideline that included riboflavin has been “retired” because of an issue unrelated to riboflavin, according to the Neurology website.

The new study ran data collected in the biennial National Health and Nutrition Examination Survey (NHANES), specifically the surveys from 2001-2002 and 2003-2004. The combined data included 5,528 adults 20-50 years old, and 3,634 with complete data and without an excluding condition such as pregnancy, diabetes, or menopause. Among the study participants 884 reported having “severe headaches or migraines,” during the 3 months preceding the survey and the remaining 2,750 people served as controls. People who reported recent severe headache or migraine overall had a significantly lower average amount of vitamin B2 in their diet than did the controls, but the two subgroups showed no significant differences in their levels of riboflavin intake from supplements, or from both diet and supplements combined.

The researchers calculated odds ratios for people having severe headaches or migraines relative to their riboflavin-intake quartile, and they adjusted the findings for age, sex, body mass index, and alcohol intake.

Further analysis that looked at total riboflavin intake, from both food and supplements, showed that the two middle quartiles for this metric, with a combined riboflavin intake of 1.6-3.8 mg/day, had a significantly reduced prevalence of recent severe or migraine headaches, compared with the lowest-intake quartile, with an odds ratio that roughly matched the dietary riboflavin analysis.

Dr. Slavin has received research funding from the Egg Nutrition Center, the Maryland Soybean Board, the McCormick Science Institute, and PepsiCo.

[email protected]

SOURCE: Slavin M. Headache. 2019 June;59[S1]:1-208, Abstract LBOR04.

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.