“PREVENTING INFECTION AFTER CESAREAN DELIVERY: 5 MORE EVIDENCE-BASED MEASURES TO CONSIDER”

KATHRYN E. PATRICK, MD; SARA L. DEATSMAN, MD; AND PATRICK DUFF, MD (DECEMEBER 2016)

Should we change instruments and gloves after closing the uterus?

In reference to the recent article series on preventing infection after cesarean delivery by Drs. Patrick, Deatsman, and Duff, what are the thoughts on using clean instruments and changing gloves after closing the uterus?

Gerrit J. Schipper, MD
Frederick, Maryland

❯❯ Drs. Patrick, Deatsman, and Duff respond:

We appreciate Dr. Schipper’s thoughtful question concerning our recent articles. At present, we are not aware of any rigorous studies that have evaluated the possible protective effect of changing to a different set of surgical instruments after closure of the uterus.

The second part of the question concerning the effect of changing gloves at a certain point in the operation is more intriguing. In an earlier report from our institution, we showed that the dominant hand of the operator becomes heavily contaminated with bacteria during the process of extracting the fetal head from the lower uterine segment.¹ The contamination is particularly heavy when the patient has had an extended duration of labor in the presence of ruptured membranes. In a subsequent investigation, we showed that avoidance of manual extraction of the placenta, a process in which the now-contaminated glove of the operator is placed between the placenta and the uterine wall, significantly reduced the frequency of postcesarean endometritis even in patients who already were receiving systemic antibiotic prophylaxis.² Whether changing gloves after delivery of the baby will further decrease the frequency of postcesarean endometritis, beyond that which can be achieved with systemic antibiotic prophylaxis combined with delivery of the placenta by traction on the cord, has not been studied in a systematic manner.

Given the low frequency of infection that can be achieved with these 2 methods, it would require a very large sample size to show that glove change offered an additional protective effect. Nevertheless, on a practical basis, we think it is very reasonable to change the glove on the dominant hand following a difficult extraction of the presenting part in a patient who has had an extended duration of labor and ruptured membranes. The glove change is particularly important if manual extraction of the placenta is contemplated.

Of note, we would like to acknowledge that the US Food and Drug Administration finalized a ban on the use of powdered surgical gloves effective January 18, 2017.³ The aerosolized glove powder on latex gloves contains proteins that can provoke severe respiratory allergic reactions in patients who are sensitive to latex. Even powdered synthetic gloves can cause airway inflammation, wound inflammation, and postoperative adhesions.

“DOES ONE PARTICULAR CESAREAN TECHNIQUE CONFER BETTER MATERNAL AND NEONATAL OUTCOMES?”

JOHN M. THORP JR, MD (EXAMINING THE EVIDENCE; NOVEMBER 2016)

Choosing a cesarean technique based on “evidence”

I appreciate the commentary by Dr. Thorp concerning cesarean delivery techniques. I have always thought that there was no difference in the outcomes of the various techniques. However, we will continue to waver to the peer pressure of this evidence-based stuff—until we find out later, like now—until things change again. “The more things change, the more they remain the same.”

Dr. Smart Ebinne
Port Harcourt, Nigeria

Share your thoughts!  Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“PREVENTING INFECTION AFTER CESAREAN DELIVERY: 5 MORE EVIDENCE-BASED MEASURES TO CONSIDER”

KATHRYN E. PATRICK, MD; SARA L. DEATSMAN, MD; AND PATRICK DUFF, MD (DECEMEBER 2016)

Should we change instruments and gloves after closing the uterus?

In reference to the recent article series on preventing infection after cesarean delivery by Drs. Patrick, Deatsman, and Duff, what are the thoughts on using clean instruments and changing gloves after closing the uterus?

Gerrit J. Schipper, MD
Frederick, Maryland

❯❯ Drs. Patrick, Deatsman, and Duff respond:

We appreciate Dr. Schipper’s thoughtful question concerning our recent articles. At present, we are not aware of any rigorous studies that have evaluated the possible protective effect of changing to a different set of surgical instruments after closure of the uterus.

The second part of the question concerning the effect of changing gloves at a certain point in the operation is more intriguing. In an earlier report from our institution, we showed that the dominant hand of the operator becomes heavily contaminated with bacteria during the process of extracting the fetal head from the lower uterine segment.¹ The contamination is particularly heavy when the patient has had an extended duration of labor in the presence of ruptured membranes. In a subsequent investigation, we showed that avoidance of manual extraction of the placenta, a process in which the now-contaminated glove of the operator is placed between the placenta and the uterine wall, significantly reduced the frequency of postcesarean endometritis even in patients who already were receiving systemic antibiotic prophylaxis.² Whether changing gloves after delivery of the baby will further decrease the frequency of postcesarean endometritis, beyond that which can be achieved with systemic antibiotic prophylaxis combined with delivery of the placenta by traction on the cord, has not been studied in a systematic manner.

Given the low frequency of infection that can be achieved with these 2 methods, it would require a very large sample size to show that glove change offered an additional protective effect. Nevertheless, on a practical basis, we think it is very reasonable to change the glove on the dominant hand following a difficult extraction of the presenting part in a patient who has had an extended duration of labor and ruptured membranes. The glove change is particularly important if manual extraction of the placenta is contemplated.

Of note, we would like to acknowledge that the US Food and Drug Administration finalized a ban on the use of powdered surgical gloves effective January 18, 2017.³ The aerosolized glove powder on latex gloves contains proteins that can provoke severe respiratory allergic reactions in patients who are sensitive to latex. Even powdered synthetic gloves can cause airway inflammation, wound inflammation, and postoperative adhesions.

“DOES ONE PARTICULAR CESAREAN TECHNIQUE CONFER BETTER MATERNAL AND NEONATAL OUTCOMES?”

JOHN M. THORP JR, MD (EXAMINING THE EVIDENCE; NOVEMBER 2016)

Choosing a cesarean technique based on “evidence”

I appreciate the commentary by Dr. Thorp concerning cesarean delivery techniques. I have always thought that there was no difference in the outcomes of the various techniques. However, we will continue to waver to the peer pressure of this evidence-based stuff—until we find out later, like now—until things change again. “The more things change, the more they remain the same.”

Dr. Smart Ebinne
Port Harcourt, Nigeria

Share your thoughts!  Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“PREVENTING INFECTION AFTER CESAREAN DELIVERY: 5 MORE EVIDENCE-BASED MEASURES TO CONSIDER”

KATHRYN E. PATRICK, MD; SARA L. DEATSMAN, MD; AND PATRICK DUFF, MD (DECEMEBER 2016)

Should we change instruments and gloves after closing the uterus?

In reference to the recent article series on preventing infection after cesarean delivery by Drs. Patrick, Deatsman, and Duff, what are the thoughts on using clean instruments and changing gloves after closing the uterus?

Gerrit J. Schipper, MD
Frederick, Maryland

❯❯ Drs. Patrick, Deatsman, and Duff respond:

We appreciate Dr. Schipper’s thoughtful question concerning our recent articles. At present, we are not aware of any rigorous studies that have evaluated the possible protective effect of changing to a different set of surgical instruments after closure of the uterus.

The second part of the question concerning the effect of changing gloves at a certain point in the operation is more intriguing. In an earlier report from our institution, we showed that the dominant hand of the operator becomes heavily contaminated with bacteria during the process of extracting the fetal head from the lower uterine segment.¹ The contamination is particularly heavy when the patient has had an extended duration of labor in the presence of ruptured membranes. In a subsequent investigation, we showed that avoidance of manual extraction of the placenta, a process in which the now-contaminated glove of the operator is placed between the placenta and the uterine wall, significantly reduced the frequency of postcesarean endometritis even in patients who already were receiving systemic antibiotic prophylaxis.² Whether changing gloves after delivery of the baby will further decrease the frequency of postcesarean endometritis, beyond that which can be achieved with systemic antibiotic prophylaxis combined with delivery of the placenta by traction on the cord, has not been studied in a systematic manner.

Given the low frequency of infection that can be achieved with these 2 methods, it would require a very large sample size to show that glove change offered an additional protective effect. Nevertheless, on a practical basis, we think it is very reasonable to change the glove on the dominant hand following a difficult extraction of the presenting part in a patient who has had an extended duration of labor and ruptured membranes. The glove change is particularly important if manual extraction of the placenta is contemplated.

Of note, we would like to acknowledge that the US Food and Drug Administration finalized a ban on the use of powdered surgical gloves effective January 18, 2017.³ The aerosolized glove powder on latex gloves contains proteins that can provoke severe respiratory allergic reactions in patients who are sensitive to latex. Even powdered synthetic gloves can cause airway inflammation, wound inflammation, and postoperative adhesions.

“DOES ONE PARTICULAR CESAREAN TECHNIQUE CONFER BETTER MATERNAL AND NEONATAL OUTCOMES?”

JOHN M. THORP JR, MD (EXAMINING THE EVIDENCE; NOVEMBER 2016)

Choosing a cesarean technique based on “evidence”

I appreciate the commentary by Dr. Thorp concerning cesarean delivery techniques. I have always thought that there was no difference in the outcomes of the various techniques. However, we will continue to waver to the peer pressure of this evidence-based stuff—until we find out later, like now—until things change again. “The more things change, the more they remain the same.”

Dr. Smart Ebinne
Port Harcourt, Nigeria

Share your thoughts!  Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Disrupted placenta: Infant anemia

An Obgyn recommended an elective transverse low incision cesarean delivery at a prenatal visit. Due to severe weather, the ObGyn was unable to come to the hospital; an on-call ObGyn consulted with the ObGyn by phone. Cesarean delivery resulted in disruption of the placenta. When the infant’s blood gasses test results were abnormal, he was transferred to the neonatal intensive care unit, where anemia was diagnosed. The infant was hospitalized for 31 days.

PARENTS’ CLAIM:

The on-call ObGyn caused the child’s injury by performing a transverse low incision. A testifying radiology expert said that ultrasonography (US) taken 5 weeks before delivery showed an anterior low-lying placenta but a clear field existed that would have allowed a vertical incision without placental disruption.

PHYSICIAN’S DEFENSE:

The delivery was within the standard of care. The ObGyn did not have access to the US cited by the testifying radiologist; standard of care did not require that she have access to them. A transverse incision minimizes blood loss; a vertical incision would have disrupted a larger area of placenta. The infant had normal blood gasses at delivery; any injury was not related to placental disruption.

VERDICT:

A Virginia defense verdict was returned.

Child has spastic CP after long labor

A 17-year-old woman's baby was delivered using vacuum extraction after a prolonged labor. Two days after birth, US results revealed diffuse brain edema in the baby. Magnetic resonance imaging demonstrated an absence of brain parenchyma in the left and right hemispheres. The baby received a diagnosis of spastic cerebral palsy (CP). She has little voluntary movement and requires a feeding tube, a portable aspiration device, and in-home attendant care.

PARENT’S CLAIM:

The baby underwent a hypoxic ischemic event during labor. Four hospital physicians failed to deliver the child early when repetitive decelerations and strong contractions with an insufficient resting period were detected in the second stage of labor. This denied oxygen to the infant, resulting in profound brain damage. The infant’s injury occurred shortly before delivery.

DEFENDANTS’ DEFENSE:

The fetus did not have a fetal heart rate pattern that would have required an earlier delivery. The injury sustained by the baby was not compatible with a prolonged hypoxic event and was more likely caused by a genetic defect. The infant suffered a subacute brain injury at least 1 week before delivery.

VERDICT:

The hospital settled for $1.25 million. A California defense verdict was returned for the physicians.

Misdiagnosed ectopic pregnancy

After a home pregnancy test was positive, a 27-year-old woman reported vaginal spotting and cramping to her ObGyn. When no uterine contents showed on US, the ObGyn suspected an ectopic pregnancy and recommended termination of pregnancy. The woman requested another US; an appointment was scheduled for the next day. Instead of waiting, the woman went to an emergency department (ED) that night. Bloodwork confirmed the pregnancy but US results showed no evidence of an intrauterine pregnancy. The ED physician diagnosed an ectopic pregnancy. The on-call ObGyn concurred and recommended termination of pregnancy by surgical intervention or methotrexate. The patient chose methotrexate, which was administered, and she was discharged.

In the on-call ObGyn’s office a week later, the patient’s beta-hGC levels had not decreased. US revealed 2 intrauterine pregnancies, one with a heartbeat. The on-call ObGyn immediately referred the patient to a maternal-fetal medicine specialist. New US results showed evidence of an abnormal intrauterine pregnancy and a second gestational sac with no embryo. Two days later US showed a twin pregnancy: a 6-week fetal pole with no heartbeat and the other with no fetal pole or yolk sac. A dilation and curettage was performed.

PARENTS’ CLAIM:

The on-call ObGyn misdiagnosed an ectopic pregnancy, failed to order additional testing, and failed to observe the patient for 48 to 72 hours before administering methotrexate. This led to the loss of twins.

DEFENDANTS’ DEFENSE:

An ectopic pregnancy is an emergency that requires prompt diagnosis and treatment. There were sufficient signs for the on-call ObGyn to diagnose an ectopic pregnancy. She would have violated the standard of care if she had not administered treatment.

VERDICT:

The hospital settled for $127,000 before trial. An Illinois defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Disrupted placenta: Infant anemia

An Obgyn recommended an elective transverse low incision cesarean delivery at a prenatal visit. Due to severe weather, the ObGyn was unable to come to the hospital; an on-call ObGyn consulted with the ObGyn by phone. Cesarean delivery resulted in disruption of the placenta. When the infant’s blood gasses test results were abnormal, he was transferred to the neonatal intensive care unit, where anemia was diagnosed. The infant was hospitalized for 31 days.

PARENTS’ CLAIM:

The on-call ObGyn caused the child’s injury by performing a transverse low incision. A testifying radiology expert said that ultrasonography (US) taken 5 weeks before delivery showed an anterior low-lying placenta but a clear field existed that would have allowed a vertical incision without placental disruption.

PHYSICIAN’S DEFENSE:

The delivery was within the standard of care. The ObGyn did not have access to the US cited by the testifying radiologist; standard of care did not require that she have access to them. A transverse incision minimizes blood loss; a vertical incision would have disrupted a larger area of placenta. The infant had normal blood gasses at delivery; any injury was not related to placental disruption.

VERDICT:

A Virginia defense verdict was returned.

Child has spastic CP after long labor

A 17-year-old woman's baby was delivered using vacuum extraction after a prolonged labor. Two days after birth, US results revealed diffuse brain edema in the baby. Magnetic resonance imaging demonstrated an absence of brain parenchyma in the left and right hemispheres. The baby received a diagnosis of spastic cerebral palsy (CP). She has little voluntary movement and requires a feeding tube, a portable aspiration device, and in-home attendant care.

PARENT’S CLAIM:

The baby underwent a hypoxic ischemic event during labor. Four hospital physicians failed to deliver the child early when repetitive decelerations and strong contractions with an insufficient resting period were detected in the second stage of labor. This denied oxygen to the infant, resulting in profound brain damage. The infant’s injury occurred shortly before delivery.

DEFENDANTS’ DEFENSE:

The fetus did not have a fetal heart rate pattern that would have required an earlier delivery. The injury sustained by the baby was not compatible with a prolonged hypoxic event and was more likely caused by a genetic defect. The infant suffered a subacute brain injury at least 1 week before delivery.

VERDICT:

The hospital settled for $1.25 million. A California defense verdict was returned for the physicians.

Misdiagnosed ectopic pregnancy

After a home pregnancy test was positive, a 27-year-old woman reported vaginal spotting and cramping to her ObGyn. When no uterine contents showed on US, the ObGyn suspected an ectopic pregnancy and recommended termination of pregnancy. The woman requested another US; an appointment was scheduled for the next day. Instead of waiting, the woman went to an emergency department (ED) that night. Bloodwork confirmed the pregnancy but US results showed no evidence of an intrauterine pregnancy. The ED physician diagnosed an ectopic pregnancy. The on-call ObGyn concurred and recommended termination of pregnancy by surgical intervention or methotrexate. The patient chose methotrexate, which was administered, and she was discharged.

In the on-call ObGyn’s office a week later, the patient’s beta-hGC levels had not decreased. US revealed 2 intrauterine pregnancies, one with a heartbeat. The on-call ObGyn immediately referred the patient to a maternal-fetal medicine specialist. New US results showed evidence of an abnormal intrauterine pregnancy and a second gestational sac with no embryo. Two days later US showed a twin pregnancy: a 6-week fetal pole with no heartbeat and the other with no fetal pole or yolk sac. A dilation and curettage was performed.

PARENTS’ CLAIM:

The on-call ObGyn misdiagnosed an ectopic pregnancy, failed to order additional testing, and failed to observe the patient for 48 to 72 hours before administering methotrexate. This led to the loss of twins.

DEFENDANTS’ DEFENSE:

An ectopic pregnancy is an emergency that requires prompt diagnosis and treatment. There were sufficient signs for the on-call ObGyn to diagnose an ectopic pregnancy. She would have violated the standard of care if she had not administered treatment.

VERDICT:

The hospital settled for $127,000 before trial. An Illinois defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Disrupted placenta: Infant anemia

An Obgyn recommended an elective transverse low incision cesarean delivery at a prenatal visit. Due to severe weather, the ObGyn was unable to come to the hospital; an on-call ObGyn consulted with the ObGyn by phone. Cesarean delivery resulted in disruption of the placenta. When the infant’s blood gasses test results were abnormal, he was transferred to the neonatal intensive care unit, where anemia was diagnosed. The infant was hospitalized for 31 days.

PARENTS’ CLAIM:

The on-call ObGyn caused the child’s injury by performing a transverse low incision. A testifying radiology expert said that ultrasonography (US) taken 5 weeks before delivery showed an anterior low-lying placenta but a clear field existed that would have allowed a vertical incision without placental disruption.

PHYSICIAN’S DEFENSE:

The delivery was within the standard of care. The ObGyn did not have access to the US cited by the testifying radiologist; standard of care did not require that she have access to them. A transverse incision minimizes blood loss; a vertical incision would have disrupted a larger area of placenta. The infant had normal blood gasses at delivery; any injury was not related to placental disruption.

VERDICT:

A Virginia defense verdict was returned.

Child has spastic CP after long labor

A 17-year-old woman's baby was delivered using vacuum extraction after a prolonged labor. Two days after birth, US results revealed diffuse brain edema in the baby. Magnetic resonance imaging demonstrated an absence of brain parenchyma in the left and right hemispheres. The baby received a diagnosis of spastic cerebral palsy (CP). She has little voluntary movement and requires a feeding tube, a portable aspiration device, and in-home attendant care.

PARENT’S CLAIM:

The baby underwent a hypoxic ischemic event during labor. Four hospital physicians failed to deliver the child early when repetitive decelerations and strong contractions with an insufficient resting period were detected in the second stage of labor. This denied oxygen to the infant, resulting in profound brain damage. The infant’s injury occurred shortly before delivery.

DEFENDANTS’ DEFENSE:

The fetus did not have a fetal heart rate pattern that would have required an earlier delivery. The injury sustained by the baby was not compatible with a prolonged hypoxic event and was more likely caused by a genetic defect. The infant suffered a subacute brain injury at least 1 week before delivery.

VERDICT:

The hospital settled for $1.25 million. A California defense verdict was returned for the physicians.

Misdiagnosed ectopic pregnancy

After a home pregnancy test was positive, a 27-year-old woman reported vaginal spotting and cramping to her ObGyn. When no uterine contents showed on US, the ObGyn suspected an ectopic pregnancy and recommended termination of pregnancy. The woman requested another US; an appointment was scheduled for the next day. Instead of waiting, the woman went to an emergency department (ED) that night. Bloodwork confirmed the pregnancy but US results showed no evidence of an intrauterine pregnancy. The ED physician diagnosed an ectopic pregnancy. The on-call ObGyn concurred and recommended termination of pregnancy by surgical intervention or methotrexate. The patient chose methotrexate, which was administered, and she was discharged.

In the on-call ObGyn’s office a week later, the patient’s beta-hGC levels had not decreased. US revealed 2 intrauterine pregnancies, one with a heartbeat. The on-call ObGyn immediately referred the patient to a maternal-fetal medicine specialist. New US results showed evidence of an abnormal intrauterine pregnancy and a second gestational sac with no embryo. Two days later US showed a twin pregnancy: a 6-week fetal pole with no heartbeat and the other with no fetal pole or yolk sac. A dilation and curettage was performed.

PARENTS’ CLAIM:

The on-call ObGyn misdiagnosed an ectopic pregnancy, failed to order additional testing, and failed to observe the patient for 48 to 72 hours before administering methotrexate. This led to the loss of twins.

DEFENDANTS’ DEFENSE:

An ectopic pregnancy is an emergency that requires prompt diagnosis and treatment. There were sufficient signs for the on-call ObGyn to diagnose an ectopic pregnancy. She would have violated the standard of care if she had not administered treatment.

VERDICT:

The hospital settled for $127,000 before trial. An Illinois defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Dementia is a common, multifaceted problem with significant implications for function and quality of life among older individuals. Current demographic shifts are magnifying this problem. Particularly troubling are neuropsychiatric symptoms, which, in addition to creating caregiver distress, also are linked to functional decline, institutionalization, higher health care costs, and mortality (even after controlling for other potential confounders and severity of cognitive impairment). Furthermore, dementia is often unrecognized and underdiagnosed, and patients with dementia historically have poor access to care, particularly those living in rural areas.

The Geriatrics/Dementia Clinic at the Baltimore Veterans Affairs Medical Center (BVAMC) is a referral resource that provides extensive, multidisciplinary evaluations as well as coordinated subspecialist and interprofessional case review. A diverse group of clinicians (representing geriatrics, geriatric psychiatry, neuropsychology, clinical pharmacy, nursing, and social work) perform a half-day evaluation, followed by a meeting of the interdisciplinary team, and feedback session where patients and their families are given the results of the testing and diagnostic impressions as well as plans for further evaluation and treatment. Finally, in addition to the benefits it provides to veterans and their families, this clinic has proven to be an important resource for professional trainees.

Yet this model can be difficult to access, and those living in more remote regions had challenges availing themselves of this resource. Often, they would have to wake before dawn to drive 2 to 4 hours to the medical center. Furthermore, despite the many obvious benefits of this comprehensive approach, veterans and their families often left the clinic with a staggering amount of information and numerous recommendations for future care but without the assurance of integrated follow-up (a burden borne particularly by those living remotely).

The DEMO Program

In response to the dual challenges of access to and coordination of care, existing resources were leveraged with about $250,000 of VA T21 funds (adding both a full-time geriatric nurse practitioner and a psychology technician to the multidisciplinary team) to design and implement the novel DEMO (Dementia Evaluation, Management and Outreach) program. This program aimed to (1) extend dementia evaluations to regional community-based outpatient clinics (CBOCs) that serve veterans in outlying regions; and (2) improve the management and the follow-up that these veterans receive, with a focus on containing costs, while improving both the quality of and veterans’ (and their families’) satisfaction with health care.

Methods

Dementia evaluations were conducted by a geriatric nurse practitioner and psychology technician teamlet at the CBOCs. In addition to neuropsychological testing, medical records were reviewed, caregivers were interviewed, and the patients were examined. The data were then brought back to the full BVAMC Geriatrics/Dementia Clinic multidisciplinary team for discussion. The team reached a consensus diagnosis and then made a comprehensive plan for the further evaluation and management of these complex patients. The plan was entered into the Computerized Patient Record System and communicated to the patient and caregiver during a follow-up CBOC visit.

The teamlet frequently provided informal education during CBOC visits in addition to formal lectures given by experts from the BVAMC and the University of Maryland. The DEMO program was introduced to providers at the CBOCs by e-mail with follow-up information sessions provided on site.

Rather than having patients simply return to their CBOC primary care providers (PCPs) and exposing patients to the risks of poor communication/coordination of care, services were expanded to include regular phone follow-up calls with case management services that augmented those of their PCPs. The goal was to improve outcomes for these patients and provide alternatives to institutionalization.

Standardized instruments were used to gauge patient and caregiver satisfaction, obtain cost data from the VA and the Centers for Medicare & Medicaid Services, and medication data from the Pharmacy Benefits files.

The institutional review board provided approval to collect data on participants to assess the program’s clinical and economic impacts. Since all patients were suspected to have dementia, the informed consent procedures included additional protections. The patient’s understanding of the pertinent information related to participation in the study was assessed to help ensure that participants with dementia truly understood the conditions to which they were consenting. If the potential participant could not provide informed consent, it was obtained from a surrogate with durable power of attorney (the person recognized by Maryland law as the substitute decision maker or the veteran’s legal guardian). Consent was assessed on an ongoing basis regardless of the patient’s capacity to give informed consent, and those willing to have their data collected were enrolled in a “research” arm. These participants were compared with veterans in the dementia clinic during the enrollment period but who did not consent to participate in the research arm, controlling for sociodemographic characteristics and prior health care utilization.

Data Analysis

Patterns of health care utilization may fluctuate with time, and enrollment may identify potential problems that otherwise would not have been found. The authors looked at health care use over 6-month and 1-year intervals before and after enrollment, examining Occupational Physical Assessment Test (OPAT) data and fee-based outpatient data for both inpatient events (including nursing home utilization and hospitalization events) and outpatient visits (including primary, specialty and mental health care services; home care visits, and emergency department [ED]). The total cost incurred by outpatient visits and inpatient care was then adjusted to 2011 dollars. The relationship between program enrollment and health care use and costs was examined with a multivariate regression analyses, controlling for age and health care use in the prior year among veterans who were in the “consent” group or “nonconsent” group.

Outcome variables included the number of primary care, ED, specialty care, home health care, mental health care clinic, and inpatient visits; total inpatient bed days; and the total costs of all the events. The authors fit different multivariate models for these events according to their distributions. Specifically, the Poisson model was used if the distribution of the outcome variable was not overdispersed (eg, ED, primary care).

A negative binomial was used if the distribution of these events was overdispersed (eg, specialty care visits). Further, because the occurrence of inpatient events is relatively rare, a logit model was used to examine the relationship between enrollment status and probability of any inpatient events, regardless of the number of events. Generalized estimating equation (GEE) model with gamma distribution and log link function was used to examine the relationship between cost and program enrollment. The authors also examined the program’s effect on medication use, focusing on high-risk medications in older adults, comparing both the number of unique medications, as well as frequency such medications prescribed 1 year before and after the enrollment.¹

Results

Two hundred ninety-eight (298) veterans were referred to DEMO from a 150-mile radius of Baltimore. Of these veterans, 132 consented to participate in this study. The study participants largely were representative of the total group as well as both the overall veteran population and the more general population of community-dwelling individuals with dementia (Table).

Veterans in the DEMO program largely had mild-to-moderate cognitive impairment with mean Mini-Mental State Examination (MMSE) score of 22 and significant functional limitations (Table). Only 3% displayed a pattern of “pure” dementia typical of Alzheimer disease, and 11% of those referred did not have significant abnormalities on neurocognitive testing.

The team averaged 10.3 recommendations (range 3-22), which focused on a diverse set of issues related to additional diagnostic and therapeutic concerns. Although screening data, including basic laboratory results and imaging, was requested in the referral form, in 71% of cases further diagnostic investigations were suggested. With regard to therapeutic suggestions, not surprisingly, medicines were cited as targets in a majority of cases (eg, discontinuing high-risk medications, initiating/titrating medications to minimize cardiovascular risk). While remaining mindful of the time to benefit and competing morbidities, measures to modify cardiovascular risk factors were suggested in more than half and treatment of depression in 15% of cases. Similarly, addressing poor sensory input was suggested in 38% of cases, with other common recommendations focusing on multiple environmental and social interventions (> 50%) as well as supports/outlets/respite for the caregivers.

The full multidisciplinary DEMO group met only weekly to review cases, and due to travel and scheduling difficulties, feedback to the patients and their families often was delayed for weeks. Although initial plans included regularly scheduled follow-up phone calls, demand quickly outstripped program resources. Nonetheless, chart reviews and abstracted adherence and utilization data revealed that PCPs successfully implemented 52% of recommendations within 2 weeks, rising to > 60% by 3 months. When patients were reevaluated at 1 year, they were remarkably stable: Mini–Mental State Examination (baseline 22.2 ± 5.0 → 22.3 ± 5.7 at follow-up) and Instrumental Activities of Daily Living scores (15.5 ± 10.6 → 17.7 ± 11.4).

Feedback

This program was enthusiastically received by both patients and their caregivers—100% and 98%, respectively—reporting overall satisfaction with the services received and 93% of caregivers indicating satisfaction with how the program met their needs. Caregivers were happy with the amount of time the provider took to answer questions (100% satisfied with the amount of time the DEMO provider spent and that they explained “what they wanted to know,” with 98% responding “good” or “great” for both), as well as with services and amount of help received (83% and 77% “very satisfied,” respectively).

In the survey, 98% of caregivers and patients felt that the program helped them deal more effectively with their problems, 97% would recommend the program to a friend in need of similar help, and 100% would come back if they were to seek help again. In keeping with DEMO’s initial aim of increasing access, there was favorable feedback on the ability to get in and be seen and convenience of location. In addition, referring providers universally expressed satisfaction with the referral process (referrals increased linearly); timeliness of scheduling; usefulness of the recommendations; and they planned on continuing to refer patients.

Although there was great variability, controlling for age and prior utilization, veterans in DEMO had statistically significant (all P < .05) fewer ED and specialty care visits and more mental health care clinic visits 183 to 365 daysafter referral dates compared with those in the nonconsented group. Veterans in the consented group also were less likely to use inpatient care than were veterans in the nonconsented group 183 to 365 days after referral dates. These trends were similarly reflected after controlling for age and prior utilization as well as when examining health care costs (data not shown). Nonetheless, DEMO did not seem to have any effect on overall inpatient bed days, primary/home-based care visits, or total costs. In fact, utilization of mental health care resources increased (Figures 1, 2, and 3).

Discussion

Cognitive issues in patients within the general population are common, and the patients cared for by the VA are no exception. Dementia is more common in rural compared with urban areas, and those living in more remote locations have reduced access to specialized evaluation, management, and support services.² The authors describe a novel program that dramatically increased patient access, bringing the normally tertiary referral services to geographically remote CBOCs at a minimal investment. These services were well received by patients, caregivers, and PCPs. As anticipated, patients and their caregivers especially appreciated the ease and convenience of access. Considering the already significant burden(s) borne every day by those caring for patients with dementia, the benefit of this approach is evident.

Clinicians often feel uncomfortable in evaluating and managing patients with cognitive deficits. Nonetheless, the role of specialized clinics in diagnosing dementia has been demonstrated previously, and the present results are in agreement with previous studies.³ The novelty here is the provision of specialized care usually found only in large, academic medical centers to local CBOCs. By bringing specialized services to geographically isolated patients, the DEMO program was able to increase both access and utilization. Furthermore, providing coordination and ongoing, focused follow-up provided increases in satisfaction and efficiency.

An additional benefit of this approach is the opportunity for PCP education. The authors even found anecdotal reductions in ED usage as well as acute hospitalization and long-term placement—although it was not a statistical significant difference. The relatively high use of mental health care services in this population is in line with previous reports in similar populations, and greater utilization of mental health care services may be one explanation why overall costs did not differ between the 2 groups.⁴ Nonetheless, this intimates that such a program may yield savings over a longer term, as has been demonstrated in patients with a variety of other psychiatric diagnoses cared for in the community rather than in institutions.^5,6

The prevalence of dementia and its associated costs are nearly $50,000 per year per person—suggesting a total cost in the hundreds of billions of dollars.⁷ Similarly, the importance of caregiver support (including psychosocial interventions, such as the one piloted here) has been demonstrated in a variety of settings (even without improvement in caregiver burden itself).⁸

There were a number of challenges in the rollout and delivery of DEMO. Although CBOC PCPs were initially somewhat uncertain of the benefit of this approach and concerned about the space requirements, referrals rapidly and dramatically increased, and the DEMO teamlet became enmeshed with CBOC staff. Similarly, potential participants and their caregivers sometimes were leery to involve others in their care. Both the CBOC PCPs and caregivers came to depend more on DEMO staff, and the DEMO staff members frequently were the first ones to be called (at times for issues unrelated to dementia).

Unfortunately, DEMO was underresourced to provide either real-time feedback true or first responder services. Misunderstandings concerning this were an early challenge to PCP acceptance. However, the longitudinal presence and close working relationships of the DEMO teamlet in each CBOC allowed their use as an adjunct to primary care, and increased the efficacy of both.

Limitations

A number of additional caveats must be made. First, this study had a relatively small number of participants, and there was great variability in health care utilization. This is particularly germane in this population of patients with dementia, which typically has an asymmetrically high use of health care resources. Additionally, the relatively limited follow-up period may have blunted the programs true effect(s). Further, although veterans in the nonconsented group were not officially enrolled in the program, there was likely spillover of the effects of the program on practice patterns, leading to an underestimation of the program’s impact.

Conclusion

With minimal resources, DEMO successfully brought expert evaluation (usually tertiary referral) services, and provided specialized case management in coordination with existing primary care to remote patients. Although there were a number of features rather unique to this setting (eg, infrastructural support; close working interdisciplinary and interprofessional relationships, buy-in at all levels, relative geographic density/demographic homogeneity of participants), specialized case management is increasingly being adopted throughout the VA (and elsewhere). Although the value of collaborative, interdisciplinary interventions has been shown in a variety of settings and conditions—nursing homes,⁹ chronic low back pain,¹⁰ safety among hospital inpatients¹¹—its utility for dementia care is relatively underexplored.

Yet the effectiveness of team-based care for individuals has been demonstrated in a number of settings, including Alzheimer disease.^12,13 In addition to involving a number of disciplines, collaborative care is marked by coordination. A number of recent systematic reviews have found that behavioral and multicomponent interventions directed towards the caregiver as well as case management were beneficial in improving some outcomes, although there is considerable heterogeneity in the effects.^14,15 Future work will focus on examining methods to focus/optimize interventions based on individual patient characteristics.

Given the epidemiologic trends, care for patients with dementia is expected to grow. Novel interventions, like DEMO, are a particularly promising option to meet this challenge. In fact, just such a collaborative practice-ready workforce has been identified by the World Health Organization as crucial to meeting the challenges of the health needs in the 21st century.¹⁶ With the feasibility of such an approach in this population now evident, further studies (including larger sample sizes, across greater geographic regions, as well as among more diverse populations) should be undertaken. These results, if replicated, suggest a novel approach to the particularly vexing problem of caring for patients with dementia with potentially far-reaching public health implications.

Acknowledgments
Supported with T21 funds from VA to expand noninstitutional alternatives to institutional extended care for veterans, as well as the Geriatrics Research and Clinical Center (GRECC) at the Baltimore VAMC.

Dementia is a common, multifaceted problem with significant implications for function and quality of life among older individuals. Current demographic shifts are magnifying this problem. Particularly troubling are neuropsychiatric symptoms, which, in addition to creating caregiver distress, also are linked to functional decline, institutionalization, higher health care costs, and mortality (even after controlling for other potential confounders and severity of cognitive impairment). Furthermore, dementia is often unrecognized and underdiagnosed, and patients with dementia historically have poor access to care, particularly those living in rural areas.

The Geriatrics/Dementia Clinic at the Baltimore Veterans Affairs Medical Center (BVAMC) is a referral resource that provides extensive, multidisciplinary evaluations as well as coordinated subspecialist and interprofessional case review. A diverse group of clinicians (representing geriatrics, geriatric psychiatry, neuropsychology, clinical pharmacy, nursing, and social work) perform a half-day evaluation, followed by a meeting of the interdisciplinary team, and feedback session where patients and their families are given the results of the testing and diagnostic impressions as well as plans for further evaluation and treatment. Finally, in addition to the benefits it provides to veterans and their families, this clinic has proven to be an important resource for professional trainees.

Yet this model can be difficult to access, and those living in more remote regions had challenges availing themselves of this resource. Often, they would have to wake before dawn to drive 2 to 4 hours to the medical center. Furthermore, despite the many obvious benefits of this comprehensive approach, veterans and their families often left the clinic with a staggering amount of information and numerous recommendations for future care but without the assurance of integrated follow-up (a burden borne particularly by those living remotely).

The DEMO Program

In response to the dual challenges of access to and coordination of care, existing resources were leveraged with about $250,000 of VA T21 funds (adding both a full-time geriatric nurse practitioner and a psychology technician to the multidisciplinary team) to design and implement the novel DEMO (Dementia Evaluation, Management and Outreach) program. This program aimed to (1) extend dementia evaluations to regional community-based outpatient clinics (CBOCs) that serve veterans in outlying regions; and (2) improve the management and the follow-up that these veterans receive, with a focus on containing costs, while improving both the quality of and veterans’ (and their families’) satisfaction with health care.

Methods

Dementia evaluations were conducted by a geriatric nurse practitioner and psychology technician teamlet at the CBOCs. In addition to neuropsychological testing, medical records were reviewed, caregivers were interviewed, and the patients were examined. The data were then brought back to the full BVAMC Geriatrics/Dementia Clinic multidisciplinary team for discussion. The team reached a consensus diagnosis and then made a comprehensive plan for the further evaluation and management of these complex patients. The plan was entered into the Computerized Patient Record System and communicated to the patient and caregiver during a follow-up CBOC visit.

The teamlet frequently provided informal education during CBOC visits in addition to formal lectures given by experts from the BVAMC and the University of Maryland. The DEMO program was introduced to providers at the CBOCs by e-mail with follow-up information sessions provided on site.

Rather than having patients simply return to their CBOC primary care providers (PCPs) and exposing patients to the risks of poor communication/coordination of care, services were expanded to include regular phone follow-up calls with case management services that augmented those of their PCPs. The goal was to improve outcomes for these patients and provide alternatives to institutionalization.

Standardized instruments were used to gauge patient and caregiver satisfaction, obtain cost data from the VA and the Centers for Medicare & Medicaid Services, and medication data from the Pharmacy Benefits files.

The institutional review board provided approval to collect data on participants to assess the program’s clinical and economic impacts. Since all patients were suspected to have dementia, the informed consent procedures included additional protections. The patient’s understanding of the pertinent information related to participation in the study was assessed to help ensure that participants with dementia truly understood the conditions to which they were consenting. If the potential participant could not provide informed consent, it was obtained from a surrogate with durable power of attorney (the person recognized by Maryland law as the substitute decision maker or the veteran’s legal guardian). Consent was assessed on an ongoing basis regardless of the patient’s capacity to give informed consent, and those willing to have their data collected were enrolled in a “research” arm. These participants were compared with veterans in the dementia clinic during the enrollment period but who did not consent to participate in the research arm, controlling for sociodemographic characteristics and prior health care utilization.

Data Analysis

Patterns of health care utilization may fluctuate with time, and enrollment may identify potential problems that otherwise would not have been found. The authors looked at health care use over 6-month and 1-year intervals before and after enrollment, examining Occupational Physical Assessment Test (OPAT) data and fee-based outpatient data for both inpatient events (including nursing home utilization and hospitalization events) and outpatient visits (including primary, specialty and mental health care services; home care visits, and emergency department [ED]). The total cost incurred by outpatient visits and inpatient care was then adjusted to 2011 dollars. The relationship between program enrollment and health care use and costs was examined with a multivariate regression analyses, controlling for age and health care use in the prior year among veterans who were in the “consent” group or “nonconsent” group.

Outcome variables included the number of primary care, ED, specialty care, home health care, mental health care clinic, and inpatient visits; total inpatient bed days; and the total costs of all the events. The authors fit different multivariate models for these events according to their distributions. Specifically, the Poisson model was used if the distribution of the outcome variable was not overdispersed (eg, ED, primary care).

A negative binomial was used if the distribution of these events was overdispersed (eg, specialty care visits). Further, because the occurrence of inpatient events is relatively rare, a logit model was used to examine the relationship between enrollment status and probability of any inpatient events, regardless of the number of events. Generalized estimating equation (GEE) model with gamma distribution and log link function was used to examine the relationship between cost and program enrollment. The authors also examined the program’s effect on medication use, focusing on high-risk medications in older adults, comparing both the number of unique medications, as well as frequency such medications prescribed 1 year before and after the enrollment.¹

Results

Two hundred ninety-eight (298) veterans were referred to DEMO from a 150-mile radius of Baltimore. Of these veterans, 132 consented to participate in this study. The study participants largely were representative of the total group as well as both the overall veteran population and the more general population of community-dwelling individuals with dementia (Table).

Veterans in the DEMO program largely had mild-to-moderate cognitive impairment with mean Mini-Mental State Examination (MMSE) score of 22 and significant functional limitations (Table). Only 3% displayed a pattern of “pure” dementia typical of Alzheimer disease, and 11% of those referred did not have significant abnormalities on neurocognitive testing.

The team averaged 10.3 recommendations (range 3-22), which focused on a diverse set of issues related to additional diagnostic and therapeutic concerns. Although screening data, including basic laboratory results and imaging, was requested in the referral form, in 71% of cases further diagnostic investigations were suggested. With regard to therapeutic suggestions, not surprisingly, medicines were cited as targets in a majority of cases (eg, discontinuing high-risk medications, initiating/titrating medications to minimize cardiovascular risk). While remaining mindful of the time to benefit and competing morbidities, measures to modify cardiovascular risk factors were suggested in more than half and treatment of depression in 15% of cases. Similarly, addressing poor sensory input was suggested in 38% of cases, with other common recommendations focusing on multiple environmental and social interventions (> 50%) as well as supports/outlets/respite for the caregivers.

The full multidisciplinary DEMO group met only weekly to review cases, and due to travel and scheduling difficulties, feedback to the patients and their families often was delayed for weeks. Although initial plans included regularly scheduled follow-up phone calls, demand quickly outstripped program resources. Nonetheless, chart reviews and abstracted adherence and utilization data revealed that PCPs successfully implemented 52% of recommendations within 2 weeks, rising to > 60% by 3 months. When patients were reevaluated at 1 year, they were remarkably stable: Mini–Mental State Examination (baseline 22.2 ± 5.0 → 22.3 ± 5.7 at follow-up) and Instrumental Activities of Daily Living scores (15.5 ± 10.6 → 17.7 ± 11.4).

Feedback

This program was enthusiastically received by both patients and their caregivers—100% and 98%, respectively—reporting overall satisfaction with the services received and 93% of caregivers indicating satisfaction with how the program met their needs. Caregivers were happy with the amount of time the provider took to answer questions (100% satisfied with the amount of time the DEMO provider spent and that they explained “what they wanted to know,” with 98% responding “good” or “great” for both), as well as with services and amount of help received (83% and 77% “very satisfied,” respectively).

In the survey, 98% of caregivers and patients felt that the program helped them deal more effectively with their problems, 97% would recommend the program to a friend in need of similar help, and 100% would come back if they were to seek help again. In keeping with DEMO’s initial aim of increasing access, there was favorable feedback on the ability to get in and be seen and convenience of location. In addition, referring providers universally expressed satisfaction with the referral process (referrals increased linearly); timeliness of scheduling; usefulness of the recommendations; and they planned on continuing to refer patients.

Although there was great variability, controlling for age and prior utilization, veterans in DEMO had statistically significant (all P < .05) fewer ED and specialty care visits and more mental health care clinic visits 183 to 365 daysafter referral dates compared with those in the nonconsented group. Veterans in the consented group also were less likely to use inpatient care than were veterans in the nonconsented group 183 to 365 days after referral dates. These trends were similarly reflected after controlling for age and prior utilization as well as when examining health care costs (data not shown). Nonetheless, DEMO did not seem to have any effect on overall inpatient bed days, primary/home-based care visits, or total costs. In fact, utilization of mental health care resources increased (Figures 1, 2, and 3).

Discussion

Cognitive issues in patients within the general population are common, and the patients cared for by the VA are no exception. Dementia is more common in rural compared with urban areas, and those living in more remote locations have reduced access to specialized evaluation, management, and support services.² The authors describe a novel program that dramatically increased patient access, bringing the normally tertiary referral services to geographically remote CBOCs at a minimal investment. These services were well received by patients, caregivers, and PCPs. As anticipated, patients and their caregivers especially appreciated the ease and convenience of access. Considering the already significant burden(s) borne every day by those caring for patients with dementia, the benefit of this approach is evident.

Clinicians often feel uncomfortable in evaluating and managing patients with cognitive deficits. Nonetheless, the role of specialized clinics in diagnosing dementia has been demonstrated previously, and the present results are in agreement with previous studies.³ The novelty here is the provision of specialized care usually found only in large, academic medical centers to local CBOCs. By bringing specialized services to geographically isolated patients, the DEMO program was able to increase both access and utilization. Furthermore, providing coordination and ongoing, focused follow-up provided increases in satisfaction and efficiency.

An additional benefit of this approach is the opportunity for PCP education. The authors even found anecdotal reductions in ED usage as well as acute hospitalization and long-term placement—although it was not a statistical significant difference. The relatively high use of mental health care services in this population is in line with previous reports in similar populations, and greater utilization of mental health care services may be one explanation why overall costs did not differ between the 2 groups.⁴ Nonetheless, this intimates that such a program may yield savings over a longer term, as has been demonstrated in patients with a variety of other psychiatric diagnoses cared for in the community rather than in institutions.^5,6

The prevalence of dementia and its associated costs are nearly $50,000 per year per person—suggesting a total cost in the hundreds of billions of dollars.⁷ Similarly, the importance of caregiver support (including psychosocial interventions, such as the one piloted here) has been demonstrated in a variety of settings (even without improvement in caregiver burden itself).⁸

There were a number of challenges in the rollout and delivery of DEMO. Although CBOC PCPs were initially somewhat uncertain of the benefit of this approach and concerned about the space requirements, referrals rapidly and dramatically increased, and the DEMO teamlet became enmeshed with CBOC staff. Similarly, potential participants and their caregivers sometimes were leery to involve others in their care. Both the CBOC PCPs and caregivers came to depend more on DEMO staff, and the DEMO staff members frequently were the first ones to be called (at times for issues unrelated to dementia).

Unfortunately, DEMO was underresourced to provide either real-time feedback true or first responder services. Misunderstandings concerning this were an early challenge to PCP acceptance. However, the longitudinal presence and close working relationships of the DEMO teamlet in each CBOC allowed their use as an adjunct to primary care, and increased the efficacy of both.

Limitations

A number of additional caveats must be made. First, this study had a relatively small number of participants, and there was great variability in health care utilization. This is particularly germane in this population of patients with dementia, which typically has an asymmetrically high use of health care resources. Additionally, the relatively limited follow-up period may have blunted the programs true effect(s). Further, although veterans in the nonconsented group were not officially enrolled in the program, there was likely spillover of the effects of the program on practice patterns, leading to an underestimation of the program’s impact.

Conclusion

With minimal resources, DEMO successfully brought expert evaluation (usually tertiary referral) services, and provided specialized case management in coordination with existing primary care to remote patients. Although there were a number of features rather unique to this setting (eg, infrastructural support; close working interdisciplinary and interprofessional relationships, buy-in at all levels, relative geographic density/demographic homogeneity of participants), specialized case management is increasingly being adopted throughout the VA (and elsewhere). Although the value of collaborative, interdisciplinary interventions has been shown in a variety of settings and conditions—nursing homes,⁹ chronic low back pain,¹⁰ safety among hospital inpatients¹¹—its utility for dementia care is relatively underexplored.

Yet the effectiveness of team-based care for individuals has been demonstrated in a number of settings, including Alzheimer disease.^12,13 In addition to involving a number of disciplines, collaborative care is marked by coordination. A number of recent systematic reviews have found that behavioral and multicomponent interventions directed towards the caregiver as well as case management were beneficial in improving some outcomes, although there is considerable heterogeneity in the effects.^14,15 Future work will focus on examining methods to focus/optimize interventions based on individual patient characteristics.

Given the epidemiologic trends, care for patients with dementia is expected to grow. Novel interventions, like DEMO, are a particularly promising option to meet this challenge. In fact, just such a collaborative practice-ready workforce has been identified by the World Health Organization as crucial to meeting the challenges of the health needs in the 21st century.¹⁶ With the feasibility of such an approach in this population now evident, further studies (including larger sample sizes, across greater geographic regions, as well as among more diverse populations) should be undertaken. These results, if replicated, suggest a novel approach to the particularly vexing problem of caring for patients with dementia with potentially far-reaching public health implications.

Acknowledgments
Supported with T21 funds from VA to expand noninstitutional alternatives to institutional extended care for veterans, as well as the Geriatrics Research and Clinical Center (GRECC) at the Baltimore VAMC.

Dementia is a common, multifaceted problem with significant implications for function and quality of life among older individuals. Current demographic shifts are magnifying this problem. Particularly troubling are neuropsychiatric symptoms, which, in addition to creating caregiver distress, also are linked to functional decline, institutionalization, higher health care costs, and mortality (even after controlling for other potential confounders and severity of cognitive impairment). Furthermore, dementia is often unrecognized and underdiagnosed, and patients with dementia historically have poor access to care, particularly those living in rural areas.

The Geriatrics/Dementia Clinic at the Baltimore Veterans Affairs Medical Center (BVAMC) is a referral resource that provides extensive, multidisciplinary evaluations as well as coordinated subspecialist and interprofessional case review. A diverse group of clinicians (representing geriatrics, geriatric psychiatry, neuropsychology, clinical pharmacy, nursing, and social work) perform a half-day evaluation, followed by a meeting of the interdisciplinary team, and feedback session where patients and their families are given the results of the testing and diagnostic impressions as well as plans for further evaluation and treatment. Finally, in addition to the benefits it provides to veterans and their families, this clinic has proven to be an important resource for professional trainees.

Yet this model can be difficult to access, and those living in more remote regions had challenges availing themselves of this resource. Often, they would have to wake before dawn to drive 2 to 4 hours to the medical center. Furthermore, despite the many obvious benefits of this comprehensive approach, veterans and their families often left the clinic with a staggering amount of information and numerous recommendations for future care but without the assurance of integrated follow-up (a burden borne particularly by those living remotely).

The DEMO Program

In response to the dual challenges of access to and coordination of care, existing resources were leveraged with about $250,000 of VA T21 funds (adding both a full-time geriatric nurse practitioner and a psychology technician to the multidisciplinary team) to design and implement the novel DEMO (Dementia Evaluation, Management and Outreach) program. This program aimed to (1) extend dementia evaluations to regional community-based outpatient clinics (CBOCs) that serve veterans in outlying regions; and (2) improve the management and the follow-up that these veterans receive, with a focus on containing costs, while improving both the quality of and veterans’ (and their families’) satisfaction with health care.

Methods

Dementia evaluations were conducted by a geriatric nurse practitioner and psychology technician teamlet at the CBOCs. In addition to neuropsychological testing, medical records were reviewed, caregivers were interviewed, and the patients were examined. The data were then brought back to the full BVAMC Geriatrics/Dementia Clinic multidisciplinary team for discussion. The team reached a consensus diagnosis and then made a comprehensive plan for the further evaluation and management of these complex patients. The plan was entered into the Computerized Patient Record System and communicated to the patient and caregiver during a follow-up CBOC visit.

The teamlet frequently provided informal education during CBOC visits in addition to formal lectures given by experts from the BVAMC and the University of Maryland. The DEMO program was introduced to providers at the CBOCs by e-mail with follow-up information sessions provided on site.

Rather than having patients simply return to their CBOC primary care providers (PCPs) and exposing patients to the risks of poor communication/coordination of care, services were expanded to include regular phone follow-up calls with case management services that augmented those of their PCPs. The goal was to improve outcomes for these patients and provide alternatives to institutionalization.

Standardized instruments were used to gauge patient and caregiver satisfaction, obtain cost data from the VA and the Centers for Medicare & Medicaid Services, and medication data from the Pharmacy Benefits files.

The institutional review board provided approval to collect data on participants to assess the program’s clinical and economic impacts. Since all patients were suspected to have dementia, the informed consent procedures included additional protections. The patient’s understanding of the pertinent information related to participation in the study was assessed to help ensure that participants with dementia truly understood the conditions to which they were consenting. If the potential participant could not provide informed consent, it was obtained from a surrogate with durable power of attorney (the person recognized by Maryland law as the substitute decision maker or the veteran’s legal guardian). Consent was assessed on an ongoing basis regardless of the patient’s capacity to give informed consent, and those willing to have their data collected were enrolled in a “research” arm. These participants were compared with veterans in the dementia clinic during the enrollment period but who did not consent to participate in the research arm, controlling for sociodemographic characteristics and prior health care utilization.

Data Analysis

Patterns of health care utilization may fluctuate with time, and enrollment may identify potential problems that otherwise would not have been found. The authors looked at health care use over 6-month and 1-year intervals before and after enrollment, examining Occupational Physical Assessment Test (OPAT) data and fee-based outpatient data for both inpatient events (including nursing home utilization and hospitalization events) and outpatient visits (including primary, specialty and mental health care services; home care visits, and emergency department [ED]). The total cost incurred by outpatient visits and inpatient care was then adjusted to 2011 dollars. The relationship between program enrollment and health care use and costs was examined with a multivariate regression analyses, controlling for age and health care use in the prior year among veterans who were in the “consent” group or “nonconsent” group.

Outcome variables included the number of primary care, ED, specialty care, home health care, mental health care clinic, and inpatient visits; total inpatient bed days; and the total costs of all the events. The authors fit different multivariate models for these events according to their distributions. Specifically, the Poisson model was used if the distribution of the outcome variable was not overdispersed (eg, ED, primary care).

A negative binomial was used if the distribution of these events was overdispersed (eg, specialty care visits). Further, because the occurrence of inpatient events is relatively rare, a logit model was used to examine the relationship between enrollment status and probability of any inpatient events, regardless of the number of events. Generalized estimating equation (GEE) model with gamma distribution and log link function was used to examine the relationship between cost and program enrollment. The authors also examined the program’s effect on medication use, focusing on high-risk medications in older adults, comparing both the number of unique medications, as well as frequency such medications prescribed 1 year before and after the enrollment.¹

Results

Two hundred ninety-eight (298) veterans were referred to DEMO from a 150-mile radius of Baltimore. Of these veterans, 132 consented to participate in this study. The study participants largely were representative of the total group as well as both the overall veteran population and the more general population of community-dwelling individuals with dementia (Table).

Veterans in the DEMO program largely had mild-to-moderate cognitive impairment with mean Mini-Mental State Examination (MMSE) score of 22 and significant functional limitations (Table). Only 3% displayed a pattern of “pure” dementia typical of Alzheimer disease, and 11% of those referred did not have significant abnormalities on neurocognitive testing.

The team averaged 10.3 recommendations (range 3-22), which focused on a diverse set of issues related to additional diagnostic and therapeutic concerns. Although screening data, including basic laboratory results and imaging, was requested in the referral form, in 71% of cases further diagnostic investigations were suggested. With regard to therapeutic suggestions, not surprisingly, medicines were cited as targets in a majority of cases (eg, discontinuing high-risk medications, initiating/titrating medications to minimize cardiovascular risk). While remaining mindful of the time to benefit and competing morbidities, measures to modify cardiovascular risk factors were suggested in more than half and treatment of depression in 15% of cases. Similarly, addressing poor sensory input was suggested in 38% of cases, with other common recommendations focusing on multiple environmental and social interventions (> 50%) as well as supports/outlets/respite for the caregivers.

The full multidisciplinary DEMO group met only weekly to review cases, and due to travel and scheduling difficulties, feedback to the patients and their families often was delayed for weeks. Although initial plans included regularly scheduled follow-up phone calls, demand quickly outstripped program resources. Nonetheless, chart reviews and abstracted adherence and utilization data revealed that PCPs successfully implemented 52% of recommendations within 2 weeks, rising to > 60% by 3 months. When patients were reevaluated at 1 year, they were remarkably stable: Mini–Mental State Examination (baseline 22.2 ± 5.0 → 22.3 ± 5.7 at follow-up) and Instrumental Activities of Daily Living scores (15.5 ± 10.6 → 17.7 ± 11.4).

Feedback

This program was enthusiastically received by both patients and their caregivers—100% and 98%, respectively—reporting overall satisfaction with the services received and 93% of caregivers indicating satisfaction with how the program met their needs. Caregivers were happy with the amount of time the provider took to answer questions (100% satisfied with the amount of time the DEMO provider spent and that they explained “what they wanted to know,” with 98% responding “good” or “great” for both), as well as with services and amount of help received (83% and 77% “very satisfied,” respectively).

In the survey, 98% of caregivers and patients felt that the program helped them deal more effectively with their problems, 97% would recommend the program to a friend in need of similar help, and 100% would come back if they were to seek help again. In keeping with DEMO’s initial aim of increasing access, there was favorable feedback on the ability to get in and be seen and convenience of location. In addition, referring providers universally expressed satisfaction with the referral process (referrals increased linearly); timeliness of scheduling; usefulness of the recommendations; and they planned on continuing to refer patients.

Although there was great variability, controlling for age and prior utilization, veterans in DEMO had statistically significant (all P < .05) fewer ED and specialty care visits and more mental health care clinic visits 183 to 365 daysafter referral dates compared with those in the nonconsented group. Veterans in the consented group also were less likely to use inpatient care than were veterans in the nonconsented group 183 to 365 days after referral dates. These trends were similarly reflected after controlling for age and prior utilization as well as when examining health care costs (data not shown). Nonetheless, DEMO did not seem to have any effect on overall inpatient bed days, primary/home-based care visits, or total costs. In fact, utilization of mental health care resources increased (Figures 1, 2, and 3).

Discussion

Cognitive issues in patients within the general population are common, and the patients cared for by the VA are no exception. Dementia is more common in rural compared with urban areas, and those living in more remote locations have reduced access to specialized evaluation, management, and support services.² The authors describe a novel program that dramatically increased patient access, bringing the normally tertiary referral services to geographically remote CBOCs at a minimal investment. These services were well received by patients, caregivers, and PCPs. As anticipated, patients and their caregivers especially appreciated the ease and convenience of access. Considering the already significant burden(s) borne every day by those caring for patients with dementia, the benefit of this approach is evident.

Clinicians often feel uncomfortable in evaluating and managing patients with cognitive deficits. Nonetheless, the role of specialized clinics in diagnosing dementia has been demonstrated previously, and the present results are in agreement with previous studies.³ The novelty here is the provision of specialized care usually found only in large, academic medical centers to local CBOCs. By bringing specialized services to geographically isolated patients, the DEMO program was able to increase both access and utilization. Furthermore, providing coordination and ongoing, focused follow-up provided increases in satisfaction and efficiency.

An additional benefit of this approach is the opportunity for PCP education. The authors even found anecdotal reductions in ED usage as well as acute hospitalization and long-term placement—although it was not a statistical significant difference. The relatively high use of mental health care services in this population is in line with previous reports in similar populations, and greater utilization of mental health care services may be one explanation why overall costs did not differ between the 2 groups.⁴ Nonetheless, this intimates that such a program may yield savings over a longer term, as has been demonstrated in patients with a variety of other psychiatric diagnoses cared for in the community rather than in institutions.^5,6

The prevalence of dementia and its associated costs are nearly $50,000 per year per person—suggesting a total cost in the hundreds of billions of dollars.⁷ Similarly, the importance of caregiver support (including psychosocial interventions, such as the one piloted here) has been demonstrated in a variety of settings (even without improvement in caregiver burden itself).⁸

There were a number of challenges in the rollout and delivery of DEMO. Although CBOC PCPs were initially somewhat uncertain of the benefit of this approach and concerned about the space requirements, referrals rapidly and dramatically increased, and the DEMO teamlet became enmeshed with CBOC staff. Similarly, potential participants and their caregivers sometimes were leery to involve others in their care. Both the CBOC PCPs and caregivers came to depend more on DEMO staff, and the DEMO staff members frequently were the first ones to be called (at times for issues unrelated to dementia).

Unfortunately, DEMO was underresourced to provide either real-time feedback true or first responder services. Misunderstandings concerning this were an early challenge to PCP acceptance. However, the longitudinal presence and close working relationships of the DEMO teamlet in each CBOC allowed their use as an adjunct to primary care, and increased the efficacy of both.

Limitations

A number of additional caveats must be made. First, this study had a relatively small number of participants, and there was great variability in health care utilization. This is particularly germane in this population of patients with dementia, which typically has an asymmetrically high use of health care resources. Additionally, the relatively limited follow-up period may have blunted the programs true effect(s). Further, although veterans in the nonconsented group were not officially enrolled in the program, there was likely spillover of the effects of the program on practice patterns, leading to an underestimation of the program’s impact.

Conclusion

With minimal resources, DEMO successfully brought expert evaluation (usually tertiary referral) services, and provided specialized case management in coordination with existing primary care to remote patients. Although there were a number of features rather unique to this setting (eg, infrastructural support; close working interdisciplinary and interprofessional relationships, buy-in at all levels, relative geographic density/demographic homogeneity of participants), specialized case management is increasingly being adopted throughout the VA (and elsewhere). Although the value of collaborative, interdisciplinary interventions has been shown in a variety of settings and conditions—nursing homes,⁹ chronic low back pain,¹⁰ safety among hospital inpatients¹¹—its utility for dementia care is relatively underexplored.

Yet the effectiveness of team-based care for individuals has been demonstrated in a number of settings, including Alzheimer disease.^12,13 In addition to involving a number of disciplines, collaborative care is marked by coordination. A number of recent systematic reviews have found that behavioral and multicomponent interventions directed towards the caregiver as well as case management were beneficial in improving some outcomes, although there is considerable heterogeneity in the effects.^14,15 Future work will focus on examining methods to focus/optimize interventions based on individual patient characteristics.

Given the epidemiologic trends, care for patients with dementia is expected to grow. Novel interventions, like DEMO, are a particularly promising option to meet this challenge. In fact, just such a collaborative practice-ready workforce has been identified by the World Health Organization as crucial to meeting the challenges of the health needs in the 21st century.¹⁶ With the feasibility of such an approach in this population now evident, further studies (including larger sample sizes, across greater geographic regions, as well as among more diverse populations) should be undertaken. These results, if replicated, suggest a novel approach to the particularly vexing problem of caring for patients with dementia with potentially far-reaching public health implications.

Acknowledgments
Supported with T21 funds from VA to expand noninstitutional alternatives to institutional extended care for veterans, as well as the Geriatrics Research and Clinical Center (GRECC) at the Baltimore VAMC.

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

“There is no safe level of smoking”—that’s the conclusion of National Cancer Institute researchers, based on data from 290,215 adults in the 2004-2005 NIH-AARP Diet and Health Study. “[S]moking even a small number of cigarettes per day has substantial negative health effects,” said Maki Inoue-Choi, PhD, lead author.

The participants responded to a questionnaire that assessed lifetime smoking intensity. Those who smoked between 1 and 10 cigarettes a day had an 87% higher risk of earlier death. But even people who smoked an average of < 1 cigarette per day over their lifetime still had a 64% higher risk of earlier death, compared with never-smokers.

The researchers also looked at specific causes of death. Not surprisingly, they found a “particularly strong” association for lung cancer mortality. But again, even people who consistently averaged < 1 cigarette per day over their lifetime had 9 times the risk of dying from lung cancer than never-smokers. Among those who smoked between 1 and 10 cigarettes a day, the risk of dying from lung cancer was nearly 12 times higher.

People who smoked between 1 and 10 cigarettes a day also had > 6 times the risk of dying from respiratory disease and about 1 and a half times the risk of dying of cardiovascular disease, compared with never-smokers.

The younger people were when they quit smoking, the lower their risk of early death.

“There is no safe level of smoking”—that’s the conclusion of National Cancer Institute researchers, based on data from 290,215 adults in the 2004-2005 NIH-AARP Diet and Health Study. “[S]moking even a small number of cigarettes per day has substantial negative health effects,” said Maki Inoue-Choi, PhD, lead author.

The participants responded to a questionnaire that assessed lifetime smoking intensity. Those who smoked between 1 and 10 cigarettes a day had an 87% higher risk of earlier death. But even people who smoked an average of < 1 cigarette per day over their lifetime still had a 64% higher risk of earlier death, compared with never-smokers.

The researchers also looked at specific causes of death. Not surprisingly, they found a “particularly strong” association for lung cancer mortality. But again, even people who consistently averaged < 1 cigarette per day over their lifetime had 9 times the risk of dying from lung cancer than never-smokers. Among those who smoked between 1 and 10 cigarettes a day, the risk of dying from lung cancer was nearly 12 times higher.

People who smoked between 1 and 10 cigarettes a day also had > 6 times the risk of dying from respiratory disease and about 1 and a half times the risk of dying of cardiovascular disease, compared with never-smokers.

The younger people were when they quit smoking, the lower their risk of early death.

“There is no safe level of smoking”—that’s the conclusion of National Cancer Institute researchers, based on data from 290,215 adults in the 2004-2005 NIH-AARP Diet and Health Study. “[S]moking even a small number of cigarettes per day has substantial negative health effects,” said Maki Inoue-Choi, PhD, lead author.

The participants responded to a questionnaire that assessed lifetime smoking intensity. Those who smoked between 1 and 10 cigarettes a day had an 87% higher risk of earlier death. But even people who smoked an average of < 1 cigarette per day over their lifetime still had a 64% higher risk of earlier death, compared with never-smokers.

The researchers also looked at specific causes of death. Not surprisingly, they found a “particularly strong” association for lung cancer mortality. But again, even people who consistently averaged < 1 cigarette per day over their lifetime had 9 times the risk of dying from lung cancer than never-smokers. Among those who smoked between 1 and 10 cigarettes a day, the risk of dying from lung cancer was nearly 12 times higher.

People who smoked between 1 and 10 cigarettes a day also had > 6 times the risk of dying from respiratory disease and about 1 and a half times the risk of dying of cardiovascular disease, compared with never-smokers.

The younger people were when they quit smoking, the lower their risk of early death.

Leukemia stem cells
Image by Robert Paulson

The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.

Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).

In vitro and in vivo experiments

showed that these mAbs can recognize

and destroy AML and MDS stem/progenitor cells.

“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.

“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”

Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.

The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.

Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
 
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.

However, the mAbs had minimal effects on normal hematopoietic stem cells.

“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.

Leukemia stem cells
Image by Robert Paulson

The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.

Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).

In vitro and in vivo experiments

showed that these mAbs can recognize

and destroy AML and MDS stem/progenitor cells.

“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.

“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”

Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.

The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.

Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
 
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.

However, the mAbs had minimal effects on normal hematopoietic stem cells.

“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.

Leukemia stem cells
Image by Robert Paulson

The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.

Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).

In vitro and in vivo experiments

showed that these mAbs can recognize

and destroy AML and MDS stem/progenitor cells.

“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.

“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”

Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.

The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.

Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
 
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.

However, the mAbs had minimal effects on normal hematopoietic stem cells.

“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.

DNA helix
Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational gene therapy AMT-060 as a treatment for patients with severe hemophilia B. 

AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. uniQure is the company developing AMT-060.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Phase 1/2 trial

The breakthrough designation for AMT-060 is based on results from an ongoing phase 1/2 study. Updated data from this study were recently presented at the 2016 ASH Annual Meeting (abstract 2314). 

In this trial, researchers are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 10¹² gc/kg, and 5 received AMT-060 at 2 x 10¹³ gc/kg.

The data presented at ASH included up to 52 weeks of follow-up from the low-dose cohort and up to 31 weeks of follow-up from the higher-dose cohort.

Data from the higher-dose cohort show a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX replacement therapy were able to stop this therapy.  

As of the data cutoff date for the ASH presentation, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.

Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who

remained on prophylaxis sustained an improved disease

phenotype and also required materially less FIX concentrate after

treatment with AMT-060.

According to uniQure, all 5 patients in the low-dose cohort continue to maintain “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.

uniQure also said AMT-060 continues to be well-tolerated, and there have been no severe adverse events.

Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.

These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.

None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.

DNA helix
Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational gene therapy AMT-060 as a treatment for patients with severe hemophilia B. 

AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. uniQure is the company developing AMT-060.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Phase 1/2 trial

The breakthrough designation for AMT-060 is based on results from an ongoing phase 1/2 study. Updated data from this study were recently presented at the 2016 ASH Annual Meeting (abstract 2314). 

In this trial, researchers are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 10¹² gc/kg, and 5 received AMT-060 at 2 x 10¹³ gc/kg.

The data presented at ASH included up to 52 weeks of follow-up from the low-dose cohort and up to 31 weeks of follow-up from the higher-dose cohort.

Data from the higher-dose cohort show a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX replacement therapy were able to stop this therapy.  

As of the data cutoff date for the ASH presentation, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.

Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who

remained on prophylaxis sustained an improved disease

phenotype and also required materially less FIX concentrate after

treatment with AMT-060.

According to uniQure, all 5 patients in the low-dose cohort continue to maintain “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.

uniQure also said AMT-060 continues to be well-tolerated, and there have been no severe adverse events.

Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.

These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.

None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.

DNA helix
Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational gene therapy AMT-060 as a treatment for patients with severe hemophilia B. 

AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. uniQure is the company developing AMT-060.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Phase 1/2 trial

The breakthrough designation for AMT-060 is based on results from an ongoing phase 1/2 study. Updated data from this study were recently presented at the 2016 ASH Annual Meeting (abstract 2314). 

In this trial, researchers are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 10¹² gc/kg, and 5 received AMT-060 at 2 x 10¹³ gc/kg.

The data presented at ASH included up to 52 weeks of follow-up from the low-dose cohort and up to 31 weeks of follow-up from the higher-dose cohort.

Data from the higher-dose cohort show a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX replacement therapy were able to stop this therapy.  

As of the data cutoff date for the ASH presentation, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.

Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who

remained on prophylaxis sustained an improved disease

phenotype and also required materially less FIX concentrate after

treatment with AMT-060.

According to uniQure, all 5 patients in the low-dose cohort continue to maintain “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.

uniQure also said AMT-060 continues to be well-tolerated, and there have been no severe adverse events.

Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.

These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.

None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.

Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?

Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.

Study design: Parallel-group, randomized, unblinded clinical trial.

Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.

Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.

Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.

Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.

Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?

Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.

Study design: Parallel-group, randomized, unblinded clinical trial.

Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.

Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.

Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.

Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.

Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?

Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.

Study design: Parallel-group, randomized, unblinded clinical trial.

Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.

Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.

Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.

Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.

AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.

In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.

In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.

In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]