Pharmacology

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

PHILADELPHIA – Testosterone gel for treatment of hypogonadism in older men boosted their left ventricular mass by 3.5% in a single year in the multicenter, double-blind, placebo-controlled Testosterone Cardiovascular Trial, although the clinical implications of this impressive increase remain unclear, Elizabeth Hutchins, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“I do think these results should be considered as part of the safety profile for testosterone gel and also represent an interesting and understudied area for future research,” said Dr. Hutchins, a hospitalist affiliated with the Los Angeles Biomedical Research Center at Harbor-UCLA Medical Center.

The Testosterone Cardiovascular Trial was one of seven coordinated placebo-controlled, double-blind clinical trials of the impact of raising serum testosterone levels in older men with low testosterone. Some results of what are known as the TTrials have previously been reported (Endocr Rev. 2018 Jun 1;39[3]:369-86).

Dr. Hutchins presented new findings on the effect of treatment with 1% topical testosterone gel on body surface area–indexed left ventricular mass. The trial utilized a widely prescribed, commercially available product known as AndroGel. The study included 123 men over age 65 with low serum testosterone and coronary CT angiography images obtained at baseline and again after 1 year of double-blind testosterone gel or placebo. More than 80% of the men were above age 75, half were obese, more than two-thirds had hypertension, and 30% had diabetes.

The men initially applied 5 g of the testosterone gel daily, providing 15 mg/day of testosterone, with subsequent dosing adjustments as needed based on serum testosterone levels measured at a central laboratory. Participants were evaluated in office visits with serum testosterone measurements every 3 months. Testosterone levels in the men assigned to active treatment quickly rose to normal range and stayed there for the full 12 months, while the placebo-treated controls continued to have below-normal testosterone throughout the trial.

The key study finding was that LV mass indexed to body surface area rose significantly in the testosterone gel group, from an average of 71.5 g/m² at baseline to 74.8 g/m² at 1 year. That’s a statistically significant 3.5% increase. In contrast, LV mass remained flat across the year in controls: 73.8 g/m² at baseline and 73.3 g/m² at 12 months.

There was, however, no change over time in left or right atrial or ventricular chamber volumes in the testosterone gel recipients, nor in the controls.

Session comoderator Eric D. Peterson, MD, professor of medicine and a cardiologist at Duke University in Durham, N.C., said that “this is a very important topic,” then posed a provocative question to Dr. Hutchins: “If the intervention had been running instead of testosterone gel, would the results have looked similar, and would you be concluding that there should be a warning around the use of running?”

Dr. Hutchins replied that she’s given that question much thought.

“Of course, exercise leads to LV hypertrophy and we consider that to be good muscle, and high blood pressure leads to LV hypertrophy and we consider that bad muscle. So which one is it in this case? From what I can find in the literature, it seems that incremental increases in LV mass in the absence of being an athlete are deleterious. But I think we would need outcomes-based research to really answer that question,” she said.

Dr. Hutchins noted that this was the first-ever randomized controlled trial to measure the effect of testosterone therapy on LV mass in humans. The documented increase achieved with 1 year of testosterone gel doesn’t come close to reaching the threshold of LV hypertrophy, which is about 125 g/m² for men. But evidence from animal and observational human studies suggests that even in the absence of LV hypertrophy, increases in LV mass are associated with increased mortality, she added.

She reported having no financial conflicts regarding her study, sponsored by the National Institutes of Health.

bjancin@mdedge.com

SOURCE: Hutchins E. AHA 2019, Session FS.AOS.04.

PHILADELPHIA – Testosterone gel for treatment of hypogonadism in older men boosted their left ventricular mass by 3.5% in a single year in the multicenter, double-blind, placebo-controlled Testosterone Cardiovascular Trial, although the clinical implications of this impressive increase remain unclear, Elizabeth Hutchins, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“I do think these results should be considered as part of the safety profile for testosterone gel and also represent an interesting and understudied area for future research,” said Dr. Hutchins, a hospitalist affiliated with the Los Angeles Biomedical Research Center at Harbor-UCLA Medical Center.

The Testosterone Cardiovascular Trial was one of seven coordinated placebo-controlled, double-blind clinical trials of the impact of raising serum testosterone levels in older men with low testosterone. Some results of what are known as the TTrials have previously been reported (Endocr Rev. 2018 Jun 1;39[3]:369-86).

Dr. Hutchins presented new findings on the effect of treatment with 1% topical testosterone gel on body surface area–indexed left ventricular mass. The trial utilized a widely prescribed, commercially available product known as AndroGel. The study included 123 men over age 65 with low serum testosterone and coronary CT angiography images obtained at baseline and again after 1 year of double-blind testosterone gel or placebo. More than 80% of the men were above age 75, half were obese, more than two-thirds had hypertension, and 30% had diabetes.

The men initially applied 5 g of the testosterone gel daily, providing 15 mg/day of testosterone, with subsequent dosing adjustments as needed based on serum testosterone levels measured at a central laboratory. Participants were evaluated in office visits with serum testosterone measurements every 3 months. Testosterone levels in the men assigned to active treatment quickly rose to normal range and stayed there for the full 12 months, while the placebo-treated controls continued to have below-normal testosterone throughout the trial.

The key study finding was that LV mass indexed to body surface area rose significantly in the testosterone gel group, from an average of 71.5 g/m² at baseline to 74.8 g/m² at 1 year. That’s a statistically significant 3.5% increase. In contrast, LV mass remained flat across the year in controls: 73.8 g/m² at baseline and 73.3 g/m² at 12 months.

There was, however, no change over time in left or right atrial or ventricular chamber volumes in the testosterone gel recipients, nor in the controls.

Session comoderator Eric D. Peterson, MD, professor of medicine and a cardiologist at Duke University in Durham, N.C., said that “this is a very important topic,” then posed a provocative question to Dr. Hutchins: “If the intervention had been running instead of testosterone gel, would the results have looked similar, and would you be concluding that there should be a warning around the use of running?”

Dr. Hutchins replied that she’s given that question much thought.

“Of course, exercise leads to LV hypertrophy and we consider that to be good muscle, and high blood pressure leads to LV hypertrophy and we consider that bad muscle. So which one is it in this case? From what I can find in the literature, it seems that incremental increases in LV mass in the absence of being an athlete are deleterious. But I think we would need outcomes-based research to really answer that question,” she said.

Dr. Hutchins noted that this was the first-ever randomized controlled trial to measure the effect of testosterone therapy on LV mass in humans. The documented increase achieved with 1 year of testosterone gel doesn’t come close to reaching the threshold of LV hypertrophy, which is about 125 g/m² for men. But evidence from animal and observational human studies suggests that even in the absence of LV hypertrophy, increases in LV mass are associated with increased mortality, she added.

She reported having no financial conflicts regarding her study, sponsored by the National Institutes of Health.

bjancin@mdedge.com

SOURCE: Hutchins E. AHA 2019, Session FS.AOS.04.

PHILADELPHIA – Testosterone gel for treatment of hypogonadism in older men boosted their left ventricular mass by 3.5% in a single year in the multicenter, double-blind, placebo-controlled Testosterone Cardiovascular Trial, although the clinical implications of this impressive increase remain unclear, Elizabeth Hutchins, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“I do think these results should be considered as part of the safety profile for testosterone gel and also represent an interesting and understudied area for future research,” said Dr. Hutchins, a hospitalist affiliated with the Los Angeles Biomedical Research Center at Harbor-UCLA Medical Center.

The Testosterone Cardiovascular Trial was one of seven coordinated placebo-controlled, double-blind clinical trials of the impact of raising serum testosterone levels in older men with low testosterone. Some results of what are known as the TTrials have previously been reported (Endocr Rev. 2018 Jun 1;39[3]:369-86).

Dr. Hutchins presented new findings on the effect of treatment with 1% topical testosterone gel on body surface area–indexed left ventricular mass. The trial utilized a widely prescribed, commercially available product known as AndroGel. The study included 123 men over age 65 with low serum testosterone and coronary CT angiography images obtained at baseline and again after 1 year of double-blind testosterone gel or placebo. More than 80% of the men were above age 75, half were obese, more than two-thirds had hypertension, and 30% had diabetes.

The men initially applied 5 g of the testosterone gel daily, providing 15 mg/day of testosterone, with subsequent dosing adjustments as needed based on serum testosterone levels measured at a central laboratory. Participants were evaluated in office visits with serum testosterone measurements every 3 months. Testosterone levels in the men assigned to active treatment quickly rose to normal range and stayed there for the full 12 months, while the placebo-treated controls continued to have below-normal testosterone throughout the trial.

The key study finding was that LV mass indexed to body surface area rose significantly in the testosterone gel group, from an average of 71.5 g/m² at baseline to 74.8 g/m² at 1 year. That’s a statistically significant 3.5% increase. In contrast, LV mass remained flat across the year in controls: 73.8 g/m² at baseline and 73.3 g/m² at 12 months.

There was, however, no change over time in left or right atrial or ventricular chamber volumes in the testosterone gel recipients, nor in the controls.

Session comoderator Eric D. Peterson, MD, professor of medicine and a cardiologist at Duke University in Durham, N.C., said that “this is a very important topic,” then posed a provocative question to Dr. Hutchins: “If the intervention had been running instead of testosterone gel, would the results have looked similar, and would you be concluding that there should be a warning around the use of running?”

Dr. Hutchins replied that she’s given that question much thought.

“Of course, exercise leads to LV hypertrophy and we consider that to be good muscle, and high blood pressure leads to LV hypertrophy and we consider that bad muscle. So which one is it in this case? From what I can find in the literature, it seems that incremental increases in LV mass in the absence of being an athlete are deleterious. But I think we would need outcomes-based research to really answer that question,” she said.

Dr. Hutchins noted that this was the first-ever randomized controlled trial to measure the effect of testosterone therapy on LV mass in humans. The documented increase achieved with 1 year of testosterone gel doesn’t come close to reaching the threshold of LV hypertrophy, which is about 125 g/m² for men. But evidence from animal and observational human studies suggests that even in the absence of LV hypertrophy, increases in LV mass are associated with increased mortality, she added.

She reported having no financial conflicts regarding her study, sponsored by the National Institutes of Health.

bjancin@mdedge.com

SOURCE: Hutchins E. AHA 2019, Session FS.AOS.04.

The Food and Drug Administration has issued a Safety Alert regarding the weight-management medication lorcaserin (Belviq, Belviq XR) after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.

bankrx/Getty Images

“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.

The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.

“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.

Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.

Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.

Lorcaserin is distributed by Eisai.*

lfranki@mdedge.com

*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin. 

The Food and Drug Administration has issued a Safety Alert regarding the weight-management medication lorcaserin (Belviq, Belviq XR) after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.

bankrx/Getty Images

“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.

The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.

“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.

Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.

Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.

Lorcaserin is distributed by Eisai.*

lfranki@mdedge.com

*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin. 

The Food and Drug Administration has issued a Safety Alert regarding the weight-management medication lorcaserin (Belviq, Belviq XR) after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.

bankrx/Getty Images

“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.

The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.

“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.

Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.

Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.

Lorcaserin is distributed by Eisai.*

lfranki@mdedge.com

*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin. 

The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.

Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.

The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.

Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.

The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.

The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.

SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.

The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.

Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.

The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.

Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.

The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.

The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.

SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.

The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.

Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.

The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.

Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.

The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.

The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.

SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.

PHILADELPHIA – A home blood pressure telemonitoring program featuring pharmacist management of patients with uncontrolled hypertension reduced cardiovascular events by half and was cost saving over the course of 5 years, even though the intervention ended after year 1, Karen L. Margolis, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The return on investment was 126%. That means that for every dollar spent on the intervention, that dollar was recouped by $1.00 plus another $1.26,” explained Dr. Margolis, a general internist who serves as executive director for research at the HealthPartners Institute in Bloomington, Minn., and professor of medicine at the University of Minnesota, Minneapolis.

She presented 5-year follow-up data from the Hyperlink (Home Blood Pressure Telemonitoring and Case Management to Control Hypertension) study, a cluster randomized controlled trial involving 16 primary care clinics. Half of the clinics were randomized to the intervention, which entailed home blood pressure telemonitoring and pharmacist-led case management in collaboration with the primary care team. The other eight clinics provided usual care. The intervention portion of the trial, which lasted for 12 months, included 450 adults with uncontrolled hypertension as defined by repeated on-treatment blood pressure readings of 140/90 mm Hg or more. Participants’ baseline mean blood pressure was 148/85 mm Hg while on an average of one and a half antihypertensive drug classes. On average, pharmacists ended up adding one additional drug from a different antihypertensive drug class to achieve improved blood pressure control.

The details of the intervention and the short-term blood pressure results have previously been reported (JAMA. 2013 Jul 3;310[1]:46-56). Briefly, 6 months into the study, patients in the intervention arm averaged 11/6 mm Hg lower blood pressure than did the usual care controls. At 12 months – when the intervention ended – the between-group difference was similar at 10/5 mm Hg. At 18 months, the difference, while attenuated, remained significant at 7/3 mm Hg in favor of the intervention group. However, at 54 months, the intervention group’s advantage – a 3–mm Hg lower SBP and a 1–mm Hg lower DBP than in controls – was no longer significant.

The exciting new findings Dr. Margolis presented at the AHA scientific sessions focused on 5-year outcomes. Since HealthPartners is an integrated health care system, follow-up was essentially complete.

“None of the other telemetry studies I’m aware of have published anything on cardiovascular events. And we were somewhat surprised when we looked at our data to see fairly substantial differences in our primary outcome,” she noted.

That outcome was a composite of MI, stroke, heart failure, or cardiovascular death occurring over 5 years. The rate was 4.4% in the intervention group and nearly double at 8.6% in controls. That translated to a 51% relative risk reduction. The biggest difference was in stroke: 4 cases in the intervention arm, 12 in usual care controls.

The 5-year coronary revascularization rate was 5.3% in the intervention arm and 10.4% in controls, for a 52% relative risk reduction.

A major caveat regarding the Hyperlink trial was that, even at 450 patients and 5 years of follow-up, the study was underpowered to show significant differences in event rates, with P =.09 for the primary endpoint.

That being said, the financial results were striking. The intervention cost $1,511 per patient in 2017 U.S. dollars. The cost of treatment for major adverse cardiovascular events totaled $758,000 in the intervention group and $1,538,000 in usual care controls. That works out to $3,420 less per patient in the intervention arm. Offset by the cost of the intervention, that spells a net savings of $1,908 per patient achieved by implementing the year-long intervention. It’s a rare instance in health care of an intervention that actually makes money.

These results were unusual enough that Dr. Margolis and her coinvestigators decided to feed their wealth of SBP readings into a microsimulation model, which they ran 1,000 times. The model predicted – in light of the fact that patients in the intervention group were on average 2 years older than the controls were – that the expected reduction in the primary endpoint was 12% rather than the observed 51% relative risk reduction.

How to explain the discrepancy? The Hyperlink results could have been due to chance. Or it could be, Dr. Margolis surmised, that the pharmacists helped accomplish improvements in other cardiovascular risk factors, such as hyperlipidemia, smoking, or sedentary behavior. That’s unknown, since the investigators focused on changes in blood pressure only. Future studies of home telemonitoring and pharmacist case management of uncontrolled hypertension should be powered to detect significant differences in cardiovascular events and should track additional risk factors, she concluded.

She reported having no financial conflicts regarding the study.

bjancin@mdedge.com

SOURCE: Margolis KL. AHA 2019. Abstract MDP232.

PHILADELPHIA – A home blood pressure telemonitoring program featuring pharmacist management of patients with uncontrolled hypertension reduced cardiovascular events by half and was cost saving over the course of 5 years, even though the intervention ended after year 1, Karen L. Margolis, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The return on investment was 126%. That means that for every dollar spent on the intervention, that dollar was recouped by $1.00 plus another $1.26,” explained Dr. Margolis, a general internist who serves as executive director for research at the HealthPartners Institute in Bloomington, Minn., and professor of medicine at the University of Minnesota, Minneapolis.

She presented 5-year follow-up data from the Hyperlink (Home Blood Pressure Telemonitoring and Case Management to Control Hypertension) study, a cluster randomized controlled trial involving 16 primary care clinics. Half of the clinics were randomized to the intervention, which entailed home blood pressure telemonitoring and pharmacist-led case management in collaboration with the primary care team. The other eight clinics provided usual care. The intervention portion of the trial, which lasted for 12 months, included 450 adults with uncontrolled hypertension as defined by repeated on-treatment blood pressure readings of 140/90 mm Hg or more. Participants’ baseline mean blood pressure was 148/85 mm Hg while on an average of one and a half antihypertensive drug classes. On average, pharmacists ended up adding one additional drug from a different antihypertensive drug class to achieve improved blood pressure control.

The details of the intervention and the short-term blood pressure results have previously been reported (JAMA. 2013 Jul 3;310[1]:46-56). Briefly, 6 months into the study, patients in the intervention arm averaged 11/6 mm Hg lower blood pressure than did the usual care controls. At 12 months – when the intervention ended – the between-group difference was similar at 10/5 mm Hg. At 18 months, the difference, while attenuated, remained significant at 7/3 mm Hg in favor of the intervention group. However, at 54 months, the intervention group’s advantage – a 3–mm Hg lower SBP and a 1–mm Hg lower DBP than in controls – was no longer significant.

The exciting new findings Dr. Margolis presented at the AHA scientific sessions focused on 5-year outcomes. Since HealthPartners is an integrated health care system, follow-up was essentially complete.

“None of the other telemetry studies I’m aware of have published anything on cardiovascular events. And we were somewhat surprised when we looked at our data to see fairly substantial differences in our primary outcome,” she noted.

That outcome was a composite of MI, stroke, heart failure, or cardiovascular death occurring over 5 years. The rate was 4.4% in the intervention group and nearly double at 8.6% in controls. That translated to a 51% relative risk reduction. The biggest difference was in stroke: 4 cases in the intervention arm, 12 in usual care controls.

The 5-year coronary revascularization rate was 5.3% in the intervention arm and 10.4% in controls, for a 52% relative risk reduction.

A major caveat regarding the Hyperlink trial was that, even at 450 patients and 5 years of follow-up, the study was underpowered to show significant differences in event rates, with P =.09 for the primary endpoint.

That being said, the financial results were striking. The intervention cost $1,511 per patient in 2017 U.S. dollars. The cost of treatment for major adverse cardiovascular events totaled $758,000 in the intervention group and $1,538,000 in usual care controls. That works out to $3,420 less per patient in the intervention arm. Offset by the cost of the intervention, that spells a net savings of $1,908 per patient achieved by implementing the year-long intervention. It’s a rare instance in health care of an intervention that actually makes money.

These results were unusual enough that Dr. Margolis and her coinvestigators decided to feed their wealth of SBP readings into a microsimulation model, which they ran 1,000 times. The model predicted – in light of the fact that patients in the intervention group were on average 2 years older than the controls were – that the expected reduction in the primary endpoint was 12% rather than the observed 51% relative risk reduction.

How to explain the discrepancy? The Hyperlink results could have been due to chance. Or it could be, Dr. Margolis surmised, that the pharmacists helped accomplish improvements in other cardiovascular risk factors, such as hyperlipidemia, smoking, or sedentary behavior. That’s unknown, since the investigators focused on changes in blood pressure only. Future studies of home telemonitoring and pharmacist case management of uncontrolled hypertension should be powered to detect significant differences in cardiovascular events and should track additional risk factors, she concluded.

She reported having no financial conflicts regarding the study.

bjancin@mdedge.com

SOURCE: Margolis KL. AHA 2019. Abstract MDP232.

PHILADELPHIA – A home blood pressure telemonitoring program featuring pharmacist management of patients with uncontrolled hypertension reduced cardiovascular events by half and was cost saving over the course of 5 years, even though the intervention ended after year 1, Karen L. Margolis, MD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The return on investment was 126%. That means that for every dollar spent on the intervention, that dollar was recouped by $1.00 plus another $1.26,” explained Dr. Margolis, a general internist who serves as executive director for research at the HealthPartners Institute in Bloomington, Minn., and professor of medicine at the University of Minnesota, Minneapolis.

She presented 5-year follow-up data from the Hyperlink (Home Blood Pressure Telemonitoring and Case Management to Control Hypertension) study, a cluster randomized controlled trial involving 16 primary care clinics. Half of the clinics were randomized to the intervention, which entailed home blood pressure telemonitoring and pharmacist-led case management in collaboration with the primary care team. The other eight clinics provided usual care. The intervention portion of the trial, which lasted for 12 months, included 450 adults with uncontrolled hypertension as defined by repeated on-treatment blood pressure readings of 140/90 mm Hg or more. Participants’ baseline mean blood pressure was 148/85 mm Hg while on an average of one and a half antihypertensive drug classes. On average, pharmacists ended up adding one additional drug from a different antihypertensive drug class to achieve improved blood pressure control.

The details of the intervention and the short-term blood pressure results have previously been reported (JAMA. 2013 Jul 3;310[1]:46-56). Briefly, 6 months into the study, patients in the intervention arm averaged 11/6 mm Hg lower blood pressure than did the usual care controls. At 12 months – when the intervention ended – the between-group difference was similar at 10/5 mm Hg. At 18 months, the difference, while attenuated, remained significant at 7/3 mm Hg in favor of the intervention group. However, at 54 months, the intervention group’s advantage – a 3–mm Hg lower SBP and a 1–mm Hg lower DBP than in controls – was no longer significant.

The exciting new findings Dr. Margolis presented at the AHA scientific sessions focused on 5-year outcomes. Since HealthPartners is an integrated health care system, follow-up was essentially complete.

“None of the other telemetry studies I’m aware of have published anything on cardiovascular events. And we were somewhat surprised when we looked at our data to see fairly substantial differences in our primary outcome,” she noted.

That outcome was a composite of MI, stroke, heart failure, or cardiovascular death occurring over 5 years. The rate was 4.4% in the intervention group and nearly double at 8.6% in controls. That translated to a 51% relative risk reduction. The biggest difference was in stroke: 4 cases in the intervention arm, 12 in usual care controls.

The 5-year coronary revascularization rate was 5.3% in the intervention arm and 10.4% in controls, for a 52% relative risk reduction.

A major caveat regarding the Hyperlink trial was that, even at 450 patients and 5 years of follow-up, the study was underpowered to show significant differences in event rates, with P =.09 for the primary endpoint.

That being said, the financial results were striking. The intervention cost $1,511 per patient in 2017 U.S. dollars. The cost of treatment for major adverse cardiovascular events totaled $758,000 in the intervention group and $1,538,000 in usual care controls. That works out to $3,420 less per patient in the intervention arm. Offset by the cost of the intervention, that spells a net savings of $1,908 per patient achieved by implementing the year-long intervention. It’s a rare instance in health care of an intervention that actually makes money.

These results were unusual enough that Dr. Margolis and her coinvestigators decided to feed their wealth of SBP readings into a microsimulation model, which they ran 1,000 times. The model predicted – in light of the fact that patients in the intervention group were on average 2 years older than the controls were – that the expected reduction in the primary endpoint was 12% rather than the observed 51% relative risk reduction.

How to explain the discrepancy? The Hyperlink results could have been due to chance. Or it could be, Dr. Margolis surmised, that the pharmacists helped accomplish improvements in other cardiovascular risk factors, such as hyperlipidemia, smoking, or sedentary behavior. That’s unknown, since the investigators focused on changes in blood pressure only. Future studies of home telemonitoring and pharmacist case management of uncontrolled hypertension should be powered to detect significant differences in cardiovascular events and should track additional risk factors, she concluded.

She reported having no financial conflicts regarding the study.

bjancin@mdedge.com

SOURCE: Margolis KL. AHA 2019. Abstract MDP232.

The Food and Drug Administration has approved Valtoco (diazepam nasal) for the acute treatment of seizure clusters in patients with epilepsy aged 6 years and older.

The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.

Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.

The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.

Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
 

jremaly@mdedge.com

The Food and Drug Administration has approved Valtoco (diazepam nasal) for the acute treatment of seizure clusters in patients with epilepsy aged 6 years and older.

The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.

Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.

The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.

Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
 

jremaly@mdedge.com

The Food and Drug Administration has approved Valtoco (diazepam nasal) for the acute treatment of seizure clusters in patients with epilepsy aged 6 years and older.

The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.

Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.

The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.

Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
 

jremaly@mdedge.com

ATLANTA – Dutch investigators at the annual meeting of the American College of Rheumatology made a good case for 6 weeks of low-dose prednisolone to help people with hand osteoarthritis get over a particularly bad spell.

M. Alexander Otto/MDedge News

A total of 42 patients randomized to prednisolone 10 mg/day fell a mean of 21.5 mm at 6 weeks from a baseline visual analog hand pain score of 54 mm (out of a possible 100 mm), versus a drop of 5.2 mm from a baseline score of 53 mm among 46 randomized to placebo; the mean group difference was 16.5 mm. Patients taking prednisolone did better on function, quality of life, and physician global assessments, too.

“This trial provides evidence that local inflammation is a suitable target for drug treatment in hand OA. We think this study provides clinicians with a short-term treatment option for patients who have a flare of their disease,” said lead investigator Féline Kroon, MD, a rheumatologist at Leiden (the Netherlands) University Medical Center.

“The large beneficial effect size exceeded that of all available therapeutic options for hand osteoarthritis,” including NSAIDs, she and her team noted in the study write-up, which was published to coincide with the meeting (Lancet. 2019 Nov 30;394[10213]:1993-2001).

Many physicians already use short-course prednisolone for hand OA, but there was no clinical evidence that it helped until now. The study also adds weight to the idea that OA has an inflammatory component – an idea that has been building for a while, Dr. Kroon said.

Leiden investigators and others have previously shown that synovial inflammation is often present in hand OA and a main determinant of pain and radiographic progression.

The 92 patients in the Low-Dose Prednisolone in Patients with Painful Hand Osteoarthritis (HOPE) trial had to have at least four interphalangeal joints (IPJs) with osteoarthritic nodes, at least one IPJ with soft swelling or erythema, and at least one with a positive power Doppler signal or grade 2 or higher synovitis on ultrasound. They also had to have flared at least 20 mm on the pain scale with NSAID washout.

There were more responders in the prednisolone group at 6 weeks (72% versus 33%), and significantly greater improvement in synovial thickening. There was no difference in power Doppler score or synovitis score per joint on MRI, but bone marrow lesions appeared less severe with prednisolone.

All the between-group differences disappeared when prednisolone was tapered after 6 weeks.

Four patients discontinued the study because of an adverse event: a myocardial infarction in the prednisolone group, and, in the control arm, a bowel surgery, an infected leg hematoma, and a case of Lyme arthritis of the knee. Adverse events were otherwise mild and similar in both arms.

The mean age in the study was 64 years, and 79% of the subjects were women. Exclusion criteria included chronic inflammatory rheumatic diseases, psoriasis, use of immune-modulating drugs within 90 days of baseline, and predominantly thumb base pain instead of finger pain.

The approach “is for short course. Long-term steroids can have important side effects, like osteoporosis. We do not think this study should be used to encourage prolonged prescribing of glucocorticoids in patients with hand OA,” Dr. Kroon said.

Two previous trials of glucocorticoids for hand OA were inconclusive. A dose of prednisone 5 mg/day for 4 weeks did not separate from placebo in one, and the second showed pain improvements with a combination of prednisolone and dipyridamole versus placebo, but with more adverse events, particularly dipyridamole headaches.

The work was funded by the Dutch Arthritis Society. Dr. Kroon did not have any disclosures.

aotto@mdedge.com

SOURCE: Kroon F et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1760.

ATLANTA – Dutch investigators at the annual meeting of the American College of Rheumatology made a good case for 6 weeks of low-dose prednisolone to help people with hand osteoarthritis get over a particularly bad spell.

M. Alexander Otto/MDedge News

A total of 42 patients randomized to prednisolone 10 mg/day fell a mean of 21.5 mm at 6 weeks from a baseline visual analog hand pain score of 54 mm (out of a possible 100 mm), versus a drop of 5.2 mm from a baseline score of 53 mm among 46 randomized to placebo; the mean group difference was 16.5 mm. Patients taking prednisolone did better on function, quality of life, and physician global assessments, too.

“This trial provides evidence that local inflammation is a suitable target for drug treatment in hand OA. We think this study provides clinicians with a short-term treatment option for patients who have a flare of their disease,” said lead investigator Féline Kroon, MD, a rheumatologist at Leiden (the Netherlands) University Medical Center.

“The large beneficial effect size exceeded that of all available therapeutic options for hand osteoarthritis,” including NSAIDs, she and her team noted in the study write-up, which was published to coincide with the meeting (Lancet. 2019 Nov 30;394[10213]:1993-2001).

Many physicians already use short-course prednisolone for hand OA, but there was no clinical evidence that it helped until now. The study also adds weight to the idea that OA has an inflammatory component – an idea that has been building for a while, Dr. Kroon said.

Leiden investigators and others have previously shown that synovial inflammation is often present in hand OA and a main determinant of pain and radiographic progression.

The 92 patients in the Low-Dose Prednisolone in Patients with Painful Hand Osteoarthritis (HOPE) trial had to have at least four interphalangeal joints (IPJs) with osteoarthritic nodes, at least one IPJ with soft swelling or erythema, and at least one with a positive power Doppler signal or grade 2 or higher synovitis on ultrasound. They also had to have flared at least 20 mm on the pain scale with NSAID washout.

There were more responders in the prednisolone group at 6 weeks (72% versus 33%), and significantly greater improvement in synovial thickening. There was no difference in power Doppler score or synovitis score per joint on MRI, but bone marrow lesions appeared less severe with prednisolone.

All the between-group differences disappeared when prednisolone was tapered after 6 weeks.

Four patients discontinued the study because of an adverse event: a myocardial infarction in the prednisolone group, and, in the control arm, a bowel surgery, an infected leg hematoma, and a case of Lyme arthritis of the knee. Adverse events were otherwise mild and similar in both arms.

The mean age in the study was 64 years, and 79% of the subjects were women. Exclusion criteria included chronic inflammatory rheumatic diseases, psoriasis, use of immune-modulating drugs within 90 days of baseline, and predominantly thumb base pain instead of finger pain.

The approach “is for short course. Long-term steroids can have important side effects, like osteoporosis. We do not think this study should be used to encourage prolonged prescribing of glucocorticoids in patients with hand OA,” Dr. Kroon said.

Two previous trials of glucocorticoids for hand OA were inconclusive. A dose of prednisone 5 mg/day for 4 weeks did not separate from placebo in one, and the second showed pain improvements with a combination of prednisolone and dipyridamole versus placebo, but with more adverse events, particularly dipyridamole headaches.

The work was funded by the Dutch Arthritis Society. Dr. Kroon did not have any disclosures.

aotto@mdedge.com

SOURCE: Kroon F et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1760.

ATLANTA – Dutch investigators at the annual meeting of the American College of Rheumatology made a good case for 6 weeks of low-dose prednisolone to help people with hand osteoarthritis get over a particularly bad spell.

M. Alexander Otto/MDedge News

A total of 42 patients randomized to prednisolone 10 mg/day fell a mean of 21.5 mm at 6 weeks from a baseline visual analog hand pain score of 54 mm (out of a possible 100 mm), versus a drop of 5.2 mm from a baseline score of 53 mm among 46 randomized to placebo; the mean group difference was 16.5 mm. Patients taking prednisolone did better on function, quality of life, and physician global assessments, too.

“This trial provides evidence that local inflammation is a suitable target for drug treatment in hand OA. We think this study provides clinicians with a short-term treatment option for patients who have a flare of their disease,” said lead investigator Féline Kroon, MD, a rheumatologist at Leiden (the Netherlands) University Medical Center.

“The large beneficial effect size exceeded that of all available therapeutic options for hand osteoarthritis,” including NSAIDs, she and her team noted in the study write-up, which was published to coincide with the meeting (Lancet. 2019 Nov 30;394[10213]:1993-2001).

Many physicians already use short-course prednisolone for hand OA, but there was no clinical evidence that it helped until now. The study also adds weight to the idea that OA has an inflammatory component – an idea that has been building for a while, Dr. Kroon said.

Leiden investigators and others have previously shown that synovial inflammation is often present in hand OA and a main determinant of pain and radiographic progression.

The 92 patients in the Low-Dose Prednisolone in Patients with Painful Hand Osteoarthritis (HOPE) trial had to have at least four interphalangeal joints (IPJs) with osteoarthritic nodes, at least one IPJ with soft swelling or erythema, and at least one with a positive power Doppler signal or grade 2 or higher synovitis on ultrasound. They also had to have flared at least 20 mm on the pain scale with NSAID washout.

There were more responders in the prednisolone group at 6 weeks (72% versus 33%), and significantly greater improvement in synovial thickening. There was no difference in power Doppler score or synovitis score per joint on MRI, but bone marrow lesions appeared less severe with prednisolone.

All the between-group differences disappeared when prednisolone was tapered after 6 weeks.

Four patients discontinued the study because of an adverse event: a myocardial infarction in the prednisolone group, and, in the control arm, a bowel surgery, an infected leg hematoma, and a case of Lyme arthritis of the knee. Adverse events were otherwise mild and similar in both arms.

The mean age in the study was 64 years, and 79% of the subjects were women. Exclusion criteria included chronic inflammatory rheumatic diseases, psoriasis, use of immune-modulating drugs within 90 days of baseline, and predominantly thumb base pain instead of finger pain.

The approach “is for short course. Long-term steroids can have important side effects, like osteoporosis. We do not think this study should be used to encourage prolonged prescribing of glucocorticoids in patients with hand OA,” Dr. Kroon said.

Two previous trials of glucocorticoids for hand OA were inconclusive. A dose of prednisone 5 mg/day for 4 weeks did not separate from placebo in one, and the second showed pain improvements with a combination of prednisolone and dipyridamole versus placebo, but with more adverse events, particularly dipyridamole headaches.

The work was funded by the Dutch Arthritis Society. Dr. Kroon did not have any disclosures.

aotto@mdedge.com

SOURCE: Kroon F et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1760.

The American College of Physicians has released new clinical guidelines providing practical recommendations for testosterone therapy in adult men with age-related low testosterone.

The evidence-based recommendations target all clinicians and were published online January 6, 2020, in Annals of Internal Medicine, highlighting data from a systematic review of evidence on the efficacy and safety of testosterone treatment in adult men with age-related low testosterone.

Serum testosterone levels drop as men age, starting in their mid-30s, and approximately 20% of American men older than 60 years have low testosterone.

However, no widely accepted testosterone threshold level exists that represents a measure below which symptoms of androgen deficiency and adverse health outcomes occur.

In addition, the role of testosterone therapy in managing this patient population is controversial.

“The purpose of this American College of Physicians guideline is to present recommendations based on the best available evidence on the benefits, harms, and costs of testosterone treatment in adult men with age-related low testosterone,” write Amir Qaseem, MD, PhD, MHA, from the American College of Physicians, Philadelphia, and colleagues.

“This guideline does not address screening or diagnosis of hypogonadism or monitoring of testosterone levels,” the authors note.

In particular, the recommendations suggest that clinicians should initiate testosterone treatment in these patients only to help them improve their sexual function.

According to the authors, moderate-certainty evidence from seven trials involving testosterone treatment in adult men with age-related low testosterone showed a small improvement in global sexual function, whereas low-certainty evidence from seven trials showed a small improvement in erectile function.

By contrast, the guideline emphasizes that clinicians should avoid prescribing testosterone treatment for any other concern in this population. Available evidence demonstrates little to no improvement in physical function, depressive symptoms, energy and vitality, or cognition among these men after receiving testosterone treatment, the authors stress.

ACP recommends that clinicians should reassess men’s symptoms within 12 months of testosterone treatment initiation, with regular reevaluations during subsequent follow up. Clinicians should discontinue treatment in men if sexual function fails to improve.

The guideline also recommends using intramuscular formulations of testosterone treatment for this patient population instead of transdermal ones, because intramuscular formulations cost less and have similar clinical effectiveness and harms.

“The annual cost in 2016 per beneficiary for TRT [testosterone replacement therapy] was $2,135.32 for the transdermal and $156.24 for the intramuscular formulation, according to paid pharmaceutical claims provided in the 2016 Medicare Part D Drug Claims data,” the authors write.

In an accompanying editorial, E. Victor Adlin, MD, of Temple University, Philadelphia, notes that these new ACP guidelines mostly mirror those recently proposed by both the Endocrine Society and the American Urological Association.

However, he predicts that many clinicians will question the ACP’s recommendation to favor use of intramuscular over transdermal formulations of testosterone.

Although Dr. Adlin acknowledges the lower cost of intramuscular preparations as a major consideration, he explains that “the need for an intramuscular injection every 1-4 weeks is a potential barrier to adherence, and some patients require visits to a health care facility for the injections, which may add to the expense.”

Fluctuating blood testosterone levels after each injection may also result in irregular symptom relief and difficulty achieving the desired blood level, he adds. “Individual preference may vary widely in the choice of testosterone therapy.”

Overall, Dr. Adlin stresses that a patient-clinician discussion should serve as the foundation for starting testosterone therapy in men with age-related low testosterone, with the patient playing a central role in treatment decision making.

This guideline was developed with financial support from the American College of Physicians’ operating budget. Study author Carrie Horwitch reports serving as a fiduciary officer for the Washington State Medical Association. Jennifer S. Lin, a member of the ACP Clinical Guidelines Committee, reports being an employee of Kaiser Permanente. Robert McLean, another member of the committee, reports being an employee of Northeast Medical Group. The remaining authors and the editorialist have disclosed no relevant financial relationships.

A version of this story appeared on Medscape.com.

The American College of Physicians has released new clinical guidelines providing practical recommendations for testosterone therapy in adult men with age-related low testosterone.

The evidence-based recommendations target all clinicians and were published online January 6, 2020, in Annals of Internal Medicine, highlighting data from a systematic review of evidence on the efficacy and safety of testosterone treatment in adult men with age-related low testosterone.

Serum testosterone levels drop as men age, starting in their mid-30s, and approximately 20% of American men older than 60 years have low testosterone.

However, no widely accepted testosterone threshold level exists that represents a measure below which symptoms of androgen deficiency and adverse health outcomes occur.

In addition, the role of testosterone therapy in managing this patient population is controversial.

“The purpose of this American College of Physicians guideline is to present recommendations based on the best available evidence on the benefits, harms, and costs of testosterone treatment in adult men with age-related low testosterone,” write Amir Qaseem, MD, PhD, MHA, from the American College of Physicians, Philadelphia, and colleagues.

“This guideline does not address screening or diagnosis of hypogonadism or monitoring of testosterone levels,” the authors note.

In particular, the recommendations suggest that clinicians should initiate testosterone treatment in these patients only to help them improve their sexual function.

According to the authors, moderate-certainty evidence from seven trials involving testosterone treatment in adult men with age-related low testosterone showed a small improvement in global sexual function, whereas low-certainty evidence from seven trials showed a small improvement in erectile function.

By contrast, the guideline emphasizes that clinicians should avoid prescribing testosterone treatment for any other concern in this population. Available evidence demonstrates little to no improvement in physical function, depressive symptoms, energy and vitality, or cognition among these men after receiving testosterone treatment, the authors stress.

ACP recommends that clinicians should reassess men’s symptoms within 12 months of testosterone treatment initiation, with regular reevaluations during subsequent follow up. Clinicians should discontinue treatment in men if sexual function fails to improve.

The guideline also recommends using intramuscular formulations of testosterone treatment for this patient population instead of transdermal ones, because intramuscular formulations cost less and have similar clinical effectiveness and harms.

“The annual cost in 2016 per beneficiary for TRT [testosterone replacement therapy] was $2,135.32 for the transdermal and $156.24 for the intramuscular formulation, according to paid pharmaceutical claims provided in the 2016 Medicare Part D Drug Claims data,” the authors write.

In an accompanying editorial, E. Victor Adlin, MD, of Temple University, Philadelphia, notes that these new ACP guidelines mostly mirror those recently proposed by both the Endocrine Society and the American Urological Association.

However, he predicts that many clinicians will question the ACP’s recommendation to favor use of intramuscular over transdermal formulations of testosterone.

Although Dr. Adlin acknowledges the lower cost of intramuscular preparations as a major consideration, he explains that “the need for an intramuscular injection every 1-4 weeks is a potential barrier to adherence, and some patients require visits to a health care facility for the injections, which may add to the expense.”

Fluctuating blood testosterone levels after each injection may also result in irregular symptom relief and difficulty achieving the desired blood level, he adds. “Individual preference may vary widely in the choice of testosterone therapy.”

Overall, Dr. Adlin stresses that a patient-clinician discussion should serve as the foundation for starting testosterone therapy in men with age-related low testosterone, with the patient playing a central role in treatment decision making.

This guideline was developed with financial support from the American College of Physicians’ operating budget. Study author Carrie Horwitch reports serving as a fiduciary officer for the Washington State Medical Association. Jennifer S. Lin, a member of the ACP Clinical Guidelines Committee, reports being an employee of Kaiser Permanente. Robert McLean, another member of the committee, reports being an employee of Northeast Medical Group. The remaining authors and the editorialist have disclosed no relevant financial relationships.

A version of this story appeared on Medscape.com.

The American College of Physicians has released new clinical guidelines providing practical recommendations for testosterone therapy in adult men with age-related low testosterone.

The evidence-based recommendations target all clinicians and were published online January 6, 2020, in Annals of Internal Medicine, highlighting data from a systematic review of evidence on the efficacy and safety of testosterone treatment in adult men with age-related low testosterone.

Serum testosterone levels drop as men age, starting in their mid-30s, and approximately 20% of American men older than 60 years have low testosterone.

However, no widely accepted testosterone threshold level exists that represents a measure below which symptoms of androgen deficiency and adverse health outcomes occur.

In addition, the role of testosterone therapy in managing this patient population is controversial.

“The purpose of this American College of Physicians guideline is to present recommendations based on the best available evidence on the benefits, harms, and costs of testosterone treatment in adult men with age-related low testosterone,” write Amir Qaseem, MD, PhD, MHA, from the American College of Physicians, Philadelphia, and colleagues.

“This guideline does not address screening or diagnosis of hypogonadism or monitoring of testosterone levels,” the authors note.

In particular, the recommendations suggest that clinicians should initiate testosterone treatment in these patients only to help them improve their sexual function.

According to the authors, moderate-certainty evidence from seven trials involving testosterone treatment in adult men with age-related low testosterone showed a small improvement in global sexual function, whereas low-certainty evidence from seven trials showed a small improvement in erectile function.

By contrast, the guideline emphasizes that clinicians should avoid prescribing testosterone treatment for any other concern in this population. Available evidence demonstrates little to no improvement in physical function, depressive symptoms, energy and vitality, or cognition among these men after receiving testosterone treatment, the authors stress.

ACP recommends that clinicians should reassess men’s symptoms within 12 months of testosterone treatment initiation, with regular reevaluations during subsequent follow up. Clinicians should discontinue treatment in men if sexual function fails to improve.

The guideline also recommends using intramuscular formulations of testosterone treatment for this patient population instead of transdermal ones, because intramuscular formulations cost less and have similar clinical effectiveness and harms.

“The annual cost in 2016 per beneficiary for TRT [testosterone replacement therapy] was $2,135.32 for the transdermal and $156.24 for the intramuscular formulation, according to paid pharmaceutical claims provided in the 2016 Medicare Part D Drug Claims data,” the authors write.

In an accompanying editorial, E. Victor Adlin, MD, of Temple University, Philadelphia, notes that these new ACP guidelines mostly mirror those recently proposed by both the Endocrine Society and the American Urological Association.

However, he predicts that many clinicians will question the ACP’s recommendation to favor use of intramuscular over transdermal formulations of testosterone.

Although Dr. Adlin acknowledges the lower cost of intramuscular preparations as a major consideration, he explains that “the need for an intramuscular injection every 1-4 weeks is a potential barrier to adherence, and some patients require visits to a health care facility for the injections, which may add to the expense.”

Fluctuating blood testosterone levels after each injection may also result in irregular symptom relief and difficulty achieving the desired blood level, he adds. “Individual preference may vary widely in the choice of testosterone therapy.”

Overall, Dr. Adlin stresses that a patient-clinician discussion should serve as the foundation for starting testosterone therapy in men with age-related low testosterone, with the patient playing a central role in treatment decision making.

This guideline was developed with financial support from the American College of Physicians’ operating budget. Study author Carrie Horwitch reports serving as a fiduciary officer for the Washington State Medical Association. Jennifer S. Lin, a member of the ACP Clinical Guidelines Committee, reports being an employee of Kaiser Permanente. Robert McLean, another member of the committee, reports being an employee of Northeast Medical Group. The remaining authors and the editorialist have disclosed no relevant financial relationships.

A version of this story appeared on Medscape.com.

SAN ANTONIO – Eluxadoline proved highly effective for alleviation of a multitude of symptoms of irritable bowel syndrome with diarrhea in patients for whom loperamide was ineffective in the phase 4 RELIEF trial, Darren M. Brenner, MD, reported at the annual meeting of the American College of Gastroenterology.

“From the totality of the clinical trials data we have now, we believe that eluxadoline can be effective both in patients who are naive to other treatments and in patients who have failed loperamide therapy,” concluded Dr. Brenner, a gastroenterologist at Northwestern University, Chicago.

Eluxadoline (Viberzi) is a novel mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist approved by the Food and Drug Administration for treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. In contrast, loperamide, a mu-opioid receptor agonist, is not approved for that indication. Yet loperamide is widely prescribed for this purpose, despite the fact that both the Canadian Association of Gastroenterology and the ACG now recommend against this practice.

“There is a lack of conclusive evidence to support the use of loperamide for the relief of global IBS-D symptoms. It works on the stool symptoms – stool frequency and texture – but has never been shown to be beneficial for the abdominal pain symptoms or discomfort or bloating. That being said, as practitioners we continue to see loperamide used as a first-line agent,” Dr. Brenner noted.

RELIEF was a multicenter, prospective, double-blind study which randomized 346 patients with moderate to severe IBS-D to eluxadoline at 100 mg twice daily or placebo for 12 weeks. All participants were required to have an intact gallbladder as per the drug’s labeling guidance, and all had a self-reported recent inadequate response to loperamide.

The primary composite endpoint in the RELIEF trial was a 40% or greater improvement from baseline in the 11-point Daily Worst Abdominal Pain score plus a Bristol Stool Form score below 5 on the same day for at least 50% of study days. At baseline, participants had an average Worst Abdominal Pain score of 6.2 on the 0-10 scale and a Bristol score of 6.2. The primary endpoint was achieved at week 12 in 23% of the eluxadoline group, significantly better than the 10% rate in controls. The eluxadoline group also showed significantly greater improvement on the many secondary endpoints having to do with urgency-free days, stool consistency, bowel movement frequency, abdominal discomfort, bloating, and the experience of adequate relief of symptoms.

The safety profile of eluxadoline mirrored that of placebo, with no serious adverse events recorded in either study arm and a 2.9% study discontinuation rate because of treatment-emergent adverse events in the eluxadoline group. Asked why he thinks eluxadoline was effective in improving the full range of IBS-D symptoms when loperamide wasn’t, even though both drugs are mu-opioid receptor agonists, Dr. Brenner replied, “The problem is mu receptors line the entire GI tract, so you can actually push somebody from diarrhea to opioid-induced constipation – and that’s not the goal. What delta does is alleviate some of the adverse events by binding to the receptor, which results in increased transit time, reduced secretion, and increased absorption. Delta brings things back towards the center. We also believe antagonism of delta potentiates analgesic effects at the mu receptor, improves the pain component, gut symptoms, and stool symptoms.”

Dr. Brenner reported serving as a consultant to and member of a speaker’s bureau for Allergan, which markets eluxadoline and sponsored the RELIEF trial.

bjancin@mdedge.com

SAN ANTONIO – Eluxadoline proved highly effective for alleviation of a multitude of symptoms of irritable bowel syndrome with diarrhea in patients for whom loperamide was ineffective in the phase 4 RELIEF trial, Darren M. Brenner, MD, reported at the annual meeting of the American College of Gastroenterology.

“From the totality of the clinical trials data we have now, we believe that eluxadoline can be effective both in patients who are naive to other treatments and in patients who have failed loperamide therapy,” concluded Dr. Brenner, a gastroenterologist at Northwestern University, Chicago.

Eluxadoline (Viberzi) is a novel mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist approved by the Food and Drug Administration for treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. In contrast, loperamide, a mu-opioid receptor agonist, is not approved for that indication. Yet loperamide is widely prescribed for this purpose, despite the fact that both the Canadian Association of Gastroenterology and the ACG now recommend against this practice.

“There is a lack of conclusive evidence to support the use of loperamide for the relief of global IBS-D symptoms. It works on the stool symptoms – stool frequency and texture – but has never been shown to be beneficial for the abdominal pain symptoms or discomfort or bloating. That being said, as practitioners we continue to see loperamide used as a first-line agent,” Dr. Brenner noted.

RELIEF was a multicenter, prospective, double-blind study which randomized 346 patients with moderate to severe IBS-D to eluxadoline at 100 mg twice daily or placebo for 12 weeks. All participants were required to have an intact gallbladder as per the drug’s labeling guidance, and all had a self-reported recent inadequate response to loperamide.

The primary composite endpoint in the RELIEF trial was a 40% or greater improvement from baseline in the 11-point Daily Worst Abdominal Pain score plus a Bristol Stool Form score below 5 on the same day for at least 50% of study days. At baseline, participants had an average Worst Abdominal Pain score of 6.2 on the 0-10 scale and a Bristol score of 6.2. The primary endpoint was achieved at week 12 in 23% of the eluxadoline group, significantly better than the 10% rate in controls. The eluxadoline group also showed significantly greater improvement on the many secondary endpoints having to do with urgency-free days, stool consistency, bowel movement frequency, abdominal discomfort, bloating, and the experience of adequate relief of symptoms.

The safety profile of eluxadoline mirrored that of placebo, with no serious adverse events recorded in either study arm and a 2.9% study discontinuation rate because of treatment-emergent adverse events in the eluxadoline group. Asked why he thinks eluxadoline was effective in improving the full range of IBS-D symptoms when loperamide wasn’t, even though both drugs are mu-opioid receptor agonists, Dr. Brenner replied, “The problem is mu receptors line the entire GI tract, so you can actually push somebody from diarrhea to opioid-induced constipation – and that’s not the goal. What delta does is alleviate some of the adverse events by binding to the receptor, which results in increased transit time, reduced secretion, and increased absorption. Delta brings things back towards the center. We also believe antagonism of delta potentiates analgesic effects at the mu receptor, improves the pain component, gut symptoms, and stool symptoms.”

Dr. Brenner reported serving as a consultant to and member of a speaker’s bureau for Allergan, which markets eluxadoline and sponsored the RELIEF trial.

bjancin@mdedge.com

SAN ANTONIO – Eluxadoline proved highly effective for alleviation of a multitude of symptoms of irritable bowel syndrome with diarrhea in patients for whom loperamide was ineffective in the phase 4 RELIEF trial, Darren M. Brenner, MD, reported at the annual meeting of the American College of Gastroenterology.

“From the totality of the clinical trials data we have now, we believe that eluxadoline can be effective both in patients who are naive to other treatments and in patients who have failed loperamide therapy,” concluded Dr. Brenner, a gastroenterologist at Northwestern University, Chicago.

Eluxadoline (Viberzi) is a novel mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist approved by the Food and Drug Administration for treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. In contrast, loperamide, a mu-opioid receptor agonist, is not approved for that indication. Yet loperamide is widely prescribed for this purpose, despite the fact that both the Canadian Association of Gastroenterology and the ACG now recommend against this practice.

“There is a lack of conclusive evidence to support the use of loperamide for the relief of global IBS-D symptoms. It works on the stool symptoms – stool frequency and texture – but has never been shown to be beneficial for the abdominal pain symptoms or discomfort or bloating. That being said, as practitioners we continue to see loperamide used as a first-line agent,” Dr. Brenner noted.

RELIEF was a multicenter, prospective, double-blind study which randomized 346 patients with moderate to severe IBS-D to eluxadoline at 100 mg twice daily or placebo for 12 weeks. All participants were required to have an intact gallbladder as per the drug’s labeling guidance, and all had a self-reported recent inadequate response to loperamide.

The primary composite endpoint in the RELIEF trial was a 40% or greater improvement from baseline in the 11-point Daily Worst Abdominal Pain score plus a Bristol Stool Form score below 5 on the same day for at least 50% of study days. At baseline, participants had an average Worst Abdominal Pain score of 6.2 on the 0-10 scale and a Bristol score of 6.2. The primary endpoint was achieved at week 12 in 23% of the eluxadoline group, significantly better than the 10% rate in controls. The eluxadoline group also showed significantly greater improvement on the many secondary endpoints having to do with urgency-free days, stool consistency, bowel movement frequency, abdominal discomfort, bloating, and the experience of adequate relief of symptoms.

The safety profile of eluxadoline mirrored that of placebo, with no serious adverse events recorded in either study arm and a 2.9% study discontinuation rate because of treatment-emergent adverse events in the eluxadoline group. Asked why he thinks eluxadoline was effective in improving the full range of IBS-D symptoms when loperamide wasn’t, even though both drugs are mu-opioid receptor agonists, Dr. Brenner replied, “The problem is mu receptors line the entire GI tract, so you can actually push somebody from diarrhea to opioid-induced constipation – and that’s not the goal. What delta does is alleviate some of the adverse events by binding to the receptor, which results in increased transit time, reduced secretion, and increased absorption. Delta brings things back towards the center. We also believe antagonism of delta potentiates analgesic effects at the mu receptor, improves the pain component, gut symptoms, and stool symptoms.”

Dr. Brenner reported serving as a consultant to and member of a speaker’s bureau for Allergan, which markets eluxadoline and sponsored the RELIEF trial.

bjancin@mdedge.com

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

jensmith@mdedge.com

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

jensmith@mdedge.com

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

jensmith@mdedge.com

SOURCE: Hill L et al. ASH 2019. Abstract 199.