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Atopic dermatitis severity reduced by topical microbiome treatment
The Beginning Assessment of Cutaneous Treatment Efficacy of Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II study, an open-label phase I/II trial, first looked at the therapeutic use of R. mucosa in 10 adults aged 18 years or older. Three sucrose mixtures with increasing doses of live R. mucosa bacteria were topically applied to two body areas – the antecubital fossae and a body surface of their choice – twice per week for 2 weeks per dose. At 6 weeks, the patients stopped using the mixtures and followed a 4-week washout phase.
Treatment was found to reduce mean antecubital SCORAD (SCORing Atopic Dermatitis) scores by 59.8%. Reduction in pruritus was even more pronounced, with a mean decrease of 78.5%. Treating the hands did not improve disease severity, even in patients whose symptoms improved in other body areas. One explanation may be the increased exposure of the hands to topical antimicrobials and environmental exposures, the researchers noted.
With the success in the adult cohort, the researchers enrolled five children aged 7-17 years in the study. These patients were treated twice weekly for 16 weeks. The pediatric patients experienced a mean decrease of 70.3% in their SCORAD scores. The mean decrease in pruritis was 78.8%.
All adults who responded continued to report improved symptoms after the washout period. The pediatric patients are now being evaluated in a washout period.
Four patients did not respond; three of them had a family history of AD persisting into adulthood. “The association between these complex medical histories and the lack of clinical response suggests that differences in heritable host and/or microbial factors may impact treatment responses,” wrote Ian A. Myles, MD, and his colleagues.
“Overall, our findings suggest the safety of topical R. mucosa therapy and justify continuation of our ongoing trial to assess safety and activity in a pediatric cohort of patients with AD. These studies will additionally assess changes in host serum markers, skin metabolomics, and the skin microbiota by culture and genomic methods.”
The researchers noted that expanding to the pediatric population will deepen understanding of topical microbiome transplantation and lay the foundation for placebo-controlled trials to assess efficacy.
This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases and the National Institutes of Health. The researchers had no disclosures.
SOURCE: Myles IA et al. JCI Insight. 2018 May 3. doi: 10.1172/jci.insight.120608.
The Beginning Assessment of Cutaneous Treatment Efficacy of Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II study, an open-label phase I/II trial, first looked at the therapeutic use of R. mucosa in 10 adults aged 18 years or older. Three sucrose mixtures with increasing doses of live R. mucosa bacteria were topically applied to two body areas – the antecubital fossae and a body surface of their choice – twice per week for 2 weeks per dose. At 6 weeks, the patients stopped using the mixtures and followed a 4-week washout phase.
Treatment was found to reduce mean antecubital SCORAD (SCORing Atopic Dermatitis) scores by 59.8%. Reduction in pruritus was even more pronounced, with a mean decrease of 78.5%. Treating the hands did not improve disease severity, even in patients whose symptoms improved in other body areas. One explanation may be the increased exposure of the hands to topical antimicrobials and environmental exposures, the researchers noted.
With the success in the adult cohort, the researchers enrolled five children aged 7-17 years in the study. These patients were treated twice weekly for 16 weeks. The pediatric patients experienced a mean decrease of 70.3% in their SCORAD scores. The mean decrease in pruritis was 78.8%.
All adults who responded continued to report improved symptoms after the washout period. The pediatric patients are now being evaluated in a washout period.
Four patients did not respond; three of them had a family history of AD persisting into adulthood. “The association between these complex medical histories and the lack of clinical response suggests that differences in heritable host and/or microbial factors may impact treatment responses,” wrote Ian A. Myles, MD, and his colleagues.
“Overall, our findings suggest the safety of topical R. mucosa therapy and justify continuation of our ongoing trial to assess safety and activity in a pediatric cohort of patients with AD. These studies will additionally assess changes in host serum markers, skin metabolomics, and the skin microbiota by culture and genomic methods.”
The researchers noted that expanding to the pediatric population will deepen understanding of topical microbiome transplantation and lay the foundation for placebo-controlled trials to assess efficacy.
This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases and the National Institutes of Health. The researchers had no disclosures.
SOURCE: Myles IA et al. JCI Insight. 2018 May 3. doi: 10.1172/jci.insight.120608.
The Beginning Assessment of Cutaneous Treatment Efficacy of Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II study, an open-label phase I/II trial, first looked at the therapeutic use of R. mucosa in 10 adults aged 18 years or older. Three sucrose mixtures with increasing doses of live R. mucosa bacteria were topically applied to two body areas – the antecubital fossae and a body surface of their choice – twice per week for 2 weeks per dose. At 6 weeks, the patients stopped using the mixtures and followed a 4-week washout phase.
Treatment was found to reduce mean antecubital SCORAD (SCORing Atopic Dermatitis) scores by 59.8%. Reduction in pruritus was even more pronounced, with a mean decrease of 78.5%. Treating the hands did not improve disease severity, even in patients whose symptoms improved in other body areas. One explanation may be the increased exposure of the hands to topical antimicrobials and environmental exposures, the researchers noted.
With the success in the adult cohort, the researchers enrolled five children aged 7-17 years in the study. These patients were treated twice weekly for 16 weeks. The pediatric patients experienced a mean decrease of 70.3% in their SCORAD scores. The mean decrease in pruritis was 78.8%.
All adults who responded continued to report improved symptoms after the washout period. The pediatric patients are now being evaluated in a washout period.
Four patients did not respond; three of them had a family history of AD persisting into adulthood. “The association between these complex medical histories and the lack of clinical response suggests that differences in heritable host and/or microbial factors may impact treatment responses,” wrote Ian A. Myles, MD, and his colleagues.
“Overall, our findings suggest the safety of topical R. mucosa therapy and justify continuation of our ongoing trial to assess safety and activity in a pediatric cohort of patients with AD. These studies will additionally assess changes in host serum markers, skin metabolomics, and the skin microbiota by culture and genomic methods.”
The researchers noted that expanding to the pediatric population will deepen understanding of topical microbiome transplantation and lay the foundation for placebo-controlled trials to assess efficacy.
This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases and the National Institutes of Health. The researchers had no disclosures.
SOURCE: Myles IA et al. JCI Insight. 2018 May 3. doi: 10.1172/jci.insight.120608.
FROM JCI INSIGHT
Key clinical point: Roseomonas mucosa reduces disease severity.
Major finding: There were reductions in SCORAD scores of 78.5% and 70.3% in the adult and pediatric cohorts, respectively.
Study details: Case study of 10 adult and 5 pediatric patients with atopic dermatitis.
Disclosures: No relevant financial disclosures were reported.
Source: Myles IA et al. JCI Insight. 2018 May 3. doi: 10.1172/jci.insight.120608.
Hyperpigmentation, paraparesis are signs of vitamin B12 deficiency
Vitamin B12 deficiency can cause skin hyperpigmentation and partial paralysis, but these issues can be easily treated early on with vitamin B12 shots, said Ashish Agarwal, MD, and his colleagues at the Postgraduate Institute of Medical Education and Research in Chandigarh, India.
A 6-year-old boy, who had been previously healthy, presented with darkening of his hands and feet over a 4-month period. It also was noted that the skin on his palms and soles was thin and shiny. His walking gait had become abnormal in the previous 2 weeks; his legs were stiff when he walked, which caused him to fall and led to difficulty climbing stairs. The boy had no personal or family history of muscle issues or neurological issues. The boy’s personal history revealed that he ate a vegetarian diet.
A clinical diagnosis was made of megaloblastic anemia with subacute degeneration of the cord caused by vitamin B12 deficiency, a diagnosis not uncommon among vegetarians. The boy was started on daily intramuscular injections of B12 for 2 weeks, followed by weekly injections for a month. Monthly injections then were administered for the next 2 months. In the first few weeks, the hyperpigmentation began improving. At his 4-month follow-up, the boy was asymptomatic with reversal of the hyperpigmentation.
Dr. Agarwal and his associates concluded that skin darkening is an important clue toward underlying hematologic and neurologic manifestations of B12 deficiency.
SOURCE: Agarwal A et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.03.073.
Vitamin B12 deficiency can cause skin hyperpigmentation and partial paralysis, but these issues can be easily treated early on with vitamin B12 shots, said Ashish Agarwal, MD, and his colleagues at the Postgraduate Institute of Medical Education and Research in Chandigarh, India.
A 6-year-old boy, who had been previously healthy, presented with darkening of his hands and feet over a 4-month period. It also was noted that the skin on his palms and soles was thin and shiny. His walking gait had become abnormal in the previous 2 weeks; his legs were stiff when he walked, which caused him to fall and led to difficulty climbing stairs. The boy had no personal or family history of muscle issues or neurological issues. The boy’s personal history revealed that he ate a vegetarian diet.
A clinical diagnosis was made of megaloblastic anemia with subacute degeneration of the cord caused by vitamin B12 deficiency, a diagnosis not uncommon among vegetarians. The boy was started on daily intramuscular injections of B12 for 2 weeks, followed by weekly injections for a month. Monthly injections then were administered for the next 2 months. In the first few weeks, the hyperpigmentation began improving. At his 4-month follow-up, the boy was asymptomatic with reversal of the hyperpigmentation.
Dr. Agarwal and his associates concluded that skin darkening is an important clue toward underlying hematologic and neurologic manifestations of B12 deficiency.
SOURCE: Agarwal A et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.03.073.
Vitamin B12 deficiency can cause skin hyperpigmentation and partial paralysis, but these issues can be easily treated early on with vitamin B12 shots, said Ashish Agarwal, MD, and his colleagues at the Postgraduate Institute of Medical Education and Research in Chandigarh, India.
A 6-year-old boy, who had been previously healthy, presented with darkening of his hands and feet over a 4-month period. It also was noted that the skin on his palms and soles was thin and shiny. His walking gait had become abnormal in the previous 2 weeks; his legs were stiff when he walked, which caused him to fall and led to difficulty climbing stairs. The boy had no personal or family history of muscle issues or neurological issues. The boy’s personal history revealed that he ate a vegetarian diet.
A clinical diagnosis was made of megaloblastic anemia with subacute degeneration of the cord caused by vitamin B12 deficiency, a diagnosis not uncommon among vegetarians. The boy was started on daily intramuscular injections of B12 for 2 weeks, followed by weekly injections for a month. Monthly injections then were administered for the next 2 months. In the first few weeks, the hyperpigmentation began improving. At his 4-month follow-up, the boy was asymptomatic with reversal of the hyperpigmentation.
Dr. Agarwal and his associates concluded that skin darkening is an important clue toward underlying hematologic and neurologic manifestations of B12 deficiency.
SOURCE: Agarwal A et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.03.073.
FROM THE JOURNAL OF PEDIATRICS
FDA advisory committee recommends volanesorsen for rare triglyceride disorder
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
ilacy@mdedge.com
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
ilacy@mdedge.com
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
ilacy@mdedge.com
REPORTING FROM an fda advisory committee meeting
Emotional regulation training lowers risk of adolescents having sex
Emotional regulation (ER) skills training lowers the likelihood that young adolescents with mental health symptoms will have vaginal sex.
“The inclusion of ER training in a small-group behavioral intervention reduced sexual risk behaviors among seventh-graders with suspected mental health symptoms over a 2.5-year follow-up beyond that achieved with more traditional health education,” wrote Chistopher Houck, PhD, and his colleagues at Bradley Hasbro Children’s Research Center, Providence, R.I., in Pediatrics. “This was true across a range of behaviors, such as engaging in fewer condom-less sex acts, being less likely to have multiple partners, and being less likely to use substances before sex.”
Students in the study participated in one of two after school intervention programs, either ER or health promotion (HP). Both programs consisted of 12 twice-weekly, hour-long sessions composed of single-sex groups of 4-8 adolescents. Two follow-up sessions were provided for both groups at 6 and 12 months. Both interventions used identical techniques, such as interactive games, videos, group discussions, and workbook assignments. ER sessions focused more on recognizing feelings, strategies for reducing momentary emotional arousal, and sexual health topics. HP exclusively focused on health topics like sexual risk and substance abuse but did not include emotional education.
During the 30-month study, 63 in the ER group (31%) and 68 students in the HP group (39%) reported having vaginal sex for the first time. This equated to an adjusted hazard ratio that indicated a delay in vaginal sex in the ER group (0.61; 95% confidence interval,0.42-0.89). Overall, students in the ER group were much less likely to endorse risky sexual behaviors than did participants in the HP group: Students in the ER group were less likely to endorse any risky sexual behavior (adjusted odds ratio, 0.52; 95% CI, 0.32-0.84), to support having multiple partners within 6 months (aOR, 0.54; 95% CI, 0.30-0.99), and to support the use of drugs before sex (aOR, 0.42; 95% CI, 0.23-0.75). Students in the ER group also reported fewer condom-less sex acts, compared with students in the HP group (adjusted rate ratio, 0.36; 95% CI, 0.14-0.90).
According to Dr. Houck and his colleagues, this study had several limitations that are common to sexual risk studies. One limitation is the reliance on self-report data, which can be biased. Dr. Houck and his associates utilized computer-assisted self-interviews to minimize biases. Another, and potentially larger, limitation is that the study was powered to assess delay of vaginal sex. Part of the patient sample was not sexually experienced, which provided less power for comparisons to other sexual behaviors.
Dr. Houck and his colleagues also spoke to the potential that ER training has in reducing risky behaviors of adolescents, as well as the issues in implementing it.
“Because ER is a skill that could influence other adolescent risk behaviors, such as substance use, violence, and truancy, addressing ER during this sensitive period in adolescent development promises significant public health benefits,” they wrote. “The challenge is the scale-up and dissemination of ER interventions. Increasing the reach of programs in which health education is enhanced with emotion education may be an important step toward improving the lives of adolescents because they are prone to beginning risk behavior.”
Dr. Houck and his associates have no relevant financial disclosures. This study received funding from the National Institutes of Health and the Providence/Boston Center for AIDS Research.
SOURCE: Houck C et al. Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-2525.
The work of Houck et al. provides an important contribution in understanding strategies to reduce sexually transmitted infections (STIs) and HIV in adolescents by utilizing emotional regulation skills.
By helping young people understand their emotions and how that relates to behavior in the context of a sexual encounter, the after school intervention program helped teens regulate positive and negative emotions. Specifically, it utilized three strategies: get out, let it out, and think it out. Games and role playing gave teens a chance to practice these strategies in scenarios of varying risk.
Teenagers who underwent emotional regulation training, rather than simply being taught about adolescent health topics, fared much better in reducing the transition to vaginal sex over a 30-month period.
Carol Ford, MD, and her colleague James Jaccard, PhD, pointed out the superiority of the emotional training, compared with just sexual health information.
“Together, these findings reveal the importance of gearing more attention toward emotions and the regulation of emotions when developing interventions aimed at influencing adolescent sexual behavior,” they wrote. “Behavioral decision theory implicates the role of adolescent cognitions about engaging in sex, norms and peer pressure, and adolescent image prototypes surrounding sex.”
More broadly, Dr. Ford and Dr. Jaccard, believe that this research is the beginning to designing better interventions.
“As we come to understand the types of cognitions and emotions that dominate working memory in high-risk sexual situations, we can effectively design interventions that help shape cognitive and affective appraisals and how youth process those appraisals when making choices.”
Carol Ford, MD, is the chief of the Craig-Dalsimer Division of Adolescent Medicine at the Children’s Hospital of Philadelphia; she holds the Orton P. Jackson Endowed Chair in Adolescent Medicine. James Jaccard, PhD, is a professor of social work at New York University Silver School of Social Work. This is a summary of their commentary that accompanied the article by Houck et al. (Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-4143). They had no financial disclosures, and there was no external funding.
The work of Houck et al. provides an important contribution in understanding strategies to reduce sexually transmitted infections (STIs) and HIV in adolescents by utilizing emotional regulation skills.
By helping young people understand their emotions and how that relates to behavior in the context of a sexual encounter, the after school intervention program helped teens regulate positive and negative emotions. Specifically, it utilized three strategies: get out, let it out, and think it out. Games and role playing gave teens a chance to practice these strategies in scenarios of varying risk.
Teenagers who underwent emotional regulation training, rather than simply being taught about adolescent health topics, fared much better in reducing the transition to vaginal sex over a 30-month period.
Carol Ford, MD, and her colleague James Jaccard, PhD, pointed out the superiority of the emotional training, compared with just sexual health information.
“Together, these findings reveal the importance of gearing more attention toward emotions and the regulation of emotions when developing interventions aimed at influencing adolescent sexual behavior,” they wrote. “Behavioral decision theory implicates the role of adolescent cognitions about engaging in sex, norms and peer pressure, and adolescent image prototypes surrounding sex.”
More broadly, Dr. Ford and Dr. Jaccard, believe that this research is the beginning to designing better interventions.
“As we come to understand the types of cognitions and emotions that dominate working memory in high-risk sexual situations, we can effectively design interventions that help shape cognitive and affective appraisals and how youth process those appraisals when making choices.”
Carol Ford, MD, is the chief of the Craig-Dalsimer Division of Adolescent Medicine at the Children’s Hospital of Philadelphia; she holds the Orton P. Jackson Endowed Chair in Adolescent Medicine. James Jaccard, PhD, is a professor of social work at New York University Silver School of Social Work. This is a summary of their commentary that accompanied the article by Houck et al. (Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-4143). They had no financial disclosures, and there was no external funding.
The work of Houck et al. provides an important contribution in understanding strategies to reduce sexually transmitted infections (STIs) and HIV in adolescents by utilizing emotional regulation skills.
By helping young people understand their emotions and how that relates to behavior in the context of a sexual encounter, the after school intervention program helped teens regulate positive and negative emotions. Specifically, it utilized three strategies: get out, let it out, and think it out. Games and role playing gave teens a chance to practice these strategies in scenarios of varying risk.
Teenagers who underwent emotional regulation training, rather than simply being taught about adolescent health topics, fared much better in reducing the transition to vaginal sex over a 30-month period.
Carol Ford, MD, and her colleague James Jaccard, PhD, pointed out the superiority of the emotional training, compared with just sexual health information.
“Together, these findings reveal the importance of gearing more attention toward emotions and the regulation of emotions when developing interventions aimed at influencing adolescent sexual behavior,” they wrote. “Behavioral decision theory implicates the role of adolescent cognitions about engaging in sex, norms and peer pressure, and adolescent image prototypes surrounding sex.”
More broadly, Dr. Ford and Dr. Jaccard, believe that this research is the beginning to designing better interventions.
“As we come to understand the types of cognitions and emotions that dominate working memory in high-risk sexual situations, we can effectively design interventions that help shape cognitive and affective appraisals and how youth process those appraisals when making choices.”
Carol Ford, MD, is the chief of the Craig-Dalsimer Division of Adolescent Medicine at the Children’s Hospital of Philadelphia; she holds the Orton P. Jackson Endowed Chair in Adolescent Medicine. James Jaccard, PhD, is a professor of social work at New York University Silver School of Social Work. This is a summary of their commentary that accompanied the article by Houck et al. (Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-4143). They had no financial disclosures, and there was no external funding.
Emotional regulation (ER) skills training lowers the likelihood that young adolescents with mental health symptoms will have vaginal sex.
“The inclusion of ER training in a small-group behavioral intervention reduced sexual risk behaviors among seventh-graders with suspected mental health symptoms over a 2.5-year follow-up beyond that achieved with more traditional health education,” wrote Chistopher Houck, PhD, and his colleagues at Bradley Hasbro Children’s Research Center, Providence, R.I., in Pediatrics. “This was true across a range of behaviors, such as engaging in fewer condom-less sex acts, being less likely to have multiple partners, and being less likely to use substances before sex.”
Students in the study participated in one of two after school intervention programs, either ER or health promotion (HP). Both programs consisted of 12 twice-weekly, hour-long sessions composed of single-sex groups of 4-8 adolescents. Two follow-up sessions were provided for both groups at 6 and 12 months. Both interventions used identical techniques, such as interactive games, videos, group discussions, and workbook assignments. ER sessions focused more on recognizing feelings, strategies for reducing momentary emotional arousal, and sexual health topics. HP exclusively focused on health topics like sexual risk and substance abuse but did not include emotional education.
During the 30-month study, 63 in the ER group (31%) and 68 students in the HP group (39%) reported having vaginal sex for the first time. This equated to an adjusted hazard ratio that indicated a delay in vaginal sex in the ER group (0.61; 95% confidence interval,0.42-0.89). Overall, students in the ER group were much less likely to endorse risky sexual behaviors than did participants in the HP group: Students in the ER group were less likely to endorse any risky sexual behavior (adjusted odds ratio, 0.52; 95% CI, 0.32-0.84), to support having multiple partners within 6 months (aOR, 0.54; 95% CI, 0.30-0.99), and to support the use of drugs before sex (aOR, 0.42; 95% CI, 0.23-0.75). Students in the ER group also reported fewer condom-less sex acts, compared with students in the HP group (adjusted rate ratio, 0.36; 95% CI, 0.14-0.90).
According to Dr. Houck and his colleagues, this study had several limitations that are common to sexual risk studies. One limitation is the reliance on self-report data, which can be biased. Dr. Houck and his associates utilized computer-assisted self-interviews to minimize biases. Another, and potentially larger, limitation is that the study was powered to assess delay of vaginal sex. Part of the patient sample was not sexually experienced, which provided less power for comparisons to other sexual behaviors.
Dr. Houck and his colleagues also spoke to the potential that ER training has in reducing risky behaviors of adolescents, as well as the issues in implementing it.
“Because ER is a skill that could influence other adolescent risk behaviors, such as substance use, violence, and truancy, addressing ER during this sensitive period in adolescent development promises significant public health benefits,” they wrote. “The challenge is the scale-up and dissemination of ER interventions. Increasing the reach of programs in which health education is enhanced with emotion education may be an important step toward improving the lives of adolescents because they are prone to beginning risk behavior.”
Dr. Houck and his associates have no relevant financial disclosures. This study received funding from the National Institutes of Health and the Providence/Boston Center for AIDS Research.
SOURCE: Houck C et al. Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-2525.
Emotional regulation (ER) skills training lowers the likelihood that young adolescents with mental health symptoms will have vaginal sex.
“The inclusion of ER training in a small-group behavioral intervention reduced sexual risk behaviors among seventh-graders with suspected mental health symptoms over a 2.5-year follow-up beyond that achieved with more traditional health education,” wrote Chistopher Houck, PhD, and his colleagues at Bradley Hasbro Children’s Research Center, Providence, R.I., in Pediatrics. “This was true across a range of behaviors, such as engaging in fewer condom-less sex acts, being less likely to have multiple partners, and being less likely to use substances before sex.”
Students in the study participated in one of two after school intervention programs, either ER or health promotion (HP). Both programs consisted of 12 twice-weekly, hour-long sessions composed of single-sex groups of 4-8 adolescents. Two follow-up sessions were provided for both groups at 6 and 12 months. Both interventions used identical techniques, such as interactive games, videos, group discussions, and workbook assignments. ER sessions focused more on recognizing feelings, strategies for reducing momentary emotional arousal, and sexual health topics. HP exclusively focused on health topics like sexual risk and substance abuse but did not include emotional education.
During the 30-month study, 63 in the ER group (31%) and 68 students in the HP group (39%) reported having vaginal sex for the first time. This equated to an adjusted hazard ratio that indicated a delay in vaginal sex in the ER group (0.61; 95% confidence interval,0.42-0.89). Overall, students in the ER group were much less likely to endorse risky sexual behaviors than did participants in the HP group: Students in the ER group were less likely to endorse any risky sexual behavior (adjusted odds ratio, 0.52; 95% CI, 0.32-0.84), to support having multiple partners within 6 months (aOR, 0.54; 95% CI, 0.30-0.99), and to support the use of drugs before sex (aOR, 0.42; 95% CI, 0.23-0.75). Students in the ER group also reported fewer condom-less sex acts, compared with students in the HP group (adjusted rate ratio, 0.36; 95% CI, 0.14-0.90).
According to Dr. Houck and his colleagues, this study had several limitations that are common to sexual risk studies. One limitation is the reliance on self-report data, which can be biased. Dr. Houck and his associates utilized computer-assisted self-interviews to minimize biases. Another, and potentially larger, limitation is that the study was powered to assess delay of vaginal sex. Part of the patient sample was not sexually experienced, which provided less power for comparisons to other sexual behaviors.
Dr. Houck and his colleagues also spoke to the potential that ER training has in reducing risky behaviors of adolescents, as well as the issues in implementing it.
“Because ER is a skill that could influence other adolescent risk behaviors, such as substance use, violence, and truancy, addressing ER during this sensitive period in adolescent development promises significant public health benefits,” they wrote. “The challenge is the scale-up and dissemination of ER interventions. Increasing the reach of programs in which health education is enhanced with emotion education may be an important step toward improving the lives of adolescents because they are prone to beginning risk behavior.”
Dr. Houck and his associates have no relevant financial disclosures. This study received funding from the National Institutes of Health and the Providence/Boston Center for AIDS Research.
SOURCE: Houck C et al. Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-2525.
FROM PEDIATRICS
Key clinical point: Emotional regulation (ER) training reduces the likelihood adolescents will have sex.
Major finding: There was a delay in vaginal sex in the ER group (adusted hazard ratio, 0.61; 95% confidence interval, 0.42-0.89), compared with the health promotion group.
Study details: The study included 420 seventh grade students aged 12-14 years from five urban Rhode Island middle schools between September 2009 and February 2012.
Disclosures: Dr. Houck and his associates have no relevant financial disclosures. This study received funding from the National Institutes of Health and the Providence/Boston Center for AIDS Research.
Source: Houck C et al. Pediatrics. 2018 May 10. doi: 10.1542/peds.2017-2525.
Slime is not sublime: It may cause hand dermatitis
A young, otherwise healthy 9-year-old girl was evaluated for pruritic hand dermatitis which lasted 5 months after exposure to homemade slime. Physical exam revealed erythematous, scaly plaques on the palmar surfaces of her hands; her fingernails had onychomadesis and longitudinal ridging. Despite frequent emolliation, her dermatitis persisted. She was then treated empirically for scabies and for culture-positive Staphylococcus aureus infection, which required a full round of cephalexin and mupirocin ointment. This also did not alleviate the dermatitis. A combination of homemade borax-containing slime avoidance, brief course of high-dose corticosteroids, and frequent bland emollients was prescribed because the dermatitis was assumed to be caused by an irritant.
After review of this case and evaluation of other children with hand dermatitis, Julia K. Gittler, MD, of Columbia University, New York, and her colleagues have made a case that “slime” and new-onset hand dermatitis may be linked.
SOURCE: Gittler JK et al. J Pediatr. 2018 May 3. doi: 10.1016/j.jpeds.2018.03.064 .
A young, otherwise healthy 9-year-old girl was evaluated for pruritic hand dermatitis which lasted 5 months after exposure to homemade slime. Physical exam revealed erythematous, scaly plaques on the palmar surfaces of her hands; her fingernails had onychomadesis and longitudinal ridging. Despite frequent emolliation, her dermatitis persisted. She was then treated empirically for scabies and for culture-positive Staphylococcus aureus infection, which required a full round of cephalexin and mupirocin ointment. This also did not alleviate the dermatitis. A combination of homemade borax-containing slime avoidance, brief course of high-dose corticosteroids, and frequent bland emollients was prescribed because the dermatitis was assumed to be caused by an irritant.
After review of this case and evaluation of other children with hand dermatitis, Julia K. Gittler, MD, of Columbia University, New York, and her colleagues have made a case that “slime” and new-onset hand dermatitis may be linked.
SOURCE: Gittler JK et al. J Pediatr. 2018 May 3. doi: 10.1016/j.jpeds.2018.03.064 .
A young, otherwise healthy 9-year-old girl was evaluated for pruritic hand dermatitis which lasted 5 months after exposure to homemade slime. Physical exam revealed erythematous, scaly plaques on the palmar surfaces of her hands; her fingernails had onychomadesis and longitudinal ridging. Despite frequent emolliation, her dermatitis persisted. She was then treated empirically for scabies and for culture-positive Staphylococcus aureus infection, which required a full round of cephalexin and mupirocin ointment. This also did not alleviate the dermatitis. A combination of homemade borax-containing slime avoidance, brief course of high-dose corticosteroids, and frequent bland emollients was prescribed because the dermatitis was assumed to be caused by an irritant.
After review of this case and evaluation of other children with hand dermatitis, Julia K. Gittler, MD, of Columbia University, New York, and her colleagues have made a case that “slime” and new-onset hand dermatitis may be linked.
SOURCE: Gittler JK et al. J Pediatr. 2018 May 3. doi: 10.1016/j.jpeds.2018.03.064 .
FROM THE JOURNAL OF PEDIATRICS
FDA advisory committee votes to recommend first once-daily aminoglycoside antibiotic
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
AGA Clinical Practice Update: Screening for Barrett’s esophagus requires consideration for those most at risk
The evidence discussed in this article supports the current recommendation of GI societies that screening endoscopy for Barrett’s esophagus be performed only in well-defined, high-risk populations. Alternative tests for screening are not now recommended; however, some of the alternative tests show great promise, and it is expected that they will soon find a useful place in clinical practice. At the same time, there should be a complementary focus on using demographic and clinical factors as well as noninvasive tools to further define populations for screening. All tests and tools should be balanced with the cost and potential risks of the screening proposed.
Stuart Spechler, MD, of the University of Texas and his colleagues looked at a variety of techniques, both conventional and novel, as well as the cost effectiveness of these strategies in a commentary published in the May issue of Gastroenterology.
Some studies have shown that endoscopic surveillance programs have identified early-stage cancer and provided better outcomes, compared with patients presenting after they already have cancer symptoms. One meta-analysis included 51 studies with 11,028 subjects and demonstrated that patients who had surveillance-detected esophageal adenocarcinoma (EAC) had a 61% reduction in their mortality risk. Other studies have shown similar results, but are susceptible to certain biases. Still other studies have refuted that the surveillance programs help at all. In fact, those with Barrett’s esophagus who died of EAC underwent similar surveillance, compared with controls, in those studies, showing that surveillance did very little to improve their outcomes.
Perhaps one of the most intriguing and cost-effective strategies is to identify patients with Barrett’s esophagus and develop a tool based on demographic and historical information. Tools like this have been developed, but have shown lukewarm results, with areas under the receiver operating characteristic curve (AUROC) ranging from 0.61 to 0.75. One study used information concerning obesity, smoking history, and increasing age, combined with weekly symptoms of gastroesophageal reflux and found that this improved results by nearly 25%. Modified versions of this model have also shown improved detection. When Thrift et al. added additional factors like education level, body mass index, smoking status, and more serious alarm symptoms like unexplained weight loss, the model was able to improve AUROC scores to 0.85 (95% confidence interval, 0.78-0.91). Of course, the clinical utility of these models is still unclear. Nonetheless, these models have influenced certain GI societies that only believe in endoscopic screening of patients with additional risk factors.
Although predictive models may assist in identifying at-risk patients, endoscopes are still needed to diagnose. Transnasal endoscopes (TNEs), the thinner cousins of the regular endoscope, tend to be better tolerated by patients and result in less gagging. One study showed that TNEs (45.7%) improved participation, compared with standard endoscopy (40.7%), and almost 80% of TNE patients were willing to undergo the procedure again. Despite the positives, TNEs provided significantly lower biopsy acquisitions than standard endoscopes (83% vs. 100%, P = .001) because of the sheathing on the endoscope. Other studies have demonstrated the strengths of TNEs, including a study in which 38% of patients had a finding that changed management of their disease. TNEs should be considered a reliable screening tool for Barrett’s esophagus.
Other advances in imaging technology like the advent of the high-resolution complementary metal oxide semiconductor (CMOS), which is small enough to fit into a pill capsule, have led researchers to look into its effectiveness as a screening tool for Barrett’s esophagus. One meta-analysis of 618 patients found that the pooled sensitivity and specificity for diagnosis were 77% and 86%, respectively. Despite its ability to produce high-quality images, the device remains difficult to control and lacks the ability to obtain biopsy samples.
Another example of a swallowed medical device, the Cytosponge-TFF3 is an ingestible capsule that degrades in stomach acid. After 5 minutes, the capsule dissolves and releases a mesh sponge that will be withdrawn through the mouth, scraping the esophagus and gathering a sample. The Cytosponge has proven effective in the Barrett’s Esophagus Screening Trials (BEST) 1. The BEST 2 looked at 463 control and 647 patients with Barrett’s esophagus across 11 United Kingdom hospitals. The trial showed that the Cytosponge exhibited sensitivity of 79.9%, which increased to 87.2% in patients with more than 3 cm of circumferential Barrett’s metaplasia.
Breaking from the invasive nature of imaging scopes and the Cytosponge, some researchers are looking to use “liquid biopsy” or blood tests to detect abnormalities in the blood like DNA or microRNA (miRNA) to identify precursors or presence of a disease. Much remains to be done to develop a clinically meaningful test, but the use of miRNAs to detect disease is an intriguing option. miRNAs control gene expression, and their dysregulation has been associated with the development of many diseases. One study found that patients with Barrett’s esophagus had increased levels of miRNA-194, 215, and 143 but these findings were not validated in a larger study. Other studies have demonstrated similar findings, but more research must be done to validate these findings in larger cohorts.
Other novel detection therapies have been investigated, including serum adipokine and electronic nose breathing tests. The serum adipokine test looks at the metabolically active adipokines secreted in obese patients and those with metabolic syndrome to see if they could predict the presence of Barrett’s esophagus. Unfortunately, the data appear to be conflicting, but these tests can be used in conjunction with other tools to detect Barrett’s esophagus. Electronic nose breathing tests also work by detecting metabolically active compounds from human and gut bacterial metabolism. One study found that analyzing these volatile compounds could delineate between Barrett’s and non-Barrett’s patients with 82% sensitivity, 80% specificity, and 81% accuracy. Both of these technologies need large prospective studies in primary care to validate their clinical utility.
A discussion of the effectiveness of these screening tools would be incomplete without a discussion of their costs. Currently, endoscopic screening costs are high. Therefore, it is important to reserve these tools for the patients who will benefit the most – in other words, patients with clear risk factors for Barrett’s esophagus. Even the capsule endoscope is quite expensive because of the cost of materials associated with the tool.
Cost-effectivenes calculations surrounding the Cytosponge are particularly complicated. One analysis found the computed incremental cost-effectiveness ratio (ICER) of endoscopy, compared with Cytosponge, to have a range of $107,583-$330,361. The potential benefit that Cytosponge offers comes at an ICER for Cytosponge screening, compared with no screening, that ranges from $26,358 to $33,307. The numbers skyrocket when you consider what society would be willing to pay (up to $50,000 per quality-adjusted life-year gained).
With all of this information in mind, it would be useful to look at Barrett’s esophagus and the tools used to diagnose it from a broader perspective.
While the adoption of a new screening strategy could succeed where others have failed, Dr. Spechler points out the potential harm.
“There also is potential for harm in identifying asymptomatic patients with Barrett’s esophagus. In addition to the high costs and small risks of standard endoscopy, the diagnosis of Barrett’s esophagus can cause psychological stress, have a negative impact on quality of life, result in higher premiums for health and life insurance, and might identify innocuous lesions that lead to potentially hazardous invasive treatments. Efforts should therefore be continued to combine biomarkers for Barrett’s with risk stratification. Overall, while these vexing uncertainties must temper enthusiasm for the unqualified endorsement of any screening test for Barrett’s esophagus, the alternative of making no attempt to stem the rapidly rising incidence of a lethal malignancy also is unpalatable.”
The development of this commentary was supported solely by the American Gastroenterological Association Institute. No conflicts of interest were disclosed for this report.
SOURCE: Spechler S et al. Gastroenterology. 2018 May doi: 10.1053/j.gastro.2018.03.031).
AGA Resource
AGA patient education on Barrett’s esophagus will help your patients better understand the disease and how to manage it. Learn more at gastro.org/patient-care.
The evidence discussed in this article supports the current recommendation of GI societies that screening endoscopy for Barrett’s esophagus be performed only in well-defined, high-risk populations. Alternative tests for screening are not now recommended; however, some of the alternative tests show great promise, and it is expected that they will soon find a useful place in clinical practice. At the same time, there should be a complementary focus on using demographic and clinical factors as well as noninvasive tools to further define populations for screening. All tests and tools should be balanced with the cost and potential risks of the screening proposed.
Stuart Spechler, MD, of the University of Texas and his colleagues looked at a variety of techniques, both conventional and novel, as well as the cost effectiveness of these strategies in a commentary published in the May issue of Gastroenterology.
Some studies have shown that endoscopic surveillance programs have identified early-stage cancer and provided better outcomes, compared with patients presenting after they already have cancer symptoms. One meta-analysis included 51 studies with 11,028 subjects and demonstrated that patients who had surveillance-detected esophageal adenocarcinoma (EAC) had a 61% reduction in their mortality risk. Other studies have shown similar results, but are susceptible to certain biases. Still other studies have refuted that the surveillance programs help at all. In fact, those with Barrett’s esophagus who died of EAC underwent similar surveillance, compared with controls, in those studies, showing that surveillance did very little to improve their outcomes.
Perhaps one of the most intriguing and cost-effective strategies is to identify patients with Barrett’s esophagus and develop a tool based on demographic and historical information. Tools like this have been developed, but have shown lukewarm results, with areas under the receiver operating characteristic curve (AUROC) ranging from 0.61 to 0.75. One study used information concerning obesity, smoking history, and increasing age, combined with weekly symptoms of gastroesophageal reflux and found that this improved results by nearly 25%. Modified versions of this model have also shown improved detection. When Thrift et al. added additional factors like education level, body mass index, smoking status, and more serious alarm symptoms like unexplained weight loss, the model was able to improve AUROC scores to 0.85 (95% confidence interval, 0.78-0.91). Of course, the clinical utility of these models is still unclear. Nonetheless, these models have influenced certain GI societies that only believe in endoscopic screening of patients with additional risk factors.
Although predictive models may assist in identifying at-risk patients, endoscopes are still needed to diagnose. Transnasal endoscopes (TNEs), the thinner cousins of the regular endoscope, tend to be better tolerated by patients and result in less gagging. One study showed that TNEs (45.7%) improved participation, compared with standard endoscopy (40.7%), and almost 80% of TNE patients were willing to undergo the procedure again. Despite the positives, TNEs provided significantly lower biopsy acquisitions than standard endoscopes (83% vs. 100%, P = .001) because of the sheathing on the endoscope. Other studies have demonstrated the strengths of TNEs, including a study in which 38% of patients had a finding that changed management of their disease. TNEs should be considered a reliable screening tool for Barrett’s esophagus.
Other advances in imaging technology like the advent of the high-resolution complementary metal oxide semiconductor (CMOS), which is small enough to fit into a pill capsule, have led researchers to look into its effectiveness as a screening tool for Barrett’s esophagus. One meta-analysis of 618 patients found that the pooled sensitivity and specificity for diagnosis were 77% and 86%, respectively. Despite its ability to produce high-quality images, the device remains difficult to control and lacks the ability to obtain biopsy samples.
Another example of a swallowed medical device, the Cytosponge-TFF3 is an ingestible capsule that degrades in stomach acid. After 5 minutes, the capsule dissolves and releases a mesh sponge that will be withdrawn through the mouth, scraping the esophagus and gathering a sample. The Cytosponge has proven effective in the Barrett’s Esophagus Screening Trials (BEST) 1. The BEST 2 looked at 463 control and 647 patients with Barrett’s esophagus across 11 United Kingdom hospitals. The trial showed that the Cytosponge exhibited sensitivity of 79.9%, which increased to 87.2% in patients with more than 3 cm of circumferential Barrett’s metaplasia.
Breaking from the invasive nature of imaging scopes and the Cytosponge, some researchers are looking to use “liquid biopsy” or blood tests to detect abnormalities in the blood like DNA or microRNA (miRNA) to identify precursors or presence of a disease. Much remains to be done to develop a clinically meaningful test, but the use of miRNAs to detect disease is an intriguing option. miRNAs control gene expression, and their dysregulation has been associated with the development of many diseases. One study found that patients with Barrett’s esophagus had increased levels of miRNA-194, 215, and 143 but these findings were not validated in a larger study. Other studies have demonstrated similar findings, but more research must be done to validate these findings in larger cohorts.
Other novel detection therapies have been investigated, including serum adipokine and electronic nose breathing tests. The serum adipokine test looks at the metabolically active adipokines secreted in obese patients and those with metabolic syndrome to see if they could predict the presence of Barrett’s esophagus. Unfortunately, the data appear to be conflicting, but these tests can be used in conjunction with other tools to detect Barrett’s esophagus. Electronic nose breathing tests also work by detecting metabolically active compounds from human and gut bacterial metabolism. One study found that analyzing these volatile compounds could delineate between Barrett’s and non-Barrett’s patients with 82% sensitivity, 80% specificity, and 81% accuracy. Both of these technologies need large prospective studies in primary care to validate their clinical utility.
A discussion of the effectiveness of these screening tools would be incomplete without a discussion of their costs. Currently, endoscopic screening costs are high. Therefore, it is important to reserve these tools for the patients who will benefit the most – in other words, patients with clear risk factors for Barrett’s esophagus. Even the capsule endoscope is quite expensive because of the cost of materials associated with the tool.
Cost-effectivenes calculations surrounding the Cytosponge are particularly complicated. One analysis found the computed incremental cost-effectiveness ratio (ICER) of endoscopy, compared with Cytosponge, to have a range of $107,583-$330,361. The potential benefit that Cytosponge offers comes at an ICER for Cytosponge screening, compared with no screening, that ranges from $26,358 to $33,307. The numbers skyrocket when you consider what society would be willing to pay (up to $50,000 per quality-adjusted life-year gained).
With all of this information in mind, it would be useful to look at Barrett’s esophagus and the tools used to diagnose it from a broader perspective.
While the adoption of a new screening strategy could succeed where others have failed, Dr. Spechler points out the potential harm.
“There also is potential for harm in identifying asymptomatic patients with Barrett’s esophagus. In addition to the high costs and small risks of standard endoscopy, the diagnosis of Barrett’s esophagus can cause psychological stress, have a negative impact on quality of life, result in higher premiums for health and life insurance, and might identify innocuous lesions that lead to potentially hazardous invasive treatments. Efforts should therefore be continued to combine biomarkers for Barrett’s with risk stratification. Overall, while these vexing uncertainties must temper enthusiasm for the unqualified endorsement of any screening test for Barrett’s esophagus, the alternative of making no attempt to stem the rapidly rising incidence of a lethal malignancy also is unpalatable.”
The development of this commentary was supported solely by the American Gastroenterological Association Institute. No conflicts of interest were disclosed for this report.
SOURCE: Spechler S et al. Gastroenterology. 2018 May doi: 10.1053/j.gastro.2018.03.031).
AGA Resource
AGA patient education on Barrett’s esophagus will help your patients better understand the disease and how to manage it. Learn more at gastro.org/patient-care.
The evidence discussed in this article supports the current recommendation of GI societies that screening endoscopy for Barrett’s esophagus be performed only in well-defined, high-risk populations. Alternative tests for screening are not now recommended; however, some of the alternative tests show great promise, and it is expected that they will soon find a useful place in clinical practice. At the same time, there should be a complementary focus on using demographic and clinical factors as well as noninvasive tools to further define populations for screening. All tests and tools should be balanced with the cost and potential risks of the screening proposed.
Stuart Spechler, MD, of the University of Texas and his colleagues looked at a variety of techniques, both conventional and novel, as well as the cost effectiveness of these strategies in a commentary published in the May issue of Gastroenterology.
Some studies have shown that endoscopic surveillance programs have identified early-stage cancer and provided better outcomes, compared with patients presenting after they already have cancer symptoms. One meta-analysis included 51 studies with 11,028 subjects and demonstrated that patients who had surveillance-detected esophageal adenocarcinoma (EAC) had a 61% reduction in their mortality risk. Other studies have shown similar results, but are susceptible to certain biases. Still other studies have refuted that the surveillance programs help at all. In fact, those with Barrett’s esophagus who died of EAC underwent similar surveillance, compared with controls, in those studies, showing that surveillance did very little to improve their outcomes.
Perhaps one of the most intriguing and cost-effective strategies is to identify patients with Barrett’s esophagus and develop a tool based on demographic and historical information. Tools like this have been developed, but have shown lukewarm results, with areas under the receiver operating characteristic curve (AUROC) ranging from 0.61 to 0.75. One study used information concerning obesity, smoking history, and increasing age, combined with weekly symptoms of gastroesophageal reflux and found that this improved results by nearly 25%. Modified versions of this model have also shown improved detection. When Thrift et al. added additional factors like education level, body mass index, smoking status, and more serious alarm symptoms like unexplained weight loss, the model was able to improve AUROC scores to 0.85 (95% confidence interval, 0.78-0.91). Of course, the clinical utility of these models is still unclear. Nonetheless, these models have influenced certain GI societies that only believe in endoscopic screening of patients with additional risk factors.
Although predictive models may assist in identifying at-risk patients, endoscopes are still needed to diagnose. Transnasal endoscopes (TNEs), the thinner cousins of the regular endoscope, tend to be better tolerated by patients and result in less gagging. One study showed that TNEs (45.7%) improved participation, compared with standard endoscopy (40.7%), and almost 80% of TNE patients were willing to undergo the procedure again. Despite the positives, TNEs provided significantly lower biopsy acquisitions than standard endoscopes (83% vs. 100%, P = .001) because of the sheathing on the endoscope. Other studies have demonstrated the strengths of TNEs, including a study in which 38% of patients had a finding that changed management of their disease. TNEs should be considered a reliable screening tool for Barrett’s esophagus.
Other advances in imaging technology like the advent of the high-resolution complementary metal oxide semiconductor (CMOS), which is small enough to fit into a pill capsule, have led researchers to look into its effectiveness as a screening tool for Barrett’s esophagus. One meta-analysis of 618 patients found that the pooled sensitivity and specificity for diagnosis were 77% and 86%, respectively. Despite its ability to produce high-quality images, the device remains difficult to control and lacks the ability to obtain biopsy samples.
Another example of a swallowed medical device, the Cytosponge-TFF3 is an ingestible capsule that degrades in stomach acid. After 5 minutes, the capsule dissolves and releases a mesh sponge that will be withdrawn through the mouth, scraping the esophagus and gathering a sample. The Cytosponge has proven effective in the Barrett’s Esophagus Screening Trials (BEST) 1. The BEST 2 looked at 463 control and 647 patients with Barrett’s esophagus across 11 United Kingdom hospitals. The trial showed that the Cytosponge exhibited sensitivity of 79.9%, which increased to 87.2% in patients with more than 3 cm of circumferential Barrett’s metaplasia.
Breaking from the invasive nature of imaging scopes and the Cytosponge, some researchers are looking to use “liquid biopsy” or blood tests to detect abnormalities in the blood like DNA or microRNA (miRNA) to identify precursors or presence of a disease. Much remains to be done to develop a clinically meaningful test, but the use of miRNAs to detect disease is an intriguing option. miRNAs control gene expression, and their dysregulation has been associated with the development of many diseases. One study found that patients with Barrett’s esophagus had increased levels of miRNA-194, 215, and 143 but these findings were not validated in a larger study. Other studies have demonstrated similar findings, but more research must be done to validate these findings in larger cohorts.
Other novel detection therapies have been investigated, including serum adipokine and electronic nose breathing tests. The serum adipokine test looks at the metabolically active adipokines secreted in obese patients and those with metabolic syndrome to see if they could predict the presence of Barrett’s esophagus. Unfortunately, the data appear to be conflicting, but these tests can be used in conjunction with other tools to detect Barrett’s esophagus. Electronic nose breathing tests also work by detecting metabolically active compounds from human and gut bacterial metabolism. One study found that analyzing these volatile compounds could delineate between Barrett’s and non-Barrett’s patients with 82% sensitivity, 80% specificity, and 81% accuracy. Both of these technologies need large prospective studies in primary care to validate their clinical utility.
A discussion of the effectiveness of these screening tools would be incomplete without a discussion of their costs. Currently, endoscopic screening costs are high. Therefore, it is important to reserve these tools for the patients who will benefit the most – in other words, patients with clear risk factors for Barrett’s esophagus. Even the capsule endoscope is quite expensive because of the cost of materials associated with the tool.
Cost-effectivenes calculations surrounding the Cytosponge are particularly complicated. One analysis found the computed incremental cost-effectiveness ratio (ICER) of endoscopy, compared with Cytosponge, to have a range of $107,583-$330,361. The potential benefit that Cytosponge offers comes at an ICER for Cytosponge screening, compared with no screening, that ranges from $26,358 to $33,307. The numbers skyrocket when you consider what society would be willing to pay (up to $50,000 per quality-adjusted life-year gained).
With all of this information in mind, it would be useful to look at Barrett’s esophagus and the tools used to diagnose it from a broader perspective.
While the adoption of a new screening strategy could succeed where others have failed, Dr. Spechler points out the potential harm.
“There also is potential for harm in identifying asymptomatic patients with Barrett’s esophagus. In addition to the high costs and small risks of standard endoscopy, the diagnosis of Barrett’s esophagus can cause psychological stress, have a negative impact on quality of life, result in higher premiums for health and life insurance, and might identify innocuous lesions that lead to potentially hazardous invasive treatments. Efforts should therefore be continued to combine biomarkers for Barrett’s with risk stratification. Overall, while these vexing uncertainties must temper enthusiasm for the unqualified endorsement of any screening test for Barrett’s esophagus, the alternative of making no attempt to stem the rapidly rising incidence of a lethal malignancy also is unpalatable.”
The development of this commentary was supported solely by the American Gastroenterological Association Institute. No conflicts of interest were disclosed for this report.
SOURCE: Spechler S et al. Gastroenterology. 2018 May doi: 10.1053/j.gastro.2018.03.031).
AGA Resource
AGA patient education on Barrett’s esophagus will help your patients better understand the disease and how to manage it. Learn more at gastro.org/patient-care.
FROM GASTROENTEROLOGY
FDA approves epinephrine autoinjector for infants and toddlers
according to a press release from Kaléo, a privately-held pharmaceutical company.
“Anaphylactic reactions can be frightening and serious, and when experienced by the very young, some of whom can’t communicate about what’s happening, these episodes can be particularly alarming,” Vivian Hernandez-Trujillo, MD, a pediatric allergist and fellow of the American Academy of Allergy, Asthma and Immunology, said in a statement. “Now, caregivers can have the AUVI-Q 0.1 mg in hand to respond to an allergic emergency and safely administer epinephrine to infants and toddlers.”
The approval comes at a time when a higher percentage of children are being admitted to the hospital for food-related anaphylaxis: a 130% increase among children aged 0-4 years and a 196% increase in children aged 5-17 years.
The epinephrine autoinjector will be available for $0 out of pocket for commercially insured patients using the AUVI-Q AffordAbility Program and Direct Delivery Service starting May 1, 2018. More information concerning this EAI can be found here.
according to a press release from Kaléo, a privately-held pharmaceutical company.
“Anaphylactic reactions can be frightening and serious, and when experienced by the very young, some of whom can’t communicate about what’s happening, these episodes can be particularly alarming,” Vivian Hernandez-Trujillo, MD, a pediatric allergist and fellow of the American Academy of Allergy, Asthma and Immunology, said in a statement. “Now, caregivers can have the AUVI-Q 0.1 mg in hand to respond to an allergic emergency and safely administer epinephrine to infants and toddlers.”
The approval comes at a time when a higher percentage of children are being admitted to the hospital for food-related anaphylaxis: a 130% increase among children aged 0-4 years and a 196% increase in children aged 5-17 years.
The epinephrine autoinjector will be available for $0 out of pocket for commercially insured patients using the AUVI-Q AffordAbility Program and Direct Delivery Service starting May 1, 2018. More information concerning this EAI can be found here.
according to a press release from Kaléo, a privately-held pharmaceutical company.
“Anaphylactic reactions can be frightening and serious, and when experienced by the very young, some of whom can’t communicate about what’s happening, these episodes can be particularly alarming,” Vivian Hernandez-Trujillo, MD, a pediatric allergist and fellow of the American Academy of Allergy, Asthma and Immunology, said in a statement. “Now, caregivers can have the AUVI-Q 0.1 mg in hand to respond to an allergic emergency and safely administer epinephrine to infants and toddlers.”
The approval comes at a time when a higher percentage of children are being admitted to the hospital for food-related anaphylaxis: a 130% increase among children aged 0-4 years and a 196% increase in children aged 5-17 years.
The epinephrine autoinjector will be available for $0 out of pocket for commercially insured patients using the AUVI-Q AffordAbility Program and Direct Delivery Service starting May 1, 2018. More information concerning this EAI can be found here.
Bipolar and seizure medication linked with serious immune system reaction
The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.
This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.
Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.
The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.
The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.
HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.
Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.
The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.
This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.
Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.
The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.
The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.
HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.
Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.
The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.
This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.
Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.
The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.
The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.
HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.
Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.
The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
FDA advisory committee votes to recommend update to celecoxib safety labeling
SILVER SPRING, MD. – An FDA advisory committee voted (15 yes, 5 no, 1 abstention) to update the safety information in the label of celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), for use in patients with osteoarthritis (OA) and rheumatoid arthritis, on the basis of results of the PRECISION trial.
A Joint Meeting ofthe Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was convened April 24-25 to address two issues, the first being the consideration of Pfizer’s application for celecoxib and the second, to assess the safety of celecoxib and other common NSAIDs like ibuprofen and naproxen.
The randomized controlled PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) trial compared celecoxib, naproxen, and ibuprofen and their cardiovascular outcomes. The PRECISION trial was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that the rates of cardiovascular events (cardiovascular death, myocardial infarction, or stroke) were 2.3% with celecoxib, 2.5% with naproxen, and 2.7% with ibuprofen during a follow-up approaching 3 years, showing noninferiority for celecoxib.
In a post hoc analysis presented by Steven Nissen, MD, patients taking ibuprofen and naproxen experienced adjudicated cardiovascular, GI, or renal events 28% and 15% more than did patients taking celecoxib.
The results of the study could inform clinical strategy, said Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “For arthritis patients who require NSAIDs to achieve an acceptable quality of life, particularly those at high cardiovascular, GI, or renal risk, the PRECISION trial suggests that a clinical strategy of starting patients on celecoxib 200 mg daily may be the safest approach, reserving full therapeutic doses of ibuprofen and naproxen for patients who do not respond to celecoxib."
SILVER SPRING, MD. – An FDA advisory committee voted (15 yes, 5 no, 1 abstention) to update the safety information in the label of celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), for use in patients with osteoarthritis (OA) and rheumatoid arthritis, on the basis of results of the PRECISION trial.
A Joint Meeting ofthe Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was convened April 24-25 to address two issues, the first being the consideration of Pfizer’s application for celecoxib and the second, to assess the safety of celecoxib and other common NSAIDs like ibuprofen and naproxen.
The randomized controlled PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) trial compared celecoxib, naproxen, and ibuprofen and their cardiovascular outcomes. The PRECISION trial was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that the rates of cardiovascular events (cardiovascular death, myocardial infarction, or stroke) were 2.3% with celecoxib, 2.5% with naproxen, and 2.7% with ibuprofen during a follow-up approaching 3 years, showing noninferiority for celecoxib.
In a post hoc analysis presented by Steven Nissen, MD, patients taking ibuprofen and naproxen experienced adjudicated cardiovascular, GI, or renal events 28% and 15% more than did patients taking celecoxib.
The results of the study could inform clinical strategy, said Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “For arthritis patients who require NSAIDs to achieve an acceptable quality of life, particularly those at high cardiovascular, GI, or renal risk, the PRECISION trial suggests that a clinical strategy of starting patients on celecoxib 200 mg daily may be the safest approach, reserving full therapeutic doses of ibuprofen and naproxen for patients who do not respond to celecoxib."
SILVER SPRING, MD. – An FDA advisory committee voted (15 yes, 5 no, 1 abstention) to update the safety information in the label of celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), for use in patients with osteoarthritis (OA) and rheumatoid arthritis, on the basis of results of the PRECISION trial.
A Joint Meeting ofthe Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was convened April 24-25 to address two issues, the first being the consideration of Pfizer’s application for celecoxib and the second, to assess the safety of celecoxib and other common NSAIDs like ibuprofen and naproxen.
The randomized controlled PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) trial compared celecoxib, naproxen, and ibuprofen and their cardiovascular outcomes. The PRECISION trial was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that the rates of cardiovascular events (cardiovascular death, myocardial infarction, or stroke) were 2.3% with celecoxib, 2.5% with naproxen, and 2.7% with ibuprofen during a follow-up approaching 3 years, showing noninferiority for celecoxib.
In a post hoc analysis presented by Steven Nissen, MD, patients taking ibuprofen and naproxen experienced adjudicated cardiovascular, GI, or renal events 28% and 15% more than did patients taking celecoxib.
The results of the study could inform clinical strategy, said Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “For arthritis patients who require NSAIDs to achieve an acceptable quality of life, particularly those at high cardiovascular, GI, or renal risk, the PRECISION trial suggests that a clinical strategy of starting patients on celecoxib 200 mg daily may be the safest approach, reserving full therapeutic doses of ibuprofen and naproxen for patients who do not respond to celecoxib."
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING