Dataset Information

Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

ABSTRACT: Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); however, fixed-dose administration of MNTX may improve ease of administration.The study objective was to assess safety and efficacy of fixed-dose MNTX in two phase 4 trials.In a double-blind, randomized, placebo-controlled trial (RCT), patients with advanced illness and OIC received MNTX (8?mg or 12?mg by body weight [38?kg to <62?kg or ?62?kg, respectively]) or placebo every other day (QOD) for two weeks. Patients completing the RCT could enroll in an open-label extension (OLE) study with MNTX administered as needed (PRN). The primary endpoint was percentage of patients with a rescue-free bowel movement (RFBM) within four hours after ?2 of the first 4 doses in the first week.In the RCT, 116 and 114 patients received MNTX and placebo, respectively, and 149 patients continued to the OLE study. The percentage of patients achieving primary endpoint was 62.9% and 9.6% for MNTX and placebo groups, respectively (p<0.0001). Median time to RFBM after the first dose was 0.8 hour and 23.6 hours in MNTX and placebo groups, respectively (p<0.0001). Efficacy results during the OLE study were consistent with the RCT. MNTX demonstrated a favorable safety profile in the RCT and OLE study.Fixed-dose MNTX administered QOD in the RCT and PRN in the OLE study demonstrated robust efficacy and was well tolerated in treating OIC in patients with advanced illness.

SUBMITTER: Bull J

PROVIDER: S-EPMC4492709 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

Bull Janet J Wellman Charles V CV Israel Robert J RJ Barrett Andrew C AC Paterson Craig C Forbes William P WP

Journal of palliative medicine 20150514 7

<h4>Background</h4>Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); however, fixed-dose administration of MNTX may improve ease of administration.<h4>Objective</h4>The study objective was to assess safety and efficacy of fixed-dose MNTX in two phase 4 trials.<h4>Methods</h4>In a double-blind, randomized, placebo-controlled trial (RCT), patients w ...[more]

PMID: 25973526

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Project description:BackgroundOpioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for OIC.ObjectiveThe purpose of this analysis was to evaluate cumulative rescue-free laxation response with repeat MNTX dosing in patients with advanced illness who were refractory to current laxative regimens and to assess the influence, if any, of poor functional status on response to MNTX treatment.MethodsThis analysis included pooled data from patients with advanced illness and established OIC who were on a stable opioid regimen in a pivotal, randomized, placebo (PBO)-controlled clinical trial (study 302 [NCT00402038]) or a randomized, PBO-controlled Food and Drug Administration-required postmarketing study (study 4000 [NCT00672477]). Patients in study 302 received subcutaneous MNTX 0.15 mg/kg or PBO every other day, whereas those in study 4000 received MNTX 8 mg (body weight ≥38 to <62 kg), MNTX 12 mg (body weight ≥62 kg), or PBO every other day. Outcomes included cumulative rescue-free laxation rates at 4- and 24-hours postdose for the first 3 doses of study drug and time to rescue-free laxation. To assess if functional status influenced treatment outcomes, we performed a secondary analysis on the outcomes stratified by baseline World Health Organization/Eastern Cooperative Oncology Group performance status, pain scores, and safety.ResultsOne hundred eighty-five patients received PBO and 179 patients received MNTX. The median age was 66.0 years, 51.5% were women, 56.5% had a baseline World Health Organization/Eastern Cooperative Oncology Group performance status score >2, and 63.4% had a primary diagnosis of cancer. Cumulative rescue-free laxation rates were significantly higher with MNTX than PBO 4- and 24-hours after doses 1, 2, and 3 (P < 0.0001), and between-treatment comparisons remained significant (P < 0.0001) regardless of performance status. The estimated time to first rescue-free laxation was shorter for patients receiving MNTX versus PBO. No new safety signals were identified.ConclusionsRepeated use of MNTX represents a safe and effective treatment for OIC in patients with advanced illness regardless of baseline performance status. ClinicalTrials.gov identifier: NCT00672477. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX)© 2023 Elsevier HS Journals, Inc.

Project description:PurposeWe evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC).Patients and methodsThis analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated.ResultsOverall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups.ConclusionMethylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

Project description:PurposeTo evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.Patients and methodsWe analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately.ResultsThe safety population (patients receiving ≥1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P<0.0001; noncancer, 48.0% vs 10.0%; P<0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P<0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was <1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in <4 and <7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts.ConclusionSC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.

Project description:BackgroundMethylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.ObjectiveThis analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.MethodsThe analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age (< 65 years and ≥ 65 years). Endpoints included pain intensity scores, symptoms of opioid withdrawal, treatment-related adverse events (TRAEs), and rescue-free laxation (RFL) within 4 h of treatment.ResultsOverall, 1323 patients were < 65 years of age (n = 908, methylnaltrexone; n = 415, placebo) and 304 patients were ≥ 65 years of age (n = 171, methylnaltrexone; n = 133, placebo). Nonsignificant pain intensity score reductions were observed in all groups. In the older cohort, measures of opioid withdrawal did not show statistical differences from baseline in either the methylnaltrexone or placebo groups. The most frequently reported TRAEs were abdominal pain, flatulence, and nausea. Relative to the first dose, gastrointestinal TRAEs potentially related to opioid withdrawal declined with the second dose and were comparable with placebo, regardless of age. RFL response within 4 h of methylnaltrexone treatment increased significantly in both age cohorts relative to placebo.ConclusionsMethylnaltrexone use did not adversely affect pain control, opioid withdrawal effects, or AEs while providing effective RFL, regardless of age. These results suggest that age does not appear to influence the safety and efficacy of methylnaltrexone for OIC. Further research is needed to assess the impact of other factors that alter BBB permeability, such as dementia, stroke, or drug interactions, on the safety and efficacy of methylnaltrexone.Clinical trial registration numbersStudy 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.

Project description:BackgroundPrevious clinical trials with birch pollen subcutaneous immunotherapy have been conducted over a 1- to 2-year treatment period and involved mostly a single geographic location.ObjectiveThis study (EudraCT-Number: 2005-000025-35) intended to evaluate the effect of subcutaneous immunotherapy with high-dose hypoallergenic birch pollen allergoid in patients with confirmed moderate to severe seasonal allergic rhinitis/rhinoconjunctivitis over a 3-year course in 19 European centres.MethodsAdults with confirmed birch pollen allergy (n = 253) were randomized to preseasonal placebo (n = 129) or active treatment (n = 124). Primary endpoint was change in Symptom Medication Score after 2 years treatment (2007).ResultsThe change in Symptom Medication Score of active- vs placebo-treated patients for the Full Analysis Set (n = 227, 15.2% reduction, P = 0.0710) and Per-Protocol Set (n = 216, 16.7% reduction, P = 0.0523) showed a positive trend, although significance was not achieved. The primary endpoint, assessed in 2007, coincided with the lowest pollination during the study period. In a subgroup analysis of patients in the north-eastern region (n = 102), where birch is the major tree and consequently patients' exposure is higher, changes in Symptom Medication Score (32.7% reduction, P = 0.0034) and median number of well days (P = 0.0232) were highly significant in favour of the active group. During the open-label third year of treatment, the mean Symptom Medication Score of active-treated patients was further reduced despite an increased pollen count. Subcutaneous immunotherapy was well tolerated and consistent with the known safety profile.Conclusions and clinical relevanceAlthough the primary endpoint was not reached for the Full Analysis Set, a significant and clinically relevant effect on Symptom Medication Score was clearly demonstrated for the subgroup of patients in the north-eastern region of Europe, where birch is the predominant tree species. Proving efficacy of birch allergen subcutaneous immunotherapy is challenging due to the numerous factors influencing birch pollen allergen exposure in field studies.

Project description:PurposeOpioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain.Patients and methodsThis post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer.ResultsA total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea.ConclusionAfter the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

Dataset Information

Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

Publications

Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

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