scholarly journals Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 891
Author(s):  
Neel Mehta ◽  
Neal E. Slatkin ◽  
Robert J. Israel ◽  
Nancy Stambler
Keyword(s):  
Clinical Trials ◽  
Adverse Event ◽  
Adverse Events ◽  
Pain Intensity ◽  
Opioid Withdrawal ◽  
Withdrawal Symptoms ◽  
Chronic Noncancer Pain ◽  
Noncancer Pain ◽  
Post Hoc ◽  
Gastrointestinal Adverse Events

Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of adverse events after the first or second dose of methylnaltrexone or placebo. Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. Adverse events, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between adverse event frequencies and RFBM response were also evaluated. Results: The analysis included 1263 adult patients with chronic noncancer pain. Treatment-emergent adverse event rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%–5.3%; placebo: 6.6%−5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal adverse events on day 1. No associations between RFBM response and the frequency of adverse events were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Conclusions: Early-onset adverse events following methylnaltrexone treatment, particularly gastrointestinal adverse events, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.

Intensity of Withdrawal Symptoms During Opioid Taper in Patients with Chronic Pain—Individualized or Fixed Starting Dosage?

Pain Medicine ◽  
2019 ◽  
Vol 20 (12) ◽  
pp. 2438-2449 ◽  
Author(s):  
Natalia Bienek ◽  
Christoph Maier ◽  
Miriam Kaisler ◽  
Beate Michel-Lauter ◽  
Andreas Schwarzer ◽  
...  
Keyword(s):  
Pain Intensity ◽  
Rating Scale ◽  
Numeric Rating Scale ◽  
Opioid Withdrawal ◽  
Withdrawal Symptoms ◽  
Chi Square ◽  
Serious Adverse Events ◽  
Chronic Noncancer Pain ◽  
Starting Dose ◽  
Noncancer Pain

AbstractObjectiveControlled opioid withdrawal is recommended for patients with chronic noncancer pain (CNCP) with insufficient pain reduction or intolerable side effects while on opioid treatment. Few studies have investigated the management of opioid withdrawal (OW). Most common are protocols with an individualized starting dosage (ISD), calculated from the last opioid intake. After two cases of overdose, we introduced a novel withdrawal protocol using a low fixed starting dosage (FSD) for safety reasons. The present study compares the intensity of withdrawal symptoms using the Subjective Opioid Withdrawal Scale (SOWS) and incidences of serious adverse events (SAE) and dropouts in each taper schedule in 195 CNCP patients with OW in an inpatient facility.MethodsTwo protocols were compared: FSD (2014–2016): N = 68, starting dose: 90 mg morphine/d; and ISD (2010–2014): N = 127, starting dose: 70% of the patient’s daily morphine equivalent dose (MED). Outcome criteria: primary: mean daily SOWS score during the first 10 days (16 questions, daily score 0–64); secondary: change in pain intensity on a numeric rating scale (0–10), rate of dropouts and SAEs. Statistics: Student test, Mann-Whitney U test, chi-square test, analysis of variance, P < 0.05.ResultsThe mean daily SOWS score was lower in the FSD group (14.9 ± 9.4 vs 16.1 ± 10, P < 0.05) due to a lower rate of high-intensity withdrawal symptoms (12.4% vs 17.6%, P < 0.01), particularly in patients on >180 mg MED (9.7% vs 18.4%, P < 0.01). Pain intensity decreased after withdrawal, and the incidence of SAEs and dropouts was low in both groups.ConclusionsThe FSD protocol provides a lesser burden of withdrawal symptoms and equal patient safety. It can be recommended for OW in CNCP patients.

scholarly journals Onset and Resolution of Key Adverse Events in Valbenazine-Treated Patients with Tardive Dyskinesia: Pooled Analyses from Two Long-Term Clinical Trials

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 151-151
Author(s):  
Stephen R. Marder ◽  
Jean-Pierre Lindenmayer ◽  
Chirag Shah ◽  
Tara Carmack ◽  
Angel S. Angelov ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Tardive Dyskinesia ◽  
Suicidal Behavior ◽  
Prolonged Exposure ◽  
First Occurrence ◽  
Balance Disorder ◽  
Clinical Interest ◽  
Post Hoc

AbstractObjectiveTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Long-term safety of the approved TD medication, valbenazine, was demonstrated in 2 clinical trials (KINECT 3 [NCT02274558], KINECT 4 [NCT02405091]). Data from these trials were analyzed post hoc to evaluate the onset and resolution of adverse events (AEs).MethodsParticipants in KINECT 3 and KINECT 4 received up to 48 weeks of once-daily valbenazine (40 or 80 mg). Data from these studies were pooled and analyzed to assess the incidence, time to first occurrence, and resolution for the following AEs of potential clinical interest: akathisia, balance disorder, dizziness, parkinsonism, somnolence/sedation, suicidal behavior/ideation, and tremor.ResultsIn the pooled population (N=314), all AEs of potential clinical interest occurred in <10% of participants, with somnolence (9.6%), suicidal behavior/ideation (6.4%), and dizziness (5.7%) being the most common AEs. Mean time to first occurrence ranged from 36 days (akathisia [n=9]) to 224 days (parkinsonism [n=2]). By end of study (or last study visit), resolution of AEs was as follows: 100% (suicidal ideation/behavior, parkinsonism); >85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).ConclusionsIn long-term clinical trials, the incidence of AEs of potential clinical interest was low (<10%) and most were resolved by end of treatment (>70–100%). All patients taking valbenazine should be routinely monitored for AEs, particularly those that may exacerbate the motor symptoms associated with TD.FundingNeurocrine Biosciences, Inc.

scholarly journals A Bayesian meta-analytic approach for safety signal detection in randomized clinical trials

2017 ◽  
Vol 14 (2) ◽  
pp. 192-200 ◽  
Author(s):  
Motoi Odani ◽  
Satoru Fukimbara ◽  
Tosiya Sato
Keyword(s):  
Clinical Trials ◽  
Adverse Event ◽  
Adverse Events ◽  
Hierarchical Structure ◽  
Meta Analysis ◽  
Event Data ◽  
Analysis Model ◽  
Exact Test ◽  
Adverse Event Data ◽  
Fisher’S Exact Test

Background/Aim: Meta-analyses are frequently performed on adverse event data and are primarily used for improving statistical power to detect safety signals. However, in the evaluation of drug safety for New Drug Applications, simple pooling of adverse event data from multiple clinical trials is still commonly used. We sought to propose a new Bayesian hierarchical meta-analytic approach based on consideration of a hierarchical structure of reported individual adverse event data from multiple randomized clinical trials. Methods: To develop our meta-analysis model, we extended an existing three-stage Bayesian hierarchical model by including an additional stage of the clinical trial level in the hierarchical model; this generated a four-stage Bayesian hierarchical model. We applied the proposed Bayesian meta-analysis models to published adverse event data from three premarketing randomized clinical trials of tadalafil and to a simulation study motivated by the case example to evaluate the characteristics of three alternative models. Results: Comparison of the results from the Bayesian meta-analysis model with those from Fisher’s exact test after simple pooling showed that 6 out of 10 adverse events were the same within a top 10 ranking of individual adverse events with regard to association with treatment. However, more individual adverse events were detected in the Bayesian meta-analysis model than in Fisher’s exact test under the body system “Musculoskeletal and connective tissue disorders.” Moreover, comparison of the overall trend of estimates between the Bayesian model and the standard approach (odds ratios after simple pooling methods) revealed that the posterior median odds ratios for the Bayesian model for most adverse events shrank toward values for no association. Based on the simulation results, the Bayesian meta-analysis model could balance the false detection rate and power to a better extent than Fisher’s exact test. For example, when the threshold value of the posterior probability for signal detection was set to 0.8, the false detection rate was 41% and power was 88% in the Bayesian meta-analysis model, whereas the false detection rate was 56% and power was 86% in Fisher’s exact test. Limitations: Adverse events under the same body system were not necessarily positively related when we used “system organ class” and “preferred term” in the Medical Dictionary for Regulatory Activities as a hierarchical structure of adverse events. For the Bayesian meta-analysis models to be effective, the validity of the hierarchical structure of adverse events and the grouping of adverse events are critical. Conclusion: Our proposed meta-analysis models considered trial effects to avoid confounding by trial and borrowed strength from both within and across body systems to obtain reasonable and stable estimates of an effect measure by considering a hierarchical structure of adverse events.

Chronic Noncancer Pain Rehabilitation With Opioid Withdrawal: Comparison of Treatment Outcomes Based on Opioid Use Status at Admission

2004 ◽  
Vol 79 (6) ◽  
pp. 759-768 ◽  
Author(s):  
Jeffrey D. Rome ◽  
Cynthia O. Townsend ◽  
Barbara K. Bruce ◽  
Christopher D. Sletten ◽  
Connie A. Luedtke ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Opioid Withdrawal ◽  
Opioid Use ◽  
Chronic Noncancer Pain ◽  
Noncancer Pain

Reconsenting patients with cancer on clinical trials: Does added risk influence continued participation?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15610-e15610
Author(s):  
A. Elegbede ◽  
A. Andrei ◽  
A. Andrei ◽  
K. D. Holen
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Event ◽  
Side Effects ◽  
Adverse Events ◽  
Study Participant ◽  
P Value ◽  
Study Participation ◽  
Grade 5 ◽  
Study Results

e15610 Background: The general policy endorsed by multiple professional societies and cooperative groups regarding patients on cancer clinical trials states that subjects should be informed of new adverse events or significant developments during study participation and re-consented to continue on study. However, no information is known as to the effect of re-consenting on a patients’ decision to continue study participation. Our research question addresses how the severity of reported risk to other study participants will impact the subjects’ decision to continue participation in a clinical trial. Methods: We surveyed 34 patients with gastrointestinal (GI) tumors all of whom were currently enrolled in a clinical trial. The survey portrayed hypothetical adverse reactions affecting another study participant ranging from Grade 1 to Grade 5 according to the National Cancer Institutes Common Terminology Criteria for Adverse Effects v. 3.0. The survey asked about subjects’ opinions of the theoretical adverse event categorized as “would not be concerned,” “would be concerned, but would continue the study,” and “would discontinue the study.” Results: Patients willingness to continue the study was highest at Grade 1 with 97% of all participants. However, willingness to continue participation progressively declined as the severity of adverse events increased such that only 44% of participants would continue participation with a reported Grade 5 adverse event. Conclusions: Among surveyed GI cancer patients, willingness to continue participation in a clinical trial declined significantly as the severity of adverse events increased from Grade 1 to Grade 3 - 5 (p-value < 0.001. This could be due to multiple factors, including the terminal nature of the patients’ cancer, the side effects of study therapy and the patients’ response to study treatment. This data could produce a reasonable adverse event grade cut-off for re-consenting patients regarding new side effects. No significant financial relationships to disclose.

Real-World Safety of Emicizumab: The First Interim Analysis of the European Haemophilia Safety Surveillance (EUHASS) Database

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Aijing Shang ◽  
Nives Selak Bienz ◽  
Ravi Gadiraju ◽  
Tiffany Chang ◽  
Peter Kuebler
Keyword(s):  
Clinical Trials ◽  
Adverse Event ◽  
Adverse Events ◽  
Real World ◽  
Event Data ◽  
Publicly Traded ◽  
Real World Data ◽  
World Data ◽  
Safety Surveillance ◽  
Adverse Event Data

Introduction: Long-term data from the HAVEN 1-4 clinical trials reaffirmed the safety and efficacy of emicizumab (HEMLIBRA®) prophylaxis in persons with hemophilia A (PwHA; Callaghan M et al. ISTH 2019 presentation). However, early data from the first Phase III trial, HAVEN 1, identified a risk for thrombotic microangiopathy (TMA) or thrombotic events (TEs) when emicizumab was used alongside activated prothrombin complex concentrate (aPCC [FEIBA]; dosed on average a cumulative amount of &gt;100 U/kg/24 hours for ≥24 hours) leading to a warning in the label and ongoing safety monitoring. European Haemophilia Safety Surveillance (EUHASS) is a large pharmacovigilance program that monitors the safety of treatments for inherited bleeding disorders. The EUHASS registry includes real-world data on the use of emicizumab in a broad, representative population of PwHA. The objective of this analysis was to summarize thrombotic, TMA, and anaphylaxis events reported to EUHASS in association with emicizumab prophylaxis. Methods: EUHASS is an investigator-led program with 86 participating centers in 27 countries, with centers reporting information on all the individuals they treat, thus minimizing selection bias. Adverse event data were collected from all PwHA in EUHASS who received emicizumab prophylaxis during 2018. EUHASS adverse event data are not collected according to Medical Dictionary for Regulatory Affairs (MedDRA) classification; however, for this exploratory analysis, events were coded at MedDRA preferred term level as far as possible; endpoints are provided as descriptive statistics. Results: Data from 148 PwHA treated with emicizumab in 2018 were included in this analysis. Concurrent treatments included recombinant activated factor VII (rFVIIa; NovoSeven®; n=23 PwHA), factor VIII, (FVIII products other than Obizur®; n=9 PwHA) and aPCC (n=1 PwHA). Two adverse events were reported in 2018 (Table 1). One event was an acute reaction (rash), reported 48 hours after dosing of a PwHA treated with emicizumab only. He recovered from the rash; the frequency was 0.7% (1/148; 95% confidence interval [CI] 0.02-3.71%). The second event was a TE-a myocardial infarction that occurred 10 hours after emicizumab dosing in a PwHA age &gt;65 years receiving emicizumab and aPCC. The frequency of TE events was calculated as 0.7% (1/148; 95% CI 0.02-3.71%). No TMA or anaphylaxis events were reported. Conclusions: Among PwHA treated with emicizumab at centers participating in EUHASS during 2018, only two adverse events were reported and there were no cases of TMA or anaphylaxis. While a full assessment is reserved for the final analysis, these interim real-world data are not inconsistent with the adverse event profile of emicizumab observed in clinical trials. No new or emerging safety signals for emicizumab were identified. However, this analysis was limited by the low number of emicizumab treated PwHA-especially in those without FVIII inhibitors, and relatively short exposure time to emicizumab. Disclosures Shang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Gadiraju:I am 50% shareholder in my own private limited company (Ravi Gadiraju Pharma Ltd): Current equity holder in private company; F. Hoffmann-La Roche Ltd, Safety Scientist (Mar 19 to current): Current Employment; Britannia Pharmaceuticals, Senior PV officer (Feb 17 to Mar 19): Ended employment in the past 24 months. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Changes in pain intensity after discontinuation of long-term opioid therapy for chronic noncancer pain

Pain ◽  
2018 ◽  
Vol 159 (10) ◽  
pp. 2097-2104 ◽  
Author(s):  
Sterling McPherson ◽  
Crystal Lederhos Smith ◽  
Steven K. Dobscha ◽  
Benjamin J. Morasco ◽  
Michael I. Demidenko ◽  
...  
Keyword(s):  
Pain Intensity ◽  
Opioid Therapy ◽  
Chronic Noncancer Pain ◽  
Noncancer Pain
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