An innovative combination of cypropheptadine and prazosin for the treatment of alcohol use disorder: a double-blind, randomised, parallel-group, three-arm, multicentre, placebo-controlled phase 2 trial
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ABSTRACT: Introduction
Animal studies have shown that the simultaneous blockade of α1b-noradrenergic receptors and 5HT2A-serotonergic receptors strongly decreases alcohol intake. In addition, recent clinical studies have indicated that the selective α1b antagonist prazosin could be effective on alcohol use reduction in alcohol-dependent subjects. Objectives
Cocktail is a double-blind, randomised, parallel-group,
SUBMITTER: Aubin H
PROVIDER: S-EPMC9567187 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Project description:ObjectiveCurrent medications for alcohol use disorder do not target brain noradrenergic pathways. Theoretical and preclinical evidence suggests that noradrenergic circuits may be involved in alcohol reinforcement and relapse. After a positive pilot study, the authors tested the α-1 adrenergic receptor antagonist prazosin to treat alcohol use disorder in a larger sample.MethodNinety-two participants with alcohol use disorder but without posttraumatic stress disorder were randomly assigned to receive prazosin or placebo in a 12-week double-blind study. Medication was titrated to a target dosing schedule of 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime by the end of week 2. The behavioral platform was medical management. Participants provided daily data on alcohol consumption. Generalized linear mixed-effects models were used to examine the impact of prazosin compared with placebo on number of drinks per week, number of drinking days per week, and number of heavy drinking days per week.ResultsEighty participants completed the titration period and were included in the primary analyses. There was a significant interaction between condition and week for both number of drinks and number of heavy drinking days, such that the rate of drinking and the probability of heavy drinking showed a greater decrease over time for participants in the prazosin condition compared with those in the placebo condition. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition.ConclusionsPrazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups.
| S-EPMC6395537 | biostudies-literature
Project description:BackgroundThere is currently insufficient evidence on the safety and efficacy of antenatal corticosteroids in preventing mortality and severe morbidity amongst late preterm newborns in low-resource countries.MethodsWe conducted a double-blind, randomized trial in four hospitals in India between 26 December 2017 to 21 May 2020. Pregnant women at risk of imminent preterm birth between 34 weeks 0 days and 36 weeks 0 days of gestation were recruited. Women were randomly assigned (1:1) to a course of 6 mg intramuscular dexamethasone or an identical placebo. All trial participants, research staff and outcome assessors were masked to allocation. Primary outcomes were neonatal death, any baby death (stillbirth or neonatal death), severe neonatal respiratory distress and possible maternal bacterial infection. The study was registered with ANZCTR (ACTRN12617001494325) and CTRI (CTRI/2017/05/008721).FindingsWe randomized 782 women, 391 to each arm. Neonatal death occurred in 11 of 412 liveborn babies (2.7%) in the dexamethasone group and 12 of 425 liveborn babies (2.8%) in the placebo group (RR 0.95; 95% CI 0.42-2.12). Any baby death occurred in 16 of 417 infants (3.8%) in the dexamethasone group and 19 of 432 infants (4.4%) in the placebo group (RR 0.87; 95% CI 0.45-1.67). Severe neonatal respiratory distress was infrequent in both groups (0.8% vs 0.5%; RR 1.56; 95% CI 0.26-9.29). Possible maternal bacterial infection did not differ between groups (2.3% vs. 3.8%, RR 0.60; 95% CI 0.27-1.35). Fewer neonates in the dexamethasone group required resuscitation at birth (RR 0.38, CI 0.15-0.97). Other secondary outcomes were similar in the two arms. The trial was stopped due to lower than expected prevalence of primary outcomes and slow recruitment.InterpretationAntenatal dexamethasone did not result in a reduction in neonatal death, stillbirth or neonatal death, or severe neonatal respiratory distress in this trial. The overall trend of effects suggests that potential benefit of dexamethasone in late preterm cannot be excluded, and further trials are required.FundingThis trial was primarily funded by the Bill and Melinda Gates Foundation (Grant OPP1136821). Additional support was provided by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research; and Department of Maternal, Newborn, Child, Adolescent Health, and Ageing, of the World Health Organization, Geneva, Switzerland.
| S-EPMC8850324 | biostudies-literature
Project description:ObjectiveThis study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain.MethodsEligible patients were randomized to receive TTX (30 μg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures.Results165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis "intent-to-treat" population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient.ConclusionsAlthough underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114).
| S-EPMC5438848 | biostudies-literature
Project description:ObjectivesTakayasu arteritis (TAK) is a rare, chronic large vessel vasculitis with unmet treatment needs. This phase 3 study aimed to evaluate efficacy, safety, pharmacokinetics and immunogenicity of ustekinumab (UST) in Japanese patients with TAK.MethodsPatients with TAK who had relapsed ≤12 weeks prior to study intervention administration and achieved remission thereafter with standard-of-care including corticosteroid intensification were randomized 1:1 to receive UST or matching placebo with protocol-defined oral glucocorticoid taper regimen. The double-blind (DB) phase was up to the patient's relapse/total of 35 relapse events, followed by the open-label extension (OLE) phase. Primary endpoint was the time to relapse of TAK per protocol-defined criteria through the end of the DB phase.ResultsThe study was terminated early due to patient recruitment challenge. Of 14 patients randomized, 8 relapsed during the DB phase (UST: 4/6; placebo: 4/8). The median time to relapse (weeks) was 11.14 (95% CI: 4.14, not estimated [NE]) for UST and 12.64 (95% confidence interval [CI]: 12.14, NE) for placebo (hazard ratio [HR] = 1.86 [95% CI: 0.41, 8.47]). In the DB phase, one patient in each group reported serious adverse event (SAE; UST: vascular pseudoaneurysm and brachiocephalic artery stenosis; placebo: cholecystitis); none were related to study intervention. Through the OLE phase, 1/4 (25.0%) patients in the UST-UST group (vascular graft infection considered related to study intervention) and none in the placebo-UST had SAEs. There were no serious infections/deaths throughout the study.ConclusionThe efficacy of UST in patients with TAK cannot be adequately assessed as the pre-determined sample size was not reached, and the study was prematurely terminated. No new safety signal of UST was identified.Trial registrationClinicaltrials.gov, https://clinicaltrials.gov, NCT04882072; jrct.niph.go.jp, https://jrct.niph.go.jp, jRCT2061210007; Clinical Registry, CR108981.
| S-EPMC11919447 | biostudies-literature
Project description:IntroductionDelirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium.Methods and analysisThe MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebo-controlled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of follow-up.Ethics and disseminationThe Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media.Trial registration numberNCT02856594.
| S-EPMC5914725 | biostudies-literature
Project description:BACKGROUND:Anxiety disorders are the most prevalent class of lifetime disorders in China, and generalized anxiety disorder (GAD) is one of the most common but frequently overlooked anxiety disorders. Conventional pharmacological treatments for GAD have varying degrees of side effects, dependency, and/or withdrawal syndromes. Traditional Chinese medicine (TCM) is considered a valuable therapeutic option for anxiety disorders and a potentially effective technique to reduce the side effects associated with antipsychotic drugs. This trial aimed to evaluate the clinical efficacy and safety of Antianxiety Granule, a granular Chinese medicine compound, for treatment of GAD. METHODS/DESIGN:The current work is a multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial with a 6-week treatment schedule. The study consists of three periods: a 1-7-day screening period, a 6-week primary treatment period, and a 1-week follow-up period. Follow-up assessments will be conducted 1 week after the last visit with a face-to-face interview or by telephone. The clinical efficacy of Antianxiety Granule for the treatment of GAD will be evaluated by examining the change in the Hamilton anxiety scale (HAMA) score, state-trait anxiety inventory (STAI) score, and TCM symptom scale in patients with GAD who receive daily TCM treatment. Moreover, an intention-to-treat (ITT) analysis will also be used in this randomized controlled trial (RCT). DISCUSSION:Our study is a multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the safety and efficacy of Antianxiety Granule for the treatment of GAD. The results of this trial will provide valuable clinical evidence for the treatment of GAD. TRIAL REGISTRATION:Chinese Clinical Trial Registry, ChiCTR1800016039. Registered on 8 May 2018.
| S-EPMC6979338 | biostudies-literature
Project description:BackgroundNeutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.MethodsIn a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.FindingsBetween June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.InterpretationBrensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.FundingSponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.
| S-EPMC9442496 | biostudies-literature
Project description:Background. Although diosmectite has demonstrated efficacy in the treatment of acute watery diarrhoea in children, its efficacy in adults still needs to be assessed. The objective of this study was therefore to assess the efficacy of diosmectite on the time to recovery in adults with acute diarrhoea. Methods. A total of 346 adults with at least three watery stools per day over a period of less than 48 hours were prospectively randomized to diosmectite (6?g tid) or placebo during four days. The primary endpoint was time to diarrhoea recovery. Results. In the intention-to-treat population, median time to recovery was 53.8 hours (range [3.7-167.3]) with diosmectite (n = 166) versus 69.0 hours [2.2-165.2] with placebo, (n = 163; P = .029), which corresponds to a difference of 15.2 hours. Diosmectite was well tolerated. Conclusion. Diosmectite at 6?g tid was well tolerated and reduced the time to recovery of acute watery diarrhoea episode in a clinically relevant manner.
| S-EPMC3132498 | biostudies-literature
Project description:BackgroundAlcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.
| S-EPMC10783749 | biostudies-literature
Project description:To investigate the effect of supplementation of standard treatment (inhaled long-acting β2 agonists, anticholinergics and corticosteroids) with vitamin D on C reactive protein and pulmonary function tests in patients with COPD exacerbation.Randomized, single-center, double-blind, placebo-controlled parallel trial. One teaching hospital Participants: 135 patients in pulmonary ward with moderate to severe COPD and exacerbations.120 patients fulfilled the study protocol.Patients were randomly divided into three groups receiving 7 day treatment with 0.25 μg calcitriol daily (n = 45), 50000 IU daily of vitamin D (n = 45) or placebo (n = 45). An independent nurse was responsible for allocation, preparation, and accounting of trial medications.Maximal expiratory flow volume (FEV1) and forced volume capacity curves (FVC) and Modified Medical Research Council (MMRC) scale.Out of 135 patients who were recruited consecutively, 45 patients randomly were randomly assigned in three groups (balance blocked randomization.15 patients were dropped out due to non-compliance for second PFT. Intention to treat analysis was carried out for 120 participants. The difference between before and after treatment FEV1 and FEV1/FVC ratio had no significant difference between treatment groups and placebo. (P = 0.43, P = 0.51, respectively)but clinical improvement was significant in patients who received calcitriol. No side effects were reported.Short term treatment with either calcitriol or 25(OH) 2Vit D didn't changed FEV1 or FVC in vitamin D sufficient patients with COPD exacerbation; nevertheless it can provide clinical benefit.Iranian Registry of Clinical Trials no. IRCT138712271774N1. Registered 10 April 2011.
| S-EPMC5002185 | biostudies-other