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Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study).

ABSTRACT: BACKGROUND:Current treatments for alcohol use disorders have limited efficacy and there is a high degree of variability in treatment response. In a randomised, placebo-controlled clinical trial, there was a large effect size for topiramate in people homozygous for the GRIK1 rs2832407*C allele. The primary aim of the TOP study is to examine prospectively the therapeutic and cost-effectiveness of topiramate versus an active control (naltrexone) in improving treatment outcomes for alcohol dependence. Participants will be stratified on rs2832407 to compare C-allele homozygotes with A-allele carriers to examine the moderating effect of rs2832407 on drinking outcomes. An exploratory aim is to examine the moderating effects of rs1799971, a polymorphism in OPRM1, on the response to naltrexone by comparing Asn40 homozygotes with Asp40 carriers. METHODS/DESIGN:This double-blind trial will randomise 180 alcohol-dependent participants to a 12-week regime of either topiramate (titrating the dose up to 200 mg/day) or naltrexone (50 mg/day). Participants will be stratified on the two polymorphisms before randomisation. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days per week and secondary drinking outcomes will include the time to relapse, the time to lapse and the percentage of abstinent days. Other secondary outcomes will include body mass index, tobacco use, anxiety symptoms and depressive symptoms. DISCUSSION:If successful, the TOP study will improve management strategies for alcohol dependence by providing support for the use of genetic biomarkers to inform medication selection. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03479086 . Registered on 27 March 2018.

SUBMITTER: Morley KC

PROVIDER: S-EPMC6097336 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study).

Morley Kirsten C KC Kranzler Henry R HR Luquin Natasha N Baillie Andrew A Shanahan Marian M Trent Ronald R Teesson Maree M Haber Paul S PS

Trials 20180816 1

<h4>Background</h4>Current treatments for alcohol use disorders have limited efficacy and there is a high degree of variability in treatment response. In a randomised, placebo-controlled clinical trial, there was a large effect size for topiramate in people homozygous for the GRIK1 rs2832407*C allele. The primary aim of the TOP study is to examine prospectively the therapeutic and cost-effectiveness of topiramate versus an active control (naltrexone) in improving treatment outcomes for alcohol d ...[more]

PMID: 30115121

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Project description:BackgroundExpansion of access to effective treatments for heroin dependence is a worldwide health priority that will also reduce HIV transmission. We compared the efficacy of naltrexone, buprenorphine, and no additional treatment, in patients receiving detoxification and subsequent drug counselling, for maintenance of heroin abstinence, prevention of relapse, and reduction of HIV risk behaviours.Methods126 detoxified heroin-dependent patients, from an outpatient research clinic and detoxification programme in Malaysia, were randomly assigned by a computer-generated randomisation sequence to 24 weeks of manual-guided drug counselling and maintenance with naltrexone (n=43), buprenorphine (n=44), or placebo (n=39). Medications were administered on a double-blind and double-dummy basis. Primary outcomes, assessed by urine testing three times per week, were days to first heroin use, days to heroin relapse (three consecutive opioid-positive urine tests), maximum consecutive days of heroin abstinence, and reductions in HIV risk behaviours over 6 months. The study was terminated after 22 months of enrolment because buprenorphine was shown to have greater efficacy in an interim safety analysis. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00383045.FindingsWe observed consistent, linear contrasts in days to first heroin use (p=0.0009), days to heroin relapse (p=0.009), and maximum consecutive days abstinent (p=0.0007), with all results best for buprenorphine and worst for placebo. Buprenorphine was associated with greater time to first heroin use than were naltrexone (hazard ratio 1.87 [95% CI 1.21-2.88]) or placebo (2.02 [1.29-3.16]). With buprenorphine, we also recorded significantly greater time to heroin relapse (2.17 [1.38-3.42]), and maximum consecutive days abstinent than with placebo (mean days 59 [95% CI 43-76] vs 24 [13-35]; p=0.003); however, for these outcomes, differences between buprenorphine and naltrexone were not significant. Differences between naltrexone and placebo were not significant for any outcomes. HIV risk behaviours were significantly reduced from baseline across all three treatments (p=0.003), but the reductions did not differ significantly between the three groups.InterpretationOur findings lend support to the widespread dissemination of maintenance treatment with buprenorphine as an effective public-health approach to reduce problems associated with heroin dependence.

Project description:BackgroundAspartame is a commonly used intense artificial sweetener, being approximately 200 times sweeter than sucrose. There have been concerns over aspartame since approval in the 1980s including a large anecdotal database reporting severe symptoms. The objective of this study was to compare the acute symptom effects of aspartame to a control preparation.MethodsThis was a double-blind randomized cross over study conducted in a clinical research unit in United Kingdom. Forty-eight individual who has self reported sensitivity to aspartame were compared to 48 age and gender matched aspartame non-sensitive individuals. They were given aspartame (100mg)-containing or control snack bars randomly at least 7 days apart. The main outcome measures were acute effects of aspartame measured using repeated ratings of 14 symptoms, biochemistry and metabonomics.ResultsAspartame sensitive and non-sensitive participants differed psychologically at baseline in handling feelings and perceived stress. Sensitive participants had higher triglycerides (2.05 ± 1.44 vs. 1.26 ± 0.84mmol/L; p value 0.008) and lower HDL-C (1.16 ± 0.34 vs. 1.35 ± 0.54 mmol/L; p value 0.04), reflected in 1H NMR serum analysis that showed differences in the baseline lipid content between the two groups. Urine metabonomic studies showed no significant differences. None of the rated symptoms differed between aspartame and control bars, or between sensitive and control participants. However, aspartame sensitive participants rated more symptoms particularly in the first test session, whether this was placebo or control. Aspartame and control bars affected GLP-1, GIP, tyrosine and phenylalanine levels equally in both aspartame sensitive and non-sensitive subjects.ConclusionUsing a comprehensive battery of psychological tests, biochemistry and state of the art metabonomics there was no evidence of any acute adverse responses to aspartame. This independent study gives reassurance to both regulatory bodies and the public that acute ingestion of aspartame does not have any detectable psychological or metabolic effects in humans.Trial registrationISRCTN Registry ISRCTN39650237.

Project description:Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV). Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid.

Project description:BACKGROUND:Untreated opioid addiction in people with HIV is associated with poor HIV treatment outcomes. Slow-release, long-acting, implantable naltrexone might improve these outcomes. Here, we present results of a study aimed to test this hypothesis. METHODS:We did a 48 week double-blind, double-dummy, placebo-controlled, phase 3, randomised trial with men and women addicted to opioids who were starting antiretroviral therapy (ART) for HIV and whose viral loads were higher than 1000 copies per mL. Participants were seeking treatment at two HIV and two narcology programme centres in Saint Petersburg, Russia, and the surrounding Leningrad region. The Pavlov statistical department created a table with stratification on gender distribution, viral load, and CD4 cell count. We stratified participants according to gender, viral load, and CD4 cells per μL, and randomly assigned (1:1) them to addiction treatment with a naltrexone implant and oral naltrexone placebo (implant group) or oral naltrexone and placebo implant (oral group). The primary outcome was plasma viral load of less than 400 copies per mL at 24 weeks and 48 weeks. We included all randomly assigned participants in outcome analyses (intention to treat). Treatment staff and patients were masked to group assignment. The study is complete and registered at ClinicalTrials.gov, NCT01101815. FINDINGS:Between July 14, 2011, and April 14, 2014, 238 potential participants were recruited and screened, 35 were excluded for not meeting inclusion criteria, three declined to participate, and 200 were randomly assigned to treatment (100 to each group). At week 24, 38 (38) participants in the implant group and 35 (35%) in the oral group had viral loads less than 400 copies per mL (risk ratio 1·1, 95% CI 0·76-1·56; p=0·77). At week 48, 66 participants in the implant group and 50 in the oral group had viral loads less than 400 copies per mL (risk ratio 1·32, 95% CI 1·04-1·68; p=0·045). There were seven serious adverse events: three deaths in the implant group (one due to heart disease, one trauma, and one AIDS), and four in the oral group (two overdoses, one pancreatic cancer, and one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. INTERPRETATION:The longer the blockade of opioid effects, the more protection an individual gets from missed ART doses and impulsive behaviours that lead to relapse and poor, even fatal, outcomes. Commercial development of implants could result in a meaningful addition to addiction treatment options. FUNDING:National Institutes of Health, National Institute on Drug Abuse, Penn Centre for AIDS Research, and Penn Mental Health AIDS Research Centre.

Project description:Naltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in young adults who engage in heavy drinking.A randomized, double-blind, placebo-controlled study was conducted in an outpatient research center in March 2008-January 2012. Participants were aged 18-25 years and reported ? 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All participants received a personalized feedback session and brief counseling every other week. Primary outcomes were percent heavy drinking days and percent days abstinent over the 8-week treatment period. Secondary outcomes included number of drinks per drinking day and percentage of days with estimated blood alcohol concentration (BAC) levels ? 0.08 g/dL.Of 140 randomized patients, 128 began treatment, comprising the evaluable sample. During treatment, percent heavy drinking days (naltrexone: mean = 21.60, SD = 16.05; placebo: mean = 22.90, SD = 13.20) (P = .58) and percent days abstinent (naltrexone: mean = 56.60, SD = 22.52; placebo: mean = 62.50, SD = 15.75) (P = .39) did not differ by group. Naltrexone significantly reduced the number of drinks per drinking day (naltrexone: mean = 4.90, SD = 2.28; placebo: mean = 5.90, SD = 2.51) (P = .009) and percentage of drinking days with estimated BAC ? 0.08 g/dL (naltrexone: mean = 35.4, SD = 28.40; placebo: mean = 45.7, SD = 26.80) (P = .042). There were no serious adverse events. Sleepiness was more common with naltrexone.Naltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce the amount of alcohol they drink.ClinicalTrials.gov identifier: NCT00568958.

Project description:IntroductionPlatelet-rich plasma (PRP) is a potentially efficacious treatment for ankle osteoarthritis (OA), but its use has not been examined in high-quality studies. Systematic reviews show that PRP injections significantly decrease pain and improve function in patients with knee OA. Ankle OA is more common than hip or knee OA in the young active population; with a prevalence of 3.4%.PRP injections in ankle OA are shown to be safe and improve quality of life over time, but no randomised controlled trial has been conducted. Our randomised controlled trial will evaluate the efficacy of PRP injections for symptom reduction and functional improvement, compared with placebo, in the treatment of ankle (talocrural) OA.Methods and analysisWe will conduct the Platelet-Rich plasma Injection Management for Ankle OA study: a multicentre, randomised, placebo-controlled trial. One hundred patients suffering from ankle OA will be randomised into two treatment groups: PRP injection or placebo (saline) injection. Both groups will receive two injections of PRP or placebo at an interval of 6 weeks. Primary outcome is the American Orthopaedic Foot and Ankle Society score at 26 weeks. Secondary outcomes determined at several follow-up moments up to 5 years, include Ankle Osteoarthritis Score, Foot and Ankle Outcome Score, pain subscale of (0-40), Visual Analogue Scale score (0-100), Ankle Activity Score (0-10), subjective patient satisfaction Short Form Health Survey-36, Global Attainment Scaling and the EuroQol-5 dimensions-3 levels utility score. A cost-effectiveness analysis will be performed at 1 year.Ethics and disseminationThe study is approved by the Medical Ethics Review Committee Amsterdam Medical Center, the Netherlands (ABR 2018-042, approved 23 July 2018) and registered in the Netherlands trial register (NTR7261). Results and new knowledge will be disseminated through the Dutch Arthritis Association (ReumaNederland), Dutch patient federation, conferences and published in a scientific peer-reviewed journal.Trial registration numberNTR7261.

Project description:Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. ClinicalTrials.gov identifier: NCT01673594.

Dataset Information

Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study).

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Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study).

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