Addiction Opiate Clinical Trial
Official title:
Evaluating the Safety of Acute Baclofen in Methadone-maintained Individuals With Opiate Dependence. An Adaptive, Single-blind, Placebo-controlled Ascending Dose Study of Acute Baclofen on Safety Parameters in Opioid Dependence During Methadone-maintenance Treatment; a Pharmacokinetic-pharmacodynamic Study
Opiate addiction is a major health challenge. The mainstay of treatment is opiate substitution therapy (OST), typically methadone, but many desire to be opiate-free. Abstinence in older opiate addicts with increasingly complex health needs may also be advantageous. Detoxification generally involves tapering of OST with adjunct medication to treat emerging symptoms, but these are often ineffective or inappropriate for longer-term prescribing. New treatments are therefore needed. The investigators propose that baclofen has the desired properties to facilitate OST detoxification. It is licensed for spasticity, is currently used to treat alcoholism and there is promising pre-clinical and clinical evidence of potential efficacy in opiate dependence. Common symptoms of withdrawal are likely to be improved by baclofen. Whilst the investigators clinical experience and other studies suggest baclofen can be taken safely with methadone, they could potentially interact causing adverse effects such as respiratory depression. Also, the possibility of abuse liability remains unexplored and is an important consideration in this indication. The investigators will therefore determine the safe dose combinations of baclofen and methadone and to assess if baclofen is 'liked'. Patients engaged in treatment for opiate dependence from community addiction services and receiving stable doses of OST with methadone will be invited to undergo screening at the Imperial Clinical Research Facility (ICRF) at Hammersmith hospital, or at their local addiction clinic. Up to 64 eligible patients will attend the ICRF for an experimental visit. Acute baclofen or placebo will be orally administered (randomised, single-blind, 3:1 ratio respectively) with the dose determined by a Bayesian adaptive trial algorithm. Measures will comprise respiratory, sedation, self-report and cardiovascular monitoring, and blood sampling for 5 hours post-dose. The study duration will be ~2-3 weeks from pre-screening phone call to the post visit follow up phone call.
This study will evaluate the safety of acute baclofen in methadone-maintained individuals with opiate dependence. The goal of the trial is to study the safety of these drugs given in combination using an adaptive, single-blind, placebo-controlled ascending dose design investigating the impact on respiratory, cardiovascular and pharmacokinetic-pharmacodynamic (PK-PD) parameters. This study will determine the maximum safe dose of baclofen depending on the prescribed dose of methadone. Methadone doses will vary depending on the recruited cohort, but the investigators anticipate an average dose of ~53mg (range 5 to 120mg), based on data from local drug and alcohol services. The investigators are seeking a minimum safe dose of 30mg baclofen in combination with a minimum of 60mg methadone. Findings will be used to inform a subsequent proof-of-concept trial of the efficacy of baclofen. The investigators will investigate each of the four factors of i) safety, ii) dose-response, iii) potential for abuse liability and iv) objective and subjective measures of GABA-B receptor sensitivity, providing clarity on the relationship between these factors. The investigators will include a placebo arm to evaluate the pharmacodynamic effects of baclofen, and to control for expectation effects. Safety will be established using a Bayesian dose-escalation adaptive model which will be informed by the occurrence of dose-limiting toxicity (DLT) events at increasing doses of baclofen at the following dose levels: 10, 30, 60, 90mg. The evaluation window for all outcomes will begin at dosing and end at 5 hours post-dose, with further follow-up by phone the following day. The DLT of primary concern is respiratory depression, and the investigators consider that the risk increases with the dose of baclofen and methadone-maintenance level. Formally, the objective is to find the combination associated with 15-25% risk of a DLT. The combination-toxicity response will be evaluated using the continual reassessment method, a model-based design for trials that aim to find the maximum tolerated dose, where the baclofen dose recommendation for each given patient with prescribed dose of methadone will be supported by the adaptive Bayesian model. Participants will be randomised (single-blind) to baclofen or placebo in a 3:1 ratio. If allocated to baclofen, participants will be dosed in groups of up to 3, with a maximum sample size of 48 allocated to baclofen, and 16 to placebo. Outcome measures that will be used to determine the incidence of a DLT will include oxygen saturation, respiratory rate, cardiovascular measures (ECG, blood pressure) and CNS effects (sedation, alertness). Transcutaneous CO2 and adverse events will also be monitored. The adaptive Bayesian model will be regularly updated (after each group of up to 3 participants administered baclofen) given the observed patients' responses, providing efficiency in decision-making, by recommending the most likely safe target individualised dose. The study can therefore be stopped earlier for safety if the model suggests that 30mg of baclofen and 60mg of methadone is highly likely to be unsafe. The study can also stop earlier if the highest dose of baclofen (90mg) is highly likely to be safe, i.e. shows no DLTs with 120mg of methadone, provided that the study has also achieved sufficient data to meet secondary endpoints. In addition to the approach described above, an evaluation of pharmacokinetic parameters will be investigated through regular blood sampling and assay of baclofen and methadone plasma concentrations. The pharmacodynamic effects of baclofen relative to placebo, and their dose separation will be determined through objective (plasma growth hormone concentrations) and subjective measures (visual analogue scales and questionnaires for drug effects, anxiety, sleep). The potential for abuse liability, relative to placebo, will be assessed using the Drug Effects Questionnaire. GABA-B receptor sensitivity will be determined through comparison of pharmacodynamic effects in comparison with historical healthy controls, using data derived from previous work using comparable measures and time-points at the 10 and 60mg baclofen dose levels. Primary & secondary endpoints: If the investigators find that all dose levels of baclofen are safe up to and including 90mg in combination with 120mg methadone (primary endpoint), the study can still continue up to the maximum sample size to achieve maximum precision for secondary outcomes, explore more methadone doses (<120mg) in a variety of participants and baclofen dose-response separation, as required. ;
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