Evaluating the Safety of Acute Baclofen in Methadone-maintained Individuals With Opiate Dependence.

NCT05161351 | Completed Phase 4 Results DMC

• 1 other identifier: 21HH6830
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Addiction Opiate

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Dose Limiting Toxicities

  The maximum safe dose of baclofen at which 15-25% of evaluable participants experience a dose limiting toxicity (DLT) for prescribed doses of methadone

  up to 24 hours after dosing

Study Arms (2)

Baclofen

EXPERIMENTAL

Participants will receive a single dose of either 10mg, 30mg, 60mg or 90mg of Baclofen administered as oral tablets.

Drug: Baclofen

Vitamin D3

PLACEBO COMPARATOR

Participants will receive a single dose of either 20μg, 60μg or 120μg of Vitamin D3 administered as oral tablets.

Drug: Vitamin D3

Interventions

Baclofen DRUG

Baclofen is the only selective GABA-B agonist licensed for human use. Originally developed as a potential anti-epileptic in the 1920s, it was found to have anti-spastic effects and is currently used for the treatment of spastic movement, especially in instances of spinal cord injury, spastic diplegia, multiple sclerosis, and amyotrophic lateral sclerosis.

Baclofen

Vitamin D3 DRUG

Placebo tablets will be vitamin D3, (colecalciferol).

Also known as: Placebo

Vitamin D3

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female
• Aged over 21
• Willing and able to comply with protocol
• Able to read, comprehend and record information written in English
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Healthy as determined by a responsible physician, based on a medical evaluation which includes medical history, a physical examination, laboratory tests (if required), and a psychiatric evaluation. A volunteer with clinical parameters outside the reference range for the population being studied may be included, only if the investigators concur that the finding is unlikely to jeopardize either subject safety or study integrity.
• DSM-5 diagnosis of current severe opioid use disorder
• Treated with methadone substitution therapy and able to maintain the same stable dose for screening and experimental visit.
• Ability to receive an acute dose of up to 90mg baclofen or up to 4800IU vitamin D (placebo).

You may not qualify if:

• Current DSM-5 substance dependence disorder for any other substance except for opiates and nicotine. Lifetime history of dependence on other substances will be allowed given very high incidence of co-dependence.
• Regular on-top use of heroin or other opiates or other illicit substances in combination with OST, which in the opinion of the investigators will interfere with subject safety or study integrity.
• Any participant taking over 120mg/day of prescribed methadone.
• Current severe DSM-5 mental health disorder (excluding opiate dependence). Current moderate or mild DSM-5 depressive, anxiety, sleep or personality disorders will be allowed given the high levels of comorbidity, provided in the opinion of the investigators, the participant is able to complete study procedures satisfactorily.
• Current or past history of enduring severe mental illness e.g. psychotic disorder (excluding drug induced), schizophrenia, bipolar affective disorder).
• Active suicidality.
• Use of regular prescription medications which in the opinion of the investigators will interfere with subject safety or study integrity. Regular use of psychotropic medication will be permitted e.g. antidepressants, provided the participant is compliant with administration and the investigators concur that they will not interfere with subject safety or study integrity.
• Participants are taking any medication that is contraindicated with baclofen or placebo (vitamin D3), or are hypersensitive to them or any of their excipients.
• Participants that are taking any medication that in the opinion of the investigators may impact on the outcome measures during the experimental session.
• Use of intermittent psychotropic medication which in the opinion of the investigators will interfere with subject safety or study integrity.
• End stage or acute renal failure.
• Severe chronic obstructive pulmonary disease (COPD) or Type 2 respiratory failure.
• Pulse rate \<40 or \>100 BPM OR systolic blood pressure \>160 and \<100 and a diastolic blood pressure \>95 and \<60 in the semi-supine position.
• Oxygen saturation \<92% at rest
• A screening ECG with a QTcB or QTcF \> 500 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T-wave) and/or with another ECG abnormality which in the opinion of the study physician is clinically significant and represents a safety risk. Note that if the initial QTc value is prolonged, the ECG should be repeated two more times (with 5 minutes between ECG readings) and the average of the 3 QTc values used to determine eligibility.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

Imperial College Healthcare Trust

London, W12 0HS, United Kingdom

Location

Related Publications (1)

• Paterson LM, Barker D, Cro S, Mozgunov P, Phillips R, Smith C, Nahar L, Paterson S, Lingford-Hughes AR. FORWARDS-1: 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. Trials. 2022 Oct 18;23(1):880. doi: 10.1186/s13063-022-06821-9.

  PMID: 36258248 RESULT

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

Baclofen; Cholecalciferol

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Results Point of Contact

• Title: Agnese Zicari,Quality Assurance Facilitator
• Organization: Imperial College London Faculty of Medicine

a.zicari08@imperial.ac.uk

+44(0)2075946615

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Adaptive, ascending-dose, parallel groups design.

Study Record Dates

• First Submitted: November 4, 2021
• First Posted: December 17, 2021
• Study Start: July 23, 2021
• Primary Completion: November 11, 2022
• Study Completion: November 11, 2022
• Last Updated: November 18, 2024
• Results First Posted: November 18, 2024

Record last verified: 2024-09

Locations

GB (1)