Clinical trial NCT05161351
Conditions: Addiction Opiate
Sponsor: Imperial College London
Start date: 2021-07-23; Completion date: 2022-11-11
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:
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.

Arms: arm 1: Participants will receive a single dose of either 10mg, 30mg, 60mg or 90mg of Baclofen administered as oral tablets. arm 2: Participants will receive a single dose of either 20μg, 60μg or 120μg of Vitamin D3 administered as oral tablets.
Interventions: intervention 1: Baclofen intervention 2: Vitamin D3
Intervention descriptions: intervention 1: 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. intervention 2: Placebo tablets will be vitamin D3, (colecalciferol).

Protocol documents:
Prot_SAP_000.pdf: 
FORWARDS-Study1 protocol 
15.06.2021 
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Neuropsychopharmacology Unit 
Division of Psychiatry 
Department of Brain Sciences 
Burlington Danes Building 
Du Cane Road 
London W12 0NN 
Tel: 0207 5947028 
 
 
Full study title: FORWARDS-1; 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.  
 
Short title: FORWARDS-1; Evaluating the safety of acute baclofen in methadone-
maintained individuals with opiate dependence 
 
Protocol Version 1.0, 15 June 2021   
 
EudraCT number: 2021-002556-36    
REC Reference:  
IRAS Project ID: 1003802 
JRCO Ref No: 21HH6830 
Projected end date: 30-09-2022 
 
Sponsor: Imperial College London 
 
Funder: Medical Research Council MRC; MR/T025557/1 (Infoed- P86340) 
 
Chief Investigator: Professor Anne Lingford-Hughes 
 
Co-Investigators: Dr Louise Paterson, Dr Suzie Cro, Dr Claire Smith, Dr Sue 
Paterson, Dr Pavel Mozgunov 
 
Study co-ordination centre:  
Neuropsychopharmacology Unit 
Centre for Psychiatry 
Division of Brain Sciences 
2nd floor Commonwealth Building 
Du Cane Road 
London W12 0NN 
Tel: 0207 5947028  
 
Protocol authorised by:  Prof Anne Lingford-Hughes, Chief Investigator 
 
 
Signature:  
 
 
Date: 15 Jun 2021  


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CONTENTS 
1. GENERAL ADMINISTRATIVE INFORMATION ................................................................................. 6 
1.1 PROTOCOL INFORMATION ......................................................................................................................... 6 
1.1.1 Sponsor ............................................................................................................................................ 6 
1.1.2 Funder .............................................................................................................................................. 6 
1.1.3 Peer-Review ..................................................................................................................................... 6 
1.2 MAIN CONTACTS ...................................................................................................................................... 6 
1.2.1 Chief Investigator- Imperial College ............................................................................................... 6 
1.2.2 Co-Investigators ............................................................................................................................... 7 
1.2.3 Study co-ordinator ........................................................................................................................... 7 
1.3 SCREENING AND CONSENT SITES .............................................................................................................. 7 
1.3.1 NIHR Imperial Clinical Research Facility ....................................................................................... 7 
1.3.2 Imperial College Healthcare Trust (ICHT)...................................................................................... 7 
1.3.3 NOCLOR Research Support ............................................................................................................ 7 
1.3.4 Central and North West NHS Foundation Trust .............................................................................. 8 
1.3.5 CIPPRes clinic ................................................................................................................................. 8 
1.4 EXPERIMENTAL VISIT SITES ...................................................................................................................... 8 
1.3.1 NIHR Imperial Clinical Research Facility ....................................................................................... 8 
1.4 ABBREVIATIONS ....................................................................................................................................... 9 
2. BACKGROUND ......................................................................................................................................... 11 
2.1 THE PROBLEM AND UNMET NEED: THE CHALLENGE OF OPIATE ADDICTION AND THE NEED FOR NEW 
TREATMENTS ................................................................................................................................................ 11 
2.1.1 The burden of opiate addiction ...................................................................................................... 11 
2.1.2 Opiate substitution therapy and other treatments .......................................................................... 11 
2.2 THE PROMISE OF BACLOFEN .................................................................................................................... 12 
2.3 BACLOFEN- CLINICAL EVIDENCE FOR EFFECTIVENESS AND SAFETY IN ALCOHOL DEPENDENCE .............. 12 
2.4 BACLOFEN- CLINICAL EVIDENCE FOR EFFECTIVENESS IN OPIATE WITHDRAWAL ..................................... 13 
2.5 RATIONALE FOR THE STUDY ................................................................................................................... 14 
2.6 POTENTIAL FOR CNS DEPRESSANT EFFECTS- RATIONALE FOR RESPIRATORY MEASURES ........................ 15 
2.6.1 Respiratory depression .................................................................................................................. 16 
2.6.2 Sedation.......................................................................................................................................... 17 
2.6.3 Cardiovascular effects ................................................................................................................... 17 
2.7 DOSING CONSIDERATIONS- LESSONS LEARNED FROM SPASTICITY & ALCOHOL DEPENDENCE ................. 17 
2.8 GABA-B RECEPTOR SENSITIVITY ........................................................................................................... 18 
2.9 ABUSE LIABILITY BACKGROUND/RATIONALE ......................................................................................... 18 
2.10 STUDY SUMMARY ................................................................................................................................. 19 
3. STUDY AIMS AND OBJECTIVES ......................................................................................................... 20 
3.1 STUDY AIMS AND OBJECTIVES: .............................................................................................................. 20 
3.1.1 Primary study objective ................................................................................................................. 20 
3.1.2 Secondary study objectives: ........................................................................................................... 21 
3.1.3 Exploratory objectives ................................................................................................................... 22 
3.2 
STUDY HYPOTHESES: .......................................................................................................................... 22 
3.4 OUTCOME MEASURES ............................................................................................................................. 23 
3.4.1 Primary Outcome Measures .......................................................................................................... 23 
3.4.2 Definition of dose-limiting toxicity (DLT) ...................................................................................... 24 
3.4.3 STIMULUS INTERVENTION LEVELS: ...................................................................................................... 24 
3.4.4  Secondary Outcome Measures ...................................................................................................... 24 
3.4.5 Exploratory Outcomes ................................................................................................................... 25 
3.4.6 Evaluation window ......................................................................................................................... 26 
3.4.7 Evaluable patient ........................................................................................................................... 26 
4 STUDY DESIGN ......................................................................................................................................... 27 
4.1 DESCRIPTION OF OVERALL STUDY DESIGN ............................................................................................ 27 
4.2 STUDY VISITS .......................................................................................................................................... 28 
4.3 STUDY DESIGN SCHEMATICS ................................................................................................................... 29 
4.3.1 Study procedure schematic ............................................................................................................ 29 
4.3.2 Experimental Visit Schematic ........................................................................................................ 30 


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4.4 TREATMENT ALGORITHM ........................................................................................................................ 30 
4.4.1 Schematic for baclofen dose algorithm .......................................................................................... 31 
4.4.2 Baclofen dose decisions ................................................................................................................. 31 
5 STUDY PROCEDURES ............................................................................................................................. 33 
5.1 PRE-SCREENING PROCEDURES ................................................................................................................ 33 
5.2 SCREENING PROCEDURES ....................................................................................................................... 33 
5.2.1 Consent .......................................................................................................................................... 33 
5.2.1 Pregnancy test ................................................................................................................................ 33 
5.2.2 Breath Alcohol Level ...................................................................................................................... 34 
5.2.3 Urine Drug Screen ......................................................................................................................... 34 
5.2.4 Vital statistics and Vital signs ........................................................................................................ 34 
5.2.5 Medical examination ...................................................................................................................... 34 
5.2.6 Physical Examination .................................................................................................................... 34 
5.2.7 Respiratory Examination ............................................................................................................... 34 
5.2.8 Blood samples for clinical laboratory testing ................................................................................ 34 
5.2.9 Psychiatric history, drug & alcohol history, demographics .......................................................... 35 
5.2.10 Questionnaire measures ............................................................................................................... 35 
5.2.11 Cardiovascular measures............................................................................................................. 35 
5.2.12 Actigraphy measures .................................................................................................................... 35 
5.3 ENROLMENT PROCEDURES ...................................................................................................................... 35 
5.3.1 Anonymisation and randomisation ................................................................................................ 35 
5.4 EXPERIMENTAL STUDY VISIT PROCEDURES ............................................................................................. 36 
5.4.1 Eligibility check.............................................................................................................................. 36 
5.4.2 Methadone Dosing ......................................................................................................................... 36 
5.4.3 Baclofen or Placebo Dosing & Administration ............................................................................. 37 
5.4.4 Respiratory measures ..................................................................................................................... 37 
5.4.5 Intervention measures .................................................................................................................... 37 
5.4.6 Sedation measures.......................................................................................................................... 38 
5.4.7 ECG measures ............................................................................................................................... 38 
5.4.8 Vital Signs ...................................................................................................................................... 38 
5.4.9 Visual analogue scales ................................................................................................................... 38 
5.4.10 Other questionnaires .................................................................................................................... 39 
5.4.11 Plasma levels – Baclofen, Methadone, Growth Hormone ........................................................... 39 
5.4.12 Adverse events .............................................................................................................................. 39 
5.4.13 Actigraphy .................................................................................................................................... 39 
5.4.14 Debrief ......................................................................................................................................... 39 
5.4.15 Discharge ..................................................................................................................................... 39 
5.4.16 Emergency contact ....................................................................................................................... 39 
5.5 FOLLOW-UP ............................................................................................................................................ 39 
5.6 SCHEDULE OF EVENTS............................................................................................................................. 41 
5.6.1 Protocol events flexibility ............................................................................................................... 42 
5.7 STUDY MEDICATIONS .............................................................................................................................. 42 
5.7.1 Baclofen in licensed indication ...................................................................................................... 42 
5.7.2 Additional Supporting Information for the dose of baclofen .......................................................... 43 
5.7.3 Pharmacy and packaging ............................................................................................................... 44 
5.7.3.1 Baclofen ...................................................................................................................................... 45 
5.7.3.2 Placebo ....................................................................................................................................... 45 
5.7.4 Emergency Unblinding Procedure ................................................................................................. 45 
5.8 STUDY DURATIONS ................................................................................................................................. 45 
5.8.1 Protocol in event of experimental day failure ................................................................................ 45 
5.8.2 Withdrawal of Participants from the Study .................................................................................... 45 
5.8.3 Duration of the study period .......................................................................................................... 46 
5.8.4 Flexible visits ................................................................................................................................. 46 
5.8.5 Duration of the follow-up period ................................................................................................... 46 
5.8.6 Loss to follow-up ............................................................................................................................ 46 
5.8.7 Definition of completion of the study for an individual participant ............................................... 46 
5.8.8 Definition of the end of the study ................................................................................................... 46 
6 PARTICIPANT RECRUITMENT ............................................................................................................ 46 


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6.1 POPULATION ........................................................................................................................................... 46 
6.2 NUMBER OF PARTICIPANTS ..................................................................................................................... 47 
6.2.1 Definition of successful completion................................................................................................ 47 
6.3 RECRUITMENT STRATEGIES .................................................................................................................... 47 
6.4 ELIGIBILITY CRITERIA ............................................................................................................................ 47 
6.4.1 Inclusion Criteria ........................................................................................................................... 47 
6.4.2 Exclusion Criteria .......................................................................................................................... 48 
7 RISKS AND BENEFITS ............................................................................................................................. 50 
7.1 ETHICAL CONSIDERATIONS ..................................................................................................................... 50 
7.1.1 Potential Risks ............................................................................................................................... 50 
7.1.2 Potential Benefits ........................................................................................................................... 51 
8 STATISTICS AND DATA ANALYSIS PLAN ......................................................................................... 52 
8.1 GENERAL STATISTICAL PRINCIPLES ........................................................................................................ 52 
8.2 METHODS OF RANDOMISATION .................................................................................................... 52 
8.3.4 ANALYSIS OF GABA-B SENSITIVITY OUTCOMES ................................................................................. 54 
8.3.5 ANALYSIS OF EXPLORATORY OUTCOMES ............................................................................................. 54 
8.3.6 ADVERSE EVENTS ................................................................................................................................ 54 
8.3.7 MISSING DATA ..................................................................................................................................... 54 
9 DATA AND STUDY MANAGEMENT ..................................................................................................... 54 
9.1 DATA MONITORING & INTERIM ANALYSES ............................................................................................ 54 
9.2 DIRECT ACCESS TO SOURCE DATA & DOCUMENTS ................................................................................ 55 
9.3 DATA HANDLING AND RECORD KEEPING ................................................................................................. 55 
9.3.1 Personal data ................................................................................................................................. 55 
9.3.2 Study data management ................................................................................................................. 55 
9.3.3 OpenClinica ................................................................................................................................... 56 
9.3.4 REDCap ......................................................................................................................................... 56 
9.3.5 Custodian of the Data .................................................................................................................... 56 
9.3.6 Format of Records ......................................................................................................................... 56 
9.3.7 Duration & Location of stored data ............................................................................................... 57 
9.4 TRAINING AND USER SUPPORT ............................................................................................................... 57 
10 ADVERSE EVENT REPORTING .......................................................................................................... 57 
10.1 ADVERSE EVENTS AND ADVERSE REACTIONS ...................................................................................... 57 
10.1.1 Definitions .................................................................................................................................... 57 
10.1.2 CAUSALITY .................................................................................................................................... 58 
10.1.3 
REPORTING PROCEDURES ................................................................................................. 59 
10.1.4 NON SERIOUS AR/AES ................................................................................................................. 59 
10.1.5 SERIOUS AR/AES........................................................................................................................... 59 
10.2 CONTACT DETAILS FOR REPORTING SAES ............................................................................................ 60 
11 REGULATORY ISSUES .......................................................................................................................... 60 
11.1 
CTA ............................................................................................................................................... 60 
11.2 
ETHICS APPROVAL ................................................................................................................... 61 
11.3 
COMBINED WAYS OF WORKING ........................................................................................... 61 
11.4 
CONSENT..................................................................................................................................... 61 
11.5 
CONFIDENTIALITY ................................................................................................................... 61 
11.6 
INDEMNITY ................................................................................................................................ 61 
11.7 
SPONSOR ..................................................................................................................................... 61 
11.8 FUNDING ........................................................................................................................................... 61 
11.9 
AUDITS AND INSPECTIONS .................................................................................................... 62 
11.10 PUBLICATION POLICY.......................................................................................................................... 62 
11.11 PROTOCOL AMENDMENTS ................................................................................................................... 62 
12. 
TRIAL MANAGEMENT .................................................................................................................. 62 
13. 
STUDY MONITORING ................................................................................................................... 62 
13.1 
RISK ASSESSMENT ................................................................................................................... 63 


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12 REFERENCES .......................................................................................................................................... 64 
 


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1. GENERAL ADMINISTRATIVE INFORMATION 
1.1 Protocol Information  
This protocol describes the FORWARDS study and provides information about 
procedures for entering participants.  Every care was taken in its drafting, but 
corrections or amendments may be necessary. These will be circulated to 
investigators in the study.  Problems relating to this study should be referred, in the 
first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Framework for 
Health and Social Care Research. It will be conducted in compliance with the 
protocol, the Data Protection Act and other regulatory requirements as appropriate.  
 
1.1.1 Sponsor 
Imperial College is the sponsor for this study.  For further information regarding the 
sponsorship conditions, please contact the Head of Research Governance and 
Integrity at: 
 
Research Governance and Integrity Team 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 221, Medical School Building 
Norfolk Place 
St Mary’s Campus 
London, W2 1PG 
Tel: 0207 594 9480 (Keith Boland)/ 0207 594 1862 (Ruth Nicholson) 
http://www.imperial.ac.uk/joint-research-compliance-office 
1.1.2 Funder 
The Medical Research Council (MRC), United Kingdom, fund the study, grant 
number MR/T025557/1. 
1.1.3 Peer-Review  
The study has been externally peer reviewed and modified through the Medical 
Research Council Developmental Pathway Funding Scheme (MRC DPFS) 
Application Procedure, through discussions with independent international 
reviewers, and through exchanges with the MRC DPFS board. 
 
1.2 Main Contacts 
1.2.1 Chief Investigator- Imperial College 
Professor Anne Lingford-Hughes, 
Professor of Addiction Biology, 
Head, Centre for Psychiatry 
Division of Brain Sciences, 
Imperial College London,  
2nd floor Commonwealth Building,  
Hammersmith campus,  


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Du Cane Road,  
London W12 0NN. 
Tel: 020 7594 8682  
 
PA: Nicole Hickey – n.hickey@ic.ac.uk 
 
1.2.2 Co-Investigators 
Dr Louise Paterson, Dr Suzie Cro, Dr Claire Smith, Dr Sue Paterson, Dr Pavel 
Mozgunov 
1.2.3 Study co-ordinator 
Dr Louise Paterson, Ph.D, 
Neuropsychopharmacology Unit, 
Division of Psychiatry 
Imperial College London,  
2nd Floor Commonweatlh Building,  
Hammersmith Campus,  
Du Cane Road,  
London W12 0NN UK 
l.paterson@imperial.ac.uk 
Tel: 020 7594 7028 
 
1.3 Screening and Consent sites 
1.3.1 NIHR Imperial Clinical Research Facility 
NIHR Imperial CRF 
Imperial Centre for Translational and Experimental Medicine 
Imperial College Healthcare NHS Trust 
Hammersmith Hospital 
Du Cane Road 
London 
W12 0HS 
Imperial.CRF@nhs.net 
020 3313 8070 
1.3.2 Imperial College Healthcare Trust (ICHT) 
Imperial College Healthcare NHS Trust 
The Bays 
South Wharf Road 
St Mary's Hospital 
London W2 1NY 
020 3311 3311 
1.3.3 NOCLOR Research Support  
Mabel Saili 
NOCLOR Research Support 
1st Floor, Bloomsbury Building St Pancras Hospital 4 St Pancras Way London 
NW1 0PE. Support team: 020 7685 5949 or 020 3317 3034 


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Contact.noclor@nhs.net 
Mabel.saili@nhs.net, 0203 3173756 
1.3.4 Central and North West NHS Foundation Trust 
Trust Headquarters 
350 Euston Road 
Regent's Place 
London 
NW1 3AX 
1.3.5 CIPPRes clinic 
CIPPRes Clinic,  
CNWL Mental Health NHS Foundation Trust,  
St Charles Hospital,  
Exmoor Street, North Kensington, London W10 6DZ 
 
 
1.4 Experimental visit sites 
1.3.1 NIHR Imperial Clinical Research Facility 
NIHR Imperial CRF 
Imperial Centre for Translational and Experimental Medicine 
Imperial College Healthcare NHS Trust 
Hammersmith Hospital 
Du Cane Road 
London 
W12 0HS 
Imperial.CRF@nhs.net 
020 3313 8070 
 
 


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1.4 Abbreviations 
AE  
 
Adverse Event 
 
AGPs  
Aerosol generating procedures 
ASSIST 
Alcohol, Smoking and Substance Involvement Screening Test 
 
AUDIT  
Alcohol Use Disorders Identification Test 
 
BDI   
Beck Depression Inventory 
BMI   
Body mass index 
 
BP 
 
Blood pressure 
BT 
 
Body temperature 
CFR  
Code of Federal Regulations 
CI  
 
Chief Investigator 
Cmax   
Maximum (or peak) plasma concentration 
COPD  
Chronic obstructive pulmonary disease 
COWS 
Clinical Opiate Withdrawal Scale 
CRF  
Case Report Form 
CRM  
Continual Reassessment Method 
CTA  
Clinical Trial Authorisation 
DEQ  
Drug Effects Questionnaire 
DLT 
 
Dose Limiting Toxicity 
DMC   
Data Monitoring Committee 
DOA  
Drugs of abuse 
DPIA  
Data protection impact assessment 
DSC  
Dose Setting Committee 
DSM-5 
Diagnostic & Statistical Manual, version 5 
DSUR  
Development Safety Update Report 
eCRF  
Electronic Case Report Form 
ETCO2 
End tidal CO2 
FISMA 
Federal Information Security Management Act 
FEV  
Forced expiratory volume 
FVC  
Forced vital capacity 
FTND  
Fagerstrom Test for Nicotine Dependence 
 
GCP   
Good Clinical Practice 
GCS  
Glasgow Coma Scale 
GDPR  
General Data Protection Regulation (UK) 
GMP   
Good manufacturing practice 
 
GP  
 
General Practitioner  
HIV   
Human Immunodeficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
 
Heart Rate 
HRA  
Health Research Authority 
ICHNT 
Imperial College Healthcare NHS Trust 
ICRF  
Imperial Clinical Research Facility 
ICMJE 
International Committee of Medical Journal Editors 
IMP   
Investigational Medicinal Product 
LSEQ  
Leeds Sleep Evaluation Questionnaire 
LOC  
Level of Consciousness 
MHRA  
Medicines & Health Care Products Regulatory Agency 
MINI   
Mini International Neuropsychiatric Interview 
MRC   
Medical Research Council  


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NEWS2 
National Early Warning Score (version 2) 
NIHR   
National Institute for Health Research 
 
NIMP  
Non- Investigational Medicinal Product 
OCDUS-H 
Obsessive Compulsive Drug Use Scale—Heroin/opiates 
OST   
Opioid substitution therapy (methadone)  
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
R&D   
Research & Development 
REC   
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
RSI 
 
Reference Safety Information 
SAE   
Serious Adverse Event  
SAR   
Serious Adverse Reaction 
SDS  
Severity of Dependence Scale 
SHAS  
Subjective high assessment scale 
SOP   
Standard Operating Procedure 
SmPC  
Summary of Product Characteristics 
SpO2  
Oxygen saturation 
SPSS  
Statistical Package for the Social Sciences 
SSAI   
Spielberger State Anxiety Inventory 
SSAR  
Suspected Serious Adverse Reaction 
STAI   
Spielberger Trait Anxiety Inventory 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2  
 
Elimination half-life 
TLFB  
Time Line Follow Back 
Tmax   
Time to reach Cmax 
TMG  
Trial Management Group 
TSC  
Trial Steering Committee 
UDS   
Urine Drug Screen  
VAS   
Visual analogue scale 
 
WTAR  
Wechsler Test of Adult Reading  
 
 
 


 
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2. BACKGROUND 
2.1 The problem and unmet need: the challenge of opiate addiction and the need 
for new treatments 
2.1.1 The burden of opiate addiction 
Opiate addiction is a major health challenge, its adverse impact on health and social 
wellbeing clearly evident with death rates rising to record levels (Office for National 
Statistics, 2018). It is estimated that opioid dependent individuals face mortality risks 
that are 6–20 times higher than the general population with about half of any cohort of 
opioid users dying before they reach 50 (Darke et al., 2011; Degenhardt et al., 2011) 
 
Heroin is the most common illicit drug for which people seek treatment. The harm 
minimisation approach to treatment with opiate substitution medication (OST) and 
psychosocial support has been highly effective, but there is now an increasing focus on 
achieving abstinence (UK Home Office, 2017). Indeed abstinence is likely to be better 
for overall health, particularly in the aging opiate addict population who have been 
receiving long-term OST and ‘have increasingly complex health and social care needs’ 
(Advisory Council on the Misuse of Drugs, 2016). Chronic opioid exposure is associated 
with impaired respiratory function, lethal disorders of sleep, cardiovascular disorders 
and impaired immune function, particularly when comorbid with HIV (Stenbacka et al., 
2010). Chronic opioid exposure is also associated with impaired cognitive functioning 
such as inhibitory control, verbal working memory, cognitive impulsivity and cognitive 
flexibility, as well as in decision-making, emotional and reward processes (Baldacchino 
et al., 2017). 
2.1.2 Opiate substitution therapy and other treatments 
Large numbers of individuals receiving OST benefit considerably from their treatment 
and do not detoxify. Many opiate addicts desire and would benefit from abstinence, but 
find this hard to achieve and maintain. Opiate withdrawal can be difficult to tolerate due 
to disturbed sleep, anxiety and craving. These problems may persist into abstinence, 
increasing the risk of relapse.  
Slow tapering of opiate substitute treatment (OST) can attenuate symptoms during 
withdrawal. Alternatively, during detoxification, a range of prescribed adjunctive 
medications may be used to ameliorate symptoms, including hypnotics, sedatives or α2 
agonists (lofexidine), but their efficacy is limited and/or can only be used short-term. 
Medications for symptomatic relief are associated with tolerance/abuse liability (Z-
drugs, benzodiazepines, pregabalin), significant hypotension (clonidine) or are 
contraindicated in women of child-bearing age (valproate). Lofexidine was previously 
prescribed to assist with detoxification, but it remains unavailable in the UK, exposing 
an unmet need. With this loss of lofexidine, this is now even more crucial to develop a 
non-opioid approach to detoxification. This is particularly relevant when opioid 
dependence is uncertain since giving opioids can be dangerous (e.g. respiratory 
depression) or impracticable (e.g. in custody).  
Overall, outcomes for successful detoxification are therefore poor with a minority (30%) 
of heroin users who enter treatment achieving stable abstinence in 10 to 30 years (Hser 
et al., 2015). There is therefore a great unmet need for new treatments. Until recently, 


 
FORWARDS-Study1 protocol 
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research into improving evidence-based pharmacological management of opiate 
detoxification has therefore been very limited and more is urgently needed. 
 
2.2 The promise of baclofen 
Based on preclinical (Phillips & Reed, 2014) and clinical evidence (see later sections 
2.3 and 2.4), we propose that the GABA-B agonist, baclofen, has the desired properties 
to facilitate opiate detoxification and prevent relapse to opiate dependence. Baclofen is 
a generic medication that is currently licensed for spasticity and is well tolerated (Simon 
& Yelnik, 2010). It is prescribed off-label to treat alcoholism, such that rapid expansion 
and adoption by addiction services would be possible if trial outcomes of safety and 
efficacy in this indication are favourable.  
 
Evidence suggests baclofen will target dysregulated neurobiology during opiate 
withdrawal like lofexidine but also target anxiety, muscle aches, insomnia, and craving 
(Agabio et al., 2013). There is also data available from a small number of trials 
suggesting possible efficacy in supporting opiate withdrawal (Ahmadi-Abhari et al., 
2001; Akhondzadeh et al., 2000; Krystal et al., 1992). If shown to be safe in 
combination with methadone, baclofen can be taken as an adjunct during detoxification 
and has potential to be continued into abstinence for relapse prevention in a community 
setting. 
 
2.3 Baclofen- clinical evidence for effectiveness and safety in alcohol 
dependence 
The majority of trials of baclofen outside of its licensed indication of spasticity have 
been in alcoholism, with far fewer in other addictions. In alcoholism, two meta-analyses 
have both concluded baclofen is efficacious with “higher rates of abstinence” compared 
with placebo (Rose & Jones, 2018) and that greater efficacy is seen with doses 
<60mg/d than with higher doses (Pierce et al., 2018). A third meta-analysis however 
found no superiority of baclofen over placebo on the primary outcomes of each study, 
though abstinence was not the only outcome assessed here (Bschor et al., 2018). 
There has been debate regarding baclofen’s dose range, safety and indications (eg 
drinking vs abstinence) in treating alcoholism. The CI (Lingford-Hughes) and study 
manager (L Paterson) were members of an international consensus group which 
produced guidelines to address these issues regarding the use of baclofen to treat 
alcoholism (Agabio et al., 2018). There is also evidence in a small number of patients 
that baclofen may reduce acute symptoms of alcohol withdrawal (G. Addolorato, F. 
Caputo, E. Capristo, L. Janiri, et al., 2002; Addolorato et al., 2003). Further, GABA-B 
PAMs are also regarded to have potential for treating alcohol use disorder based on 
preclinical evidence  (Augier, 2021; Maccioni & Colombo, 2019). 
 
In cocaine addiction, baclofen blunts limbic activation associated with salient drug cues  
(Franklin et al., 2011; Young et al., 2014) and whilst baclofen (60mg/d) showed promise 
in reducing cocaine use in heavier users (Shoptaw et al., 2003), a larger follow-up study 
failed to show that baclofen helped achieve abstinence (Kahn et al., 2009). The authors 
queried whether baclofen doses needed to be higher to treat addiction than for 
spasticity.  
 
Preclinical work continues into developing positive allosteric modulators of GABA-B to 
treat a range of disorders including addiction (cf Addex partnership with Indivior and 


 
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NIDA; https://www.globenewswire.com/news-release/2019/02/14/1725152/0/en/Addex-
and-Indivior-to-Accelerate-Additional-GABAB-PAM-Compounds-for-Addiction-as-
Indivior-Elects-to-Stop-Development-of-ADX71441.html  
https://www.globenewswire.com/news-release/2020/11/02/2118115/0/en/Addex-
Receives-Additional-2-8-million-from-Indivior-and-Extends-GABAB-PAM-Research-
Collaboration.html  
 
2.4 Baclofen- clinical evidence for effectiveness in opiate withdrawal 
 
Many opiate addicts find detoxification and early abstinence challenging due to 
presence or fear of withdrawal symptoms including anxiety, insomnia, muscle aches, 
restless legs and craving that are prominent features of withdrawal. Clinical evidence 
suggests that such symptoms are likely to be improved by baclofen. In clinical studies, 
baclofen has demonstrated efficacy in relieving anxiety (G. Addolorato, F. Caputo, E. 
Capristo, M. Domenicali, et al., 2002; Breslow et al., 1989; Drake et al., 2003; Garbutt et 
al., 2010; Krupitsky et al., 1993), sleep disturbance (Orr et al., 2012) and restless legs 
(Mackie et al., 2017; Sandyk et al., 1988), as well as its known efficacy in its licensed 
indication for muscle spasms. Pre-clinical evidence of efficacy in animal models of 
opiate dependence include decreased self-administration of heroin, antagonism of 
conditioned place preference (CPP) to morphine, reduction in stress- and drug-induced 
reinstatement of opioid CPP and attenuation of morphine withdrawal in response to 
baclofen (for review see Phillips & Reed, 2014).  Clinical evidence of its efficacy in 
alcohol and cocaine dependence (see above), coincides with some small-scale studies 
investigating the potential efficacy of baclofen in opiate dependence.  
 
A lab-based study showed that baclofen (40mg, 60mg) attenuated ‘relatively mild’ 
opiate withdrawal symptoms from reducing or not taking methadone (66.4±23mg) (Jaffe 
et al., 1982). Another study investigating cocaine addiction recruited some (Bagley et 
al., 2005; Bagley et al., 2011) participants taking methadone (70-140mg/d)(Haney et al., 
2006). Whilst baclofen’s (30mg/d, 60mg/d) effects on cocaine-related outcomes were 
equivocal, no safety issues arose. Further evidence comes from two clinical trials in 
opiate withdrawal and one in relapse prevention. An open-label inpatient study found 
that baclofen (mean:68+13mg/d) improved opiate withdrawal after abruptly stopping 
methadone (15-25mg/d) in 2 of 5 participants and was well tolerated (Krystal et al., 
1992). Further, Krystal concluded that baclofen may have a role as an adjunct in 
managing opiate withdrawal though noted it did not meet their expectation in treating 
clonidine-resistant symptoms and that higher baclofen doses may be required to 
suppress withdrawal symptoms. In an Iranian study of addicts withdrawing from illicit 
opiate use, baclofen alone (≤40mg/d) compared favourably with clonidine in improving 
‘mental’ and physical withdrawal (Ahmadi-Abhari et al., 2001; Akhondzadeh et al., 
2000). Treatment retention and drop-out rates were equivalent (~50%). The majority of 
participants reported no side-effects. In abstinence, a relapse prevention study reported 
that baclofen (60mg/d) showed no benefit in opiate-positive urinalysis but some 
improvements in treatment retention and symptoms (Assadi et al., 2003). No particular 
safety concerns were raised in these studies.  
 
The full extent of studies of baclofen in opiate dependence are summarised below in 
Table 1. Comparative details of our proposed proof-of-concept efficacy study that would 
follow on from successful completion of this safety trial is given in the final column. 


 
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Table 1: Clinical trials in opiate addiction compared with our proposed efficacy 
study, FORWARDS-2. 
Study 
Krystal 1992 
Akhondzaheh 
2000 & Ahmadi-
Abhari 2001 
Assadi, 2003 
FORWARDS-2 
Country 
US 
Iran 
Iran  
UK 
Number 
5 
62 
40 
56 
Setting 
Inpatient  
Unclear  
Outpatient  
Outpatient  
Design 
Open 
RCT 
RCT 
RCT 
Treatment stage  Detoxification: 
methadone 
stopped abruptly 
Detoxification: 
stopped illicit 
use; no OST 
Relapse 
prevention after 
opiate detox 
Detox: reduction 
in methadone  
<12 weeks 
OST and dose 
Methadone  
21 + 4.2 mg/day 
None  
None 
Methadone, 
from study 1 
Baclofen  
Alone 
Alone  
Alone 
Adjunct 
Baclofen dose: 
(divided doses) 
68.0 +13mg/d; 
(max <80mg/d  
40mg/d 
60mg/d 
<90mg/d 
Comparator 
None 
Clonidine 
Placebo 
Placebo 
Outcome  
2/5 participants 
completed 
baclofen 
protocol; 
completers had 
less opiate 
withdrawal 
Baclofen showed 
promise treating 
‘physical and 
mental’ 
symptoms 
Baclofen resulted 
in better 
treatment 
retention, less 
withdrawal, 
depressive 
symptoms but not 
fewer +ve opiate 
urines 
 
Side-effects, 
adverse events, 
safety. 
No information 
about how these 
were evaluated 
though stated “ 
80 mg/day was 
tolerated without 
evidence of side 
effects in this 
group of 
patients”. 
“baclofen 
seemed 
remarkably 
benign”, with an 
absence of 
sedation or 
hypotension 
(unlike clonidine) 
Not described 
Adverse events 
were assessed 
systematically 
with a designed 
score sheet. No 
pts in either of the 
treatment groups 
reported adverse 
effects that 
required dose 
reduction or 
termination from 
the study; no 
statistically 
significant 
differences in 
adverse effects 
were found btw 
the 2 groups  
We will 
systematically 
assess side-
effects, adverse 
event and safety  
 
2.5 Rationale for the study  
Our targeted need is to facilitate opiate detoxification to improve outcomes for those 
opiate addicts who are on OST but want to be opiate-free. Whilst the evidence from the 
trials of baclofen-assisted detoxification in opiate dependence are supportive and 
showed no particular safety concerns, their target population differs from that within the 


 
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UK, where typical community detoxification involves gradual OST reduction over the 
course of 12 weeks or so.  
 
To investigate whether baclofen facilitates opiate detoxification, we must first establish 
that baclofen can be used safely in a typical UK population of opiate addicts undergoing 
community-based detoxification.  
 
As baclofen and the most common opiate substitute treatment, methadone, are CNS 
depressants, we must determine what dose of each is safe to co-prescribe, particularly 
as patients may take other CNS depressants that are known to contribute to opiate-
related deaths (ACMD, 2016). We also need to assess the abuse liability of baclofen in 
this vulnerable population given the additional risk posed to the individual and the 
possibility for diversion. 
 
Of primary importance is safety, i.e. what dose of baclofen is safe to co-prescribe with 
methadone, however we also wish to minimize the potential issue of dose uncertainty in 
opiate addiction, by determining safety parameters alongside assessing GABA-B 
system sensitivity in our target population.  
 
Therefore, the following additional important factors must be considered:  
 
1. The potential for CNS depressant effects of combining baclofen and methadone, in 
particular, the potential for interaction to cause respiratory depression, marked sedation 
and cardiovascular effects.  
2. Dose. The range of doses suggested to be most effective in alcoholism (30-60mg/d) 
are broadly consistent with those administered in the opiate withdrawal studies of 
baclofen described (40-80mg/d). Therefore we aim for 30mg as a minimum target dose 
in our indication, but uncertainty exists around the target maintenance dose.  
3. GABA-B receptor sensitivity. Related to the above, we have shown that 
pharmacodynamic responses to baclofen are markedly blunted in alcoholism 
suggesting possible alterations in receptor function (Durant et al., 2018). The same may 
also apply in opiate dependence, with potential consequences for dosing and efficacy 
signal.  
4. The potential for abuse liability- if a signal exists, there are particular risks in this 
vulnerable population of misuse and diversion, and these must be mitigated in any 
future study.  
 
2.6 Potential for CNS depressant effects- rationale for respiratory measures  
 
There are no formal RCT studies directly assessing the CNS depressant effects of 
baclofen in combination with opioids. A retrospective cohort study of opioid overdose 
found a small increased odds ratio for concomitant baclofen use compared with opioid 
use alone (Li et al., 2020) , however those with substance use disorder were specifically 
excluded. There are also no specific reports of an interaction between baclofen and 
methadone specifically, although baclofen has been shown to potentiate opioid effects 
such as morphine-induced analgesia (Gordon et al., 1995) and fentanyl-induced 
anaesthesia ((Corli et al., 1984; Panerai et al., 1985) with iv or im dosing). The potential 
for a mechanistic interaction is plausible due to co-localisation of spinal GABA-B and 
opioid receptors in lamina II of the dorsal horn, an important site for nociceptive 


 
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processing in C fibre primary afferent neurones, although a supraspinal mechanism 
cannot be ruled out.  
Baclofen alone can cause sedation and has been shown to cause respiratory 
depression at high doses. In alcohol dependence chronic baclofen was found to be 
associated with increased risk of all-cause hospitalization and mortality, particularly at 
high doses (>180mg/day, (Chaignot et al., 2018)). Again, those receiving OST were 
specifically excluded from the analysis. 
In other studies of baclofen alone, a case series collected over 5 years identified signs 
of toxicity in 9 individuals suffering from severe renal impairment after taking a short 
course of baclofen (Chen et al., 1997). The authors noted that altered consciousness 
was the major presenting feature and that respiratory depression was relatively 
uncommon. A more recent observational study has suggested an association between 
respiratory depression and baclofen use in spasticity with chronic kidney disease, 
related to increased circulating baclofen levels (Mitsuboshi, 2021). Other studies 
mentioning incidence of respiratory depression have been in the context of overdose 
e.g. in adolescents consuming between 60 and >600mg baclofen in a non-lethal ‘mass 
intoxication’ (Perry et al., 1998). 
Cases of sleep disordered breathing have been reported amongst those taking chronic 
baclofen e.g. central sleep apnoea in four individuals receiving chronic baclofen for 
alcohol withdrawal (NB n=3 were taking >150mg daily, (Olivier et al., 2016)), which was 
subsequently managed by adaptive servi-ventilation or baclofen cessation. In contrast, 
in a study of susceptible snorers baclofen (25mg) did not alter sleep disordered 
breathing (Finnimore et al., 1995). Chronic opioid use, including methadone, is also 
associated with central sleep apnoeas (Correa et al., 2015). 
Due to the inherent risks of combining CNS depressant drugs such as baclofen and 
methadone, and the vulnerability of this patient group, we will seek to understand 
whether any respiratory, sedative and cardiovascular effects occur following baclofen 
administration in combination with methadone in a single ascending dose study, 
incorporating pharmacokinetic-pharmacodynamic measures. 
Monitoring of both cardiovascular and respiratory function will occur, and both will be 
assessed for significant clinical impairment at screening and forms part of the exclusion 
criteria.  
2.6.1 Respiratory depression 
Standard clinical practice for measuring respiratory depression involves monitoring for 
hypoventilation using pulse oximetry and respiratory rate. However, when combined 
with measures of carbon dioxide partial pressure (pCO2), this can provide a more 
sensitive and earlier indicator of respiratory depression. In addition, evidence suggests 
that individuals with opiate dependence may display hyposensitivity to pCO2 (Jolley et 
al., 2015; Tas et al., 2020). 
 
Whilst there is no unified definition of ‘respiratory depression’ the most well described 
indicators of significant respiratory depression are as follows:  
• Persistent reductions in SpO2 (e.g. <90% for more than 10 seconds; (Jolley et al., 
2015) 
• Absence of inspiratory airflow (apnoea) > 30 seconds combined with a sustained 
fall in SpO2 
• Sustained ETCO2% per breath exceeding 6.5% (Jolley et al., 2015) 


 
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• Sustained CO2 partial pressure increase by 1kPa (normal range 4.7-6.0 kPa) 
• Respiratory rate <9/min (from the NEWS2 score) 
 
In the UK, NHS England has adopted the National Early Warning Score (NEWS2), first 
produced in 2012 and updated in December 2017, which advocates a system to 
standardise the assessment and response to acute illness. We will use NEWS2 
definitions for the thresholds for triggering an urgent ward-based response as our 
criteria for determining whether a dose-limiting ‘toxicity’ (DLT) event has occurred 
following co-administration of baclofen and methadone. This will include monitoring of 
respiratory rate, oxygen saturation, body temperature, systolic blood pressure, pulse 
rate and level of consciousness or new confusion (ACVPU; alert, confusion, voice, pain, 
unresponsive).  
2.6.2 Sedation 
Sedation is the most common side effect of baclofen, particularly at higher doses. In 
healthy controls, we observed mild to moderate sedation in a healthy control cohort 
following acute doses of 60mg and above, but no such sedation in alcohol dependent 
participants with doses up to 90mg (Durant et al., 2018). We will monitor sedation using 
the Glasgow Coma Scale, NEWS2 scale and self-reported drug effects (Subjective High 
Assessment Scale (SHAS) and Leeds Sleep Evaluation Questionnaire (LSEQ) which 
both include specific items related to sedation. 
2.6.3 Cardiovascular effects 
Cardiovascular effects are not commonly reported in response to baclofen, except in 
studies of renal impairment or after very high doses e.g. in overdose (Nugent et al., 
1986; Roberge et al., 1994). Evans et al reported a small effect of 80mg acute baclofen 
to increase heart rate (increase of 10 bpm) and blood pressure (121 to 125 mmHg) at 2 
hours post dose, which returned to normal after 6 hours (Evans & Bisaga, 2009). In our 
acute study, we observed no overall significant effects on heart rate or blood pressure 
(Durant et al., 2018). 
Methadone is reported to prolong QT interval, however there are no reports of QT 
prolongation following baclofen, therefore there is no indication that they are not safe to 
use together with respect to QT intervals. 
We will monitor QT and cardiovascular parameters for signs of acute change after 
baclofen administration. 
2.7 Dosing considerations- lessons learned from spasticity & alcohol dependence  
In prescribing baclofen for alcohol dependence, variability in response and the lack of 
robust biomarkers to guide the target maintenance dose means that the target dose for 
an individual is not well characterised. It is therefore titrated up until clinical benefit is 
achieved. Typically, 30mg daily or above is prescribed, to be taken in 3 divided doses. 
This minimum target dose of 30mg for this trial is supported by the literature suggesting 
that baclofen is efficacious in relapse prevention and in the reduction in daily drinking (G 
Addolorato et al., 2002; G Addolorato et al., 2007; Flannery et al., 2004) 
 
The main dose and titration limiting factor for baclofen is sedation, though this is also 
variable, with some individuals able to tolerate very high doses. Consequently, high 
doses of baclofen were in use for some patients in alcohol dependence (≤300mg/d; 10x 
higher than initial RCT). However, since meta-analyses have since established that 


 
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doses ≥60mg are no more effective than lower doses, safety concerns led the French 
authorities to approve use of baclofen in alcoholism only up to 80mg/d (Inserim et al., 
2017). We have no reason to believe that doses over 90mg will be required in opiate 
dependence, so do not intend to go above this. 
2.8 GABA-B receptor sensitivity  
Consistent with historical prescribing of high doses of baclofen in alcohol dependence, 
we previously conducted a pharmacokinetic-pharmacodynamic (PK/PD) study to 
understand if the pharmacokinetics of baclofen and/or the sensitivity of the GABA-B 
system itself is altered in alcoholism that might inform what is the optimal dose (Durant 
et al 2018). We successfully established a protocol using a range of subjective and 
objective measures as well as an assay to measure plasma baclofen levels in healthy 
controls (n=12) and abstinent alcohol dependent individuals (n=8), who received single 
oral doses of baclofen or placebo in a crossover design, suggesting reduced GABA-B 
sensitivity in alcohol dependence. Preliminary evidence is suggestive of similarly 
blunted sensitivity in opiate dependence (Volpi et al., 1992). This may contribute to the 
variability in treatment response, variability in the emergence of side-effects, and may 
explain the lack of superiority of baclofen over placebo in some studies in alcoholism. 
  
The association between the dose of baclofen, experience of sedation and other 
pharmacodynamic effects, and the relationship to subsequent treatment efficacy, is 
currently poorly understood. In addition, baclofen dose is known to be a poor predictor 
of blood concentrations, adding further heterogeneity to the signal. It is therefore 
important to develop a better understanding of this dose-response relationship. If we 
were to demonstrate the safety of baclofen, and proceeded with an efficacy trial using 
flexible dosing without knowing the PK-PD parameters, this would hamper our ability to 
titrate effectively. This is important because from clinical experience, individuals require 
resolution of their difficulties quickly so being able to titrate faster to a maximum dose, 
as required, will be advantageous.  
 
We will therefore apply a similar PK-PD protocol to assess GABA-B sensitivity in opiate 
addicts receiving methadone with enhanced measurements to assess safety. Data 
derived from historical controls who took part in the previous protocol will be used in the 
current protocol to provide a comparator group. This will empirically test whether our 
opiate population are similarly more tolerant to baclofen as we found in alcoholism. If 
similar sub-sensitivity is observed in opiate dependence, this would be highly 
suggestive that it would also be found in other addictions, such as cocaine, and 
therefore more broadly inform development of medications targeting GABA-B system in 
addiction. 
 
2.9 Abuse liability background/rationale 
Concerns have been raised about the potential for abuse liability of baclofen (Gahr et 
al., 2014; Praharaj, 2018), and following reports of ‘liking’ in alcoholic populations. So 
far, this possibility is not borne out by evidence in RCTs of chronic baclofen in alcohol 
dependence. Acutely, our own study reported no significant “alcohol-like” or “drunk” 
effects on the subjective high assessment scale (SHAS) following 60 or 90 mg of 
baclofen. However on the drug expectancy questionnaire (DEQ), although there were 
no overall significant effects, there was a suggestion of increased “high” and “liking” 
effects after the 90 mg dose. Anecdotally, several participants stated that they enjoyed 
the effects, and likened them to those of opiates or benzodiazepines. This has potential 


 
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implications for abuse liability, particularly at higher doses, and requires further study. 
Another study in heavy social drinkers observed no liking effect, but did report ‘good 
grud effect’ and ‘evevated mood after 80mg acute baclofen (Evans & Bisaga, 2009). 
In other studies, possible evidence of abuse liability of baclofen in alcohol dependence 
was observed when used in combination with alcohol, but baclofen alone did not result 
in any measurable change in signal (Farokhnia et al., 2017).  
The extent of this possible abuse liability needs to be assessed in the vulnerable opiate 
population due to a possible risk of misuse, in particular when combined with OST, with 
the aim to address this in future studies, if an abuse liability signal is detected. 
 
2.10 Study Summary 
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 we anticipate an average dose of ~53mg (range 5 to 120mg), based on data 
from local drug and alcohol services. We 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. We 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. We 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 we 
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 (Wheeler et al., 2019), 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). End tidal CO2 and adverse events will also be 
monitored. 


 
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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 (Durant et al., 2018). 
 
Primary & secondary endpoints: If we 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 variery of 
participants and baclofen dose-response separation, as required. 
 
3. STUDY AIMS AND OBJECTIVES 
 
3.1 Study Aims and Objectives: 
The primary objective of our programme of research is to establish whether baclofen 
can facilitate successful opiate detoxification. Due to the inherent risks of combining 
CNS depressant drugs, we will first determine the safety parameters of taking baclofen 
in combination with methadone in a single ascending dose study using a Bayesian 
dose-escalation adaptive model, incorporating pharmacokinetic-pharmacodynamic 
measures in a randomised, placebo-controlled design. 
3.1.1 Primary study objective 
 
1. Aim to determine whether we can safely proceed prescribing a minimum of 30mg 
baclofen to clients receiving a range of doses of methadone (a minimum of 60mg) 
through determination of: 
o Lack of CNS depressant activity using measures of respiratory function, 
cardiovascular function and sedation as follows: 
▪ Respiratory function (respiration rate, oxygen saturation, end-tidal and/or 
transcutaneous CO2) 
▪ Requirement for intervention (scored according to step-wise algorithm) 


 
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▪ Cardiovascular function (ECG, blood pressure, heart rate) 
▪ Sedation (rating scales, National Early Warning Score- NEWS2, Glasgow 
Coma Scale) 
 
If clinically significant CNS depressant activity is observed, this will be considered a 
dose-limiting toxicity (DLT) event (see section 3.4.2 for definition and criteria) and will 
inform the adaptive model in determining the next dose of baclofen to be administered, 
according to the next patient’s prescribed methadone dose. 
 
Our target dose is for 90mg baclofen to be safely prescribed in those receiving 
maintenance doses of methadone up to and including 120mg daily. This would provide 
the full range of prescribing freedom within current guidelines for prescribing of baclofen 
in spasticity (BNF guidelines, max 100mg/day), and meets recommendations for off-
label prescribing in alcoholism (max 80mg/day granted for French temporary license 
(Rolland et al., 2020), and recommended efficacious doses 30-60mg/day (Agabio et al., 
2018). This is also in line with prescribing of methadone as opiate substitution therapy 
according to Department of Health ‘Orange’ and NICE guidelines, both of which 
recommend 60mg/day of methadone as clinical therapeutic target with a maximum of 
120mg/d methadone. 
 
Our minimum acceptable dose is 30mg baclofen to be safely prescribed in those 
receiving maintenance doses of methadone up to and including 60mg daily. Baclofen 
doses below 30mg/d have not demonstrated efficacy in alcoholism (Agabio et al., 
2018), and although the minimum daily recommended doses outlined in Orange and 
NICE guidelines is 60mg/d methadone, the majority of clients in our services are on 
methadone doses lower than 60mg/d (average 56.3mg/d), and our target population for 
those on detoxification or tapering pathways are on even lower doses (i.e. <40mg/day 
with methadone estimated average of 25mg). Therefore, these ‘acceptable minimums’ 
will still capture the majority of clients that we wish to enrol. 
3.1.2 Secondary study objectives: 
 
Secondary aims will be investigated and findings used to inform the design of the 
subsequent proof-of-concept efficacy study 2 and will include: 
 
2. Aim to identify whether there is any evidence of sub-threshold DLT respiratory, 
cardiovascular or sedation changes in response to baclofen relative to placebo. 
 
Evidence of a sub-threshold DLT changes in response to baclofen would not prevent 
initiation of further studies in this indication, but would guide prescribing behaviour in 
subsequent studies. 
 
3. Aim to determine whether there is any evidence of abuse liability signal for baclofen 
relative to placebo, in combination with methadone, through determination of: 
o Lack of abuse liability as measured by: 
▪ Drug effects questionnaire (DEQ) 
 
Presence of an abuse liability signal would not prevent initiation of further studies in this 
indication, but would signal the need for additional monitoring and risk mitigation in 
future studies. 


 
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4. Aim to determine whether there is evidence of reduced sensitivity to baclofen 
relative to placebo through determination of Subjective drug response (Subjective 
High Assessment scale, SHAS). 
 
Evidence of a reduced sensitivity to baclofen would not prevent initiation of further 
studies in this indication, but would guide prescribing behaviour in subsequent studies. 
 
 
5. Explore the variability in response to baclofen at different baclofen dose levels for (i) 
CNS depressant activity using measures of respiratory function, cardiovascular 
function and sedation, (ii) abuse liability measured by DEQ and (iii) subjective drug 
response (SHAS) 
6. Explore the variability in response to baclofen at different methadone levels for (i) 
CNS depressant activity using measures of respiratory function, cardiovascular 
function and sedation, (ii) abuse liability measured by DEQ and (iii) subjective drug 
response (SHAS) 
7. Explore the variability in response to baclofen by gender for (i) CNS depressant 
activity using measures of respiratory function, cardiovascular function and 
sedation, and (ii) abuse liability measured by DEQ and (iii) subjective drug response 
(SHAS) 
3.1.3 Exploratory objectives 
 
Additional exploratory aims will be investigated and include: 
 
8. Aim to determine whether there is evidence of reduced sensitivity to baclofen 
through determination of: 
a. Objective 
and 
subjective 
pharmacokinetic-pharmacodynamic 
(PK-PD) 
responses using the following measures: 
i. Plasma growth hormone levels 
ii. Plasma baclofen levels 
iii. Plasma methadone levels 
b. The following measures are also to be compared with those of historic controls 
and those with alcohol dependence (Durant et al., 2018). 
i. Subjective drug response (Subjective High Assessment scale, SHAS) 
ii. Plasma growth hormone levels 
iii. Plasma baclofen levels 
9. To investigate the variability in PK-PD responses to baclofen at different baclofen 
dose levels 
10. To investigate the variability in PK-PD responses to baclofen at different methadone 
levels 
11. To investigate variability in response by; tolerability aspects, demographic factors 
(e.g. age) 
12. To identify possible markers of efficacy of baclofen relative to placebo (e.g. sleep, 
anxiety, restless legs) 
 
3.2  Study hypotheses: 
 
1) CNS depressant activity 


 
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a) We anticipate no evidence of clinically significant respiratory depression or 
cardiovascular changes in doses up to 90mg baclofen in those on daily 
methadone doses up to and including 120mg. 
b) We hypothesise that we will observe increased self-reported measures of drug 
effect, including sedation, with doses at or above 60mg baclofen relative to 
placebo, in combination with methadone doses at or above 60mg. 
• Increased T-SHAS drug effect score relative to placebo, at peak effect (2-3 h 
following dosing). 
• We hypothesise that signs of sedation in this opiate dependent cohort will be 
blunted in response to baclofen as compared with historic controls (Durant et 
al., 2018). 
• Reduced peak subjective response following baclofen administration at doses 
of 60mg or above. 
2) Abuse liability 
a) We hypothesise that we will observe no indication of abuse liability of baclofen 
relative to placebo in combination with methadone. 
• No clinically meaningful change from placebo in DEQ ‘liking’ or ‘want more’ 
subscales. 
3) PK-PD measures 
a) We anticipate that opiate dependent individuals will demonstrate lower sensitivity 
to baclofen as compared with historic controls, as follows: 
• Reduced growth hormone response relative to controls at peak effect (~2h 
post dose) following 60mg baclofen 
• Reduced sedation response (self-report measures) relative to controls at 
peak effect (2-3h post dose) following 60mg baclofen 
b) We anticipate that opiate dependent participants will demonstrate a comparable 
pharmacokinetic profile in response to baclofen as compared with healthy 
controls and those with alcohol dependence (data from (Durant et al., 2018)) 
4) We expect that baclofen will reduce anxiety after acute dosing and improve sleep 
measures during the subsequent night of sleep, compared with placebo. 
 
3.4 Outcome measures 
3.4.1 Primary Outcome Measures 
 
Primary outcome: The maximum safe dose of baclofen at which 15-25% of evaluable 
participants experience a dose limiting toxicity (DLT) for prescribed doses of 
methadone, where a DLT is defined in section 3.4.2 and is comprised of the following 
components: 
 
1) Intervention level (0 to 4) as described in section 3.4.3  
2) National Early Warning Score (NEWS2), measured at discrete time-points 
3) Glasgow Coma Scale (GCS) score, measured at discrete time-points 
4) QTc on ECG trace, measured at discrete time-points  
5) Measures of respiratory function, measured continuously at discrete time-points 
a) Oxygen saturation (SPO2) 
b) Respiratory (ventilation) rate 
c) Incidence of apnoea 
 


 
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Definitions of the evaluation window and evaluable participants can be found in sections 
3.4.6 and 3.4.7 respectively, and the discrete time-points are given in section 4.3.2. 
 
3.4.2 Definition of dose-limiting toxicity (DLT) 
 
A Bivariate Bayesian Logistic Regression Adaptive Model (see sections 4.4 and 8) will 
be used to determine whether safety limits are exceeded using one or more of the 
following outcomes as a 'dose limiting toxicity (DLT)':  
 
1) Situation requiring intervention level ≥4 (section 3.4.3) at any time 
2) NEWS2 score >4 or score of 3 in any parameter (threshold for trigger of urgent 
ward-based response) 
3) Measures of respiration with a persistent change in at least one of: 
a) Reduction in SPO2 [≤91% for more than 30 seconds or >5% reduction in 
SpO2 for more than 30 seconds 
b) Reduced respiratory rate (≤8/min)  
c) Absence of inspiratory airflow for >30s combined with a sustained fall in 
SpO2 
4) GCS score <12 
5) Persistent QTc prolongation (>500ms or increase of >60ms; if the initial QTc value 
at any time-point 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 DLT). 
 
3.4.3 Stimulus Intervention levels: 
If marked sedation or apnoea >30s occurs, the following levels of stimulus intervention 
will be utilised and scored accordingly (0; no intervention). 
 
1. Indirect noise e.g. door opening, closure, cough etc 
2. Interrupt patient with direct speech 
3. Touch 
4. Unable to rouse patient with touch 
 
Any intervention at level 4 or above will meet criteria for a DLT and a clinical decision 
will be made as to further action. 
 
In the event of the need for clinical intervention, a crash trolley is available within the 
Clinical Research Facility, and a crash team is available at Hammersmith Hospital. 
Naloxone will be available in the ICRF as a rescue medication in the event of 
respiratory depression requiring intervention. 
 
If further emergency clinical investigation and interventions are required, this will involve 
transfer to the emergency department at Charing Cross Hospital, via ambulance. 
3.4.4  Secondary Outcome Measures 
 
Components of DLT: 
 


 
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• Intervention level (0 to 4) as described in section 3.4.3  
• National Early Warning Score (NEWS2), measured at discrete time-points 
• Glasgow Coma Scale (GCS) score, measured at discrete time-points 
• QTc on ECG trace, measured at discrete time-points  
• Measures of respiratory function, measured continuously at discrete time-points: 
a) Oxygen saturation (SpO2) 
b) Respiratory (ventilation) rate 
c) Incidence of apnoea 
 
Respiratory measures:  
 
These will be investigated at each baclofen dose level, for signs of sub-threshold 
respiratory depression. 
 
• SpO2- instances of <92% or of >5% reduction for more than 10 seconds 
• CO2- instances of ETCO2% per breath exceeding 6.5% (Jolley et al., 2015) or a 
partial pressure CO2 increase by 1kPa (advice from respiratory physician) 
• Respiratory rate- instances of absence of inspiratory airflow for more than 10 
seconds or respiratory rate drops <9/min 
• Time course of SpO2, CO2 and respiratory rate following baclofen dosing, relative 
to placebo. 
 
Sedation measures: 
• T-SHAS score (total score on Subjective High Assessment Scale) 
o Mean Total-SHAS score at peak PD response (2-3h) at each baclofen 
dose level, relative to placebo 
o Time-course of T-SHAS at each baclofen dose level, relative to placebo 
 
Symptom measures:  
• Drug Effects Questionnaire (DEQ)  
o Mean ‘Drug liking’ and ‘want more’ scores at peak PD response (2-3h) at 
each baclofen dose level, relative to placebo 
o Time-course of DEQ scale at each baclofen dose level, relative to placebo 
 
3.4.5 Exploratory Outcomes 
 
Sedation measures: 
• T-SHAS score (total score on Subjective High Assessment Scale)- self-rated 
o Mean Total-SHAS score at peak PD response (2-3h) at 60mg baclofen 
dose level, relative to historical controls 
o Time-course of T-SHAS at each baclofen dose level, relative to placebo 
 
Plasma levels: PK and growth hormone measures:  
• Plasma baclofen concentrations 
o Mean peak plasma concentration (2-4h) at each baclofen dose level, 
relative to placebo 
o Time-course of plasma baclofen levels 


 
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o Cmax (maximum (or peak) plasma concentration, Tmax (time to reach Cmax), 
t1/2 (elimination half-life)  
o Variability in PK parameters by gender 
• Plasma methadone concentrations 
o Mean plasma concentration (2-4h) at each baclofen dose level, relative to 
placebo 
o Time-course of plasma methadone levels 
• Plasma [growth hormone (GH)], a surrogate marker of GABA-B receptor 
function. 
o Mean peak plasma concentration (2h) at each baclofen dose level, 
relative to placebo 
o Mean peak plasma concentration (2h) at the 60mg baclofen dose level, 
relative to controls 
o Time-course of plasma GH levels 
o Variability in GH profile by gender  
 
Symptom measures:  
• Visual analogue scales for anxiety, craving at each baclofen dose level, relative 
to placebo 
• Sleep measure (LSEQ) at each baclofen dose level relative to placebo 
o Improvement in LSEQ score for ‘getting to sleep’ and ‘quality of sleep’ 
factors, no change in ‘awakening following sleep’ or behaviour following 
wake’ factors. 
 
Other outcomes: actigraphy, heart rate, blood pressure, body temperature. 
 
Phenotypic measures: demographic (gender, age), clinical (methadone dose), drug & 
alcohol history, validated questionnaire measures. 
 
These measures will be related to the primary and secondary outcomes to support the 
validity of the adaptive trial design, estimate variability in the signal across these 
demographic features, to establish novel relationships or conversely, to control for 
outlier effects. 
3.4.6 Evaluation window 
 
The evaluation window for primary and secondary outcome measures will begin at 
dosing and end at 5 hours post-dose, with the exception of the ‘intervention level’ (as 
defined in the DLT definition) which will begin at dosing and continue until the last 
follow-up phone call. This call will be conducted the following day, and the window will 
be extended if the participant is experiencing sedation or other symptoms. 
3.4.7 Evaluable patient 
An evaluable participant is defined as one who has received study medication and has 
provided sufficient data to meet the primary endpoint of determining the presence or 
absence of a DLT, and sufficient data relating to the main secondary outcome 
measures. Whether sufficient data has been obtained for this purpose will be 
determined by clinical judgement on an individual participant basis. 
 


 
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In the unlikely event that a participant decided to self-discharge themselves after dosing 
but prior to the end of the 5 hour evaluation window, this participant could be counted 
as an evaluable patient with no DLTs provided they had completed the 2-3h timepoint 
and that this self-discharge had occurred within a clinical picture of stable or 
normalising observations. Attempts to complete the follow-up phone call would be made 
to confirm absence of DLT as defined by ‘intervention level’. 
 
In the event of an inability to acquire sufficient data, as defined above, the decision on 
whether to include an individual’s data in the primary (DLT) or secondary analysis, or 
whether that individual would be replaced, would be made on a case by case basis. 
 
 
4 STUDY DESIGN  
4.1 Description of Overall Study Design  
 
This will be a single-blind, adaptive, randomised, placebo-controlled ascending dose 
study of a single dose of baclofen in opiate-dependent individuals stably maintained on 
methadone. Participants will be randomised in a 3:1 ratio to baclofen or placebo. 
Participants allocated to baclofen will be dosed in groups of up to 3, with a maximum 
available sample size of 64 (up to 48 on baclofen and 16 on placebo). An adaptive 
model will inform the dosage of baclofen for each patient group based on the trial data 
accumulated to date. 
 
The primary objective is determination of the maximum safe dose of baclofen at which 
15-25% of evaluable participants experience a dose limiting toxicity (DLT, defined in 
section 3.4.2) for prescribed doses of methadone. 
 
Potentially eligible participants will be identified by telephone screening and invited to 
attend a screening visit at one of the study sites. Following informed consent, this visit 
will ascertain study eligibility, medical, psychiatric and dependence history, obtain self-
report and rater-report questionnaire measures and administer an actiwatch, to be worn 
until the morning after the experimental visit.  
 
Eligible participants will be enrolled into the study and randomised to receive baclofen 
or placebo in a 3:1 ratio. The baclofen dose allocation recommendation (10, 30, 60 or 
90mg) will be made by the Bayesian adaptive algorithm, based on the participant’s 
prescribed methadone dose level and previous learning accumulated by the adaptive 
model. The Dose setting committee (DSC) retains the ability to override the alogrithm’s 
dose recommendation if clinically indicated.  
 
Following randomisation, participants will attend the Imperial Clinical Research Facility 
(ICRF) for a single experimental visit, during which they will consume their usual daily 
dose of methadone under observation soon after arrival, followed by an acute oral dose 
of baclofen or placebo approximately 1 hour later, as determined by the adaptive trial 
algorithm.  
 
Measures of respiratory, cardiovascular, subjective and PK will be obtained periodically 
for up to 5 hours after baclofen dose.  
 


 
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The following day, participants will receive a follow-up phone call to check welfare and 
will be required to return their actiwatch via pre-paid envelope, or to their local addiction 
service, as appropriate. 
 
4.2 Study visits  
 
All eligible participants will have: 
• Pre-screening assessment by telephone or in their usual clinical addiction 
service, as appropriate 
• One in-person clinical screening visit. 
• Randomisation/enrolment 
• One in-person experimental study visit 
• One follow-up phone-call following the experimental study visit to check for 
adverse events. 
 


 
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4.3 Study design schematics  
4.3.1 Study procedure schematic 
 
 
 
Key: SPO2; Blood Oxygen Saturation, ETCO2; End Tidal Carbon Dioxide, RR; Respiration Rate, ECG; Electrocardiogram, COWS; 
Clinical Opiate Withdrawal Scale, Plasma; Blood Sample, GCS; Glasgow Coma Scale, NEWS2; National Early Warning Score 2, 
BP; Blood Pressure, BT; Body Temperature, HR; Heart Rate,  SHAS; Subjective high assessment scale, DEQ; Drug Evaluation, 
Questionnaire, VAS; Visual Analogue Scale, LSEQ; Leeds Sleep Evaluation  Questionnaire.


 
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4.3.2 Experimental Visit Schematic 
Experimental study day duration will be approximately 6-7 hours. Start times will be 
determined according to participant’s preference but a typical study day would look like 
this: 
 
Procedure 
Timepoint (mins) 
#Baseline 
15 
30 
60 
90 
120 
180 
240 
300 
NEWS2 
x 
- 
- 
x 
- 
x 
x 
x 
x 
SpO2 
x 
x* 
x* 
x 
x* 
x 
x 
x 
x 
RR 
x 
x* 
x* 
x 
x* 
x 
x 
x 
x 
BP 
x 
- 
- 
x 
- 
x 
x 
x 
x 
HR 
x 
- 
- 
x 
- 
x 
x 
x 
x 
Body Temp 
x 
- 
- 
x 
- 
x 
x 
x 
x 
LOC 
x 
- 
- 
x 
- 
x 
x 
x 
x 
GCS 
x 
- 
- 
x 
- 
x 
x 
x 
x 
ECG 
x 
- 
- 
- 
- 
x 
- 
- 
x 
CO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SHAS 
x 
- 
- 
x 
- 
x 
x 
x 
x 
DEQ 
x 
- 
- 
x 
- 
x 
x 
x 
x 
VAS 
x 
- 
- 
x 
- 
x 
x 
x 
x 
Blood Plasma 
x 
- 
- 
x 
- 
x 
x 
- 
x 
COWS 
x 
- 
- 
- 
- 
x 
- 
- 
x 
 
#Baseline refers to measurements obtained prior to Time 0, which represents the time 
at which baclofen/placebo is administered. Shaded area are measures comprising the 
NEWS2 score. *At these time points SpO2 and RR measures will be taken in addition to 
those associated with the NEWS2.  
 
4.4 Treatment algorithm 
 
A Bayesian dose-escalation adaptive model will be used to determine the baclofen dose 
allocation and will be informed by the occurrence of dose-limiting toxicity (DLT) events 
at increasing doses of baclofen (10, 30, 60, 90mg). Participants will be randomised 
(single-blind) to baclofen or placebo in a 3:1 ratio. If allocated to baclofen, the adaptive 
model will recommend the dose level for a given patient according to their prescribed 
dose of methadone and prior information regarding the incidence of DLTs. The model 
will be updated after each group of up to 3 participants, according to the observed 
patients’ responses. The Dose setting committee (DSC) retains the ability to override 
the algorithms dose recommendation if clinically indicated. 
 
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 


 
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earlier if the highest dose of baclofen (90mg) is highly likely to be safe, i.e. below the 
target toxicity with 120mg of methadone, provided that the study has also achieved 
sufficient data to meet secondary endpoints.  
4.4.1 Schematic for baclofen dose algorithm 
 
 
 
 
 
Please see section 4.4.2 for definitions of p(DLT), p(safe), p(target) 
 
4.4.2 Baclofen dose decisions 
 
The lowest dose of baclofen (10mg) will be allocated to the first group of 3 participants 
assigned to receive baclofen. The dose-toxicity model will be continuously updated after 
each group of at most 3 participants, to recommend dosing for the subsequent group of 
participants. The model will describe the probability of a patient experiencing a DLT; 
p(DLT), at a given methadone-baclofen dose, the probability of the given dose being 
safe; p(safe), and the probability of the dose being within the target toxicity interval; 
p(target). 
 
The model will establish the combination-toxicity relationship which borrows information 
between different doses across both drugs, leading to an efficient use of data. The 
model will output the dosing function that provides the safe dose of baclofen that is 
most likely to be associated with 15-25% DLT risk for a given dose of methadone. 
 
According to the model, if any of these DLTs are met, then the next group of patients 
will be assigned to the current (or lower) dose of baclofen, without dose escalation, 


 
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depending on the prescribed dose of methadone for the next individual that enters the 
study. 
 
If there is no DLT, a dose escalation may be advised by the model, again, depending on 
the prescribed dose of methadone for the next individual that enters the study. 
 
The model will recommend to stop the trial earlier due to safety concerns if the 
probability that the risk of DLT for 60mg of methadone in combination with 30mg of 
baclofen exceeds the target range is 25% or more. The model will recommend to stop 
the trial earlier due to all doses of baclofen being safe if the probability that the risk of 
DLT for 120mg of methadone in combination with 90mg of baclofen does not exceed 
the target range is 92.5% or more, representing the ‘all-safe-stop criteria’. 
 
The Dose Setting Committee (DSC, comprised of a statistician, clinician and member of 
the research team) can decide to over-ride any recommendation made by the model, if 
clinically indicated. Outside of the model parameters, clinical judgement will determine 
whether responses to baclofen are sufficiently concerning to cease escalation, escalate 
to a lower dose than planned by the model, or to reduce the average methadone dose 
for each dose of baclofen examined. If doses of 90mg baclofen are deemed safe by the 
model with up to and including 120mg methadone, further escalation will cease 
provided that the data required for secondary endpoints are met. 
 
Should the study team witness multiple DLTs, using their clinical experience they can 
halt the trial early over safety concerns. 
 
In the scenario that there is a very high probability that all doses are safe before 
reaching the maximum recruitment of n=48 receiving baclofen, the study will retain the 
ability to override the all-safe-stop criteria to continue recruitment until we have tested a 
sufficient range of doses of methadone to ensure we have covered the clinical range of 
potential methadone doses and/or to explore baclofen dose separation to achieve 
maximum precision on secondary outcomes.  
 
Given no safety concerns, we expect the minimum numbers of participants at each of 
the doses to be as follows: n=3 @10mg baclofen, n=3 @ 30mg baclofen, n=12 @ 60mg 
baclofen and n=12 @ 90mg baclofen, with n=10 receiving placebo, providing sufficient 
data to allow adequate exploration of dose separation on primary and secondary 
outcomes across a range of methadone dose levels, and an assessment of GABA-B 
receptor sensitivity and any gender effects. These numbers might be exceeded if the 
variability in response is larger than anticipated, female representation is lower than we 
would like, or we have not yet been able to test the full range of methadone doses. If a 
particular baclofen dose is deemed unsafe, then the lower doses would be similarly 
explored. 


 
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5 STUDY PROCEDURES 
 
5.1 Pre-Screening Procedures 
Pre-screening appointments will take place via telephone or within the local addiction 
services as appropriate, to ensure that participants are likely to be interested, and 
eligible according to DSM-5 and study criteria. This will take approximately 20 minutes. 
 
5.2 Screening Procedures 
Informed consent will take place either at the Imperial Clinical Research Facility, or at 
the local addiction service within CNWL, or other HRA approved specified sites, as 
required. The local addiction service where participants are receiving treatment, and/or 
the participants’ general practitioner will be notified of their patient’s participation. 
5.2.1 Consent 
The PIS and consent forms will be read through carefully with the participant. If they 
wish to participate, they will be informed that participation is entirely voluntary and that 
they can leave the study at any time without their decision affecting the treatment that 
they will be receiving. Written informed consent will be taken by a member of the 
research or clinical team under the supervision of the chief investigator. 
 
Consenting participants will undergo enrolment and routine screening to ensure they 
are medically fit and eligible to take part. Members of the research team will discuss the 
study in detail, and the subject's eligibility to participate assessed against inclusion and 
exclusion criteria. A clinical member of the team will take a detailed clinical history of 
current and previous health and perform a physical examination to check for current 
health. In addition to eligibility assessment through history and examination, blood tests 
will be undertaken, where it is deemed clinically necessary e.g. if participant has a 
history of kidney/hepatic impairment that requires confirmation of current status.  
 
Screening visits will last approximately 2-3 hours.  For the majority of participants, the 
screening procedures will take place at the Imperial Clinical Research Facility (CRF) at 
Hammersmith hospital. However, to provide flexibility for our opiate dependent 
participants, the screening visit may be undertaken within our partner trust at Central 
and North West London NHS Foundation (CNWL) trust (CIPPres clinic), or certain 
aspects of screening (e.g. consent, questionnaires) may be completed at the local 
addiction service within CNWL, as applicable, to reduce the cognitive burden and 
increase study flexibility, acceptability and compliance. 
 
Participants will undergo the following procedures at the screening visit: 
5.2.1 Pregnancy test 
Female participants will undertake a urine pregnancy test. 


 
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5.2.2 Breath Alcohol Level 
Screening for alcohol content will be conducted with alcohol breath test. Additional 
random alcohol screens may be performed during the study at the Investigator's 
discretion.  
5.2.3 Urine Drug Screen  
Urine will be screened for drugs of abuse including amphetamines, benzodiazepines, 
cannabinoids, cocaine, methadone, opiates. Participants will be assured that results of 
these tests (and all other information obtained in the study) are confidential and will not 
be reported to key workers, GP or participating addiction services. 
5.2.4 Vital statistics and Vital signs  
Height, weight and body mass index will be measured. Vital signs will comprise systolic 
and diastolic blood pressure, pulse rate, body temperature and blood oxygenation.  
5.2.5 Medical examination 
Medical examination will be assessed by structured interview as related to the eligibility 
criteria listed.  
5.2.6 Physical Examination 
Physical examination will include assessments of the head, nose, throat, skin, thyroid, 
neurological, lungs, cardiovascular, abdomen, lymph nodes and extremities.   
5.2.7 Respiratory Examination 
Participants will be asked about risk factors for respiratory disease e.g. history of 
persistent cough or breathlessness at rest, previous verified diagnosis of chronic 
obstructive pulmonary disease (COPD), hospital admission due to COPD, non-invasive 
ventilation for type 2 respiratory failure, use of inhalers for respiratory compromise, 
ventilation due to COVID-19, history of inhalation/smoking of substances e.g. heroin, 
tobacco, crack cocaine. 
 
If further tests are clinically indicated to determine signs of current COPD or respiratory 
function, participants will undergo a 6 minute walk test with SpO2 monitoring, for signs 
of respiratory compromise. 
 
If clinically indicated, participants will complete spirometry examination to measure 
forced expiratory volume/forced vital capacity (FEV1/FVC) ratio. Due to COVID-19 
restrictions for aerosol generating procedures (AGPs), this may be undertaken outside 
or at home under guidance of the study team via video link. 
5.2.8 Blood samples for clinical laboratory testing 
Given that blood sampling is required for the experimental visit, an assessment of 
venous access will be made. Blood samples will be collected via venepuncture if 
clinically indicated e.g. for full blood count, urea and electrolytes, and liver function 
tests. Venous access is a particular problem that is common in injecting heroin users, 
therefore failure to provide a blood sample will not exclude a participant as long as all 
other eligibility criteria are met and clinicians are satisfied that participation will be safe.  


 
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5.2.9 Psychiatric history, drug & alcohol history, demographics 
Psychiatric diagnoses according to DSM-5 criteria will be assessed by a psychiatrist, or 
by a study clinician and reviewed by a psychiatrist. Semi-structured interviews for 
assessment of sleep, alcohol, nicotine and drug use will be conducted, including a 
record of abstinence periods, recent on-top use. Demographic parameters will be 
captured in the case report form. 
5.2.10 Questionnaire measures 
The following validated questionnaires will be administered to aid diagnoses and for 
characterising clinical status: 
 
Mini International Neuropsychiatric interview (M.I.N.I.) (Sheehan DV et al., 1998)  
Beck Depression Inventory, BDI-II, (Beck et al., 1996) 
STAI; Spielberger State & Trait Anxiety Scale, (Spielberger et al., 1983) 
 
Visual Analogue Scales (VAS) of craving, anxiety 
Severity of Dependence Scale; SDS, (Gossop et al., 1995) 
Obsessive-Compulsive Drug Use Scale; OCDUS-H, (Franken  et al., 2002). 
Fagerstrom test for nicotine dependence (Heatherton et al., 1991) 
Alcohol, Smoking, Substance Involvement & Screening Test (ASSIST)  
Alcohol current intake (AUDIT) 
Pittsburgh Sleep Quality Index (PSQI) (Buysse et al., 1989) 
Epworth Sleepiness Scale (ESS) (Johns, 1991) 
Restless legs severity scale (RLS scale), https://www.rls-uk.org/diagnosis  
5.2.11 Cardiovascular measures 
An ECG will be obtained at screening to determine suitability for QT measurements. 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. 
5.2.12 Actigraphy measures 
An actigraph to remotely monitor sleep-wake cycles will be administered to eligible 
participants to wear continuously until the day after the experimental visit. This is a non-
invasive wrist-worn device that captures movement. 
 
5.3 Enrolment procedures  
Participants who are eligible at screening will be invited to attend the experimental 
study visit and upon confirmation of attendance will undergo enrolment and 
randomisation.  
5.3.1 Anonymisation and randomisation  
Each participant will be given a unique participant identification number upon entering 
the study which will not change.  
 
The randomisation to either baclofen or placebo (3:1 ratio) will be performed using the 
online software application, Sealed Envelope TM.  
 
Then the participant’s current prescribed dose of methadone will be entered into the 
Bayesian adaptive model which, in conjunction with previous DLT toxicity data, will 


 
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recommend the baclofen dose to be assigned as either 10, 30, 60 or 90mg baclofen. As 
previously stated, this recommendation can be over-ridden based on cumulative clinical 
experience. The adaptive Bayesian model will be programmed into R. A custom-built 
OpenClinica Clinical Data Management and Electronic Data Capture software 
database, will store the output of the randomisation and baclofen dose where relevant. 
 
After randomisation, if a participant does not attend the experimental visit within the 
expected time window, the research team will have the option to replace this individual 
with a new participant, as appropriate. The new participant would receive the same 
allocation of placebo or baclofen, but if allocated to baclofen the allocated dose might 
change, depending on the methadone dose-level and recommendation of the adaptive 
model at that point in time. This would not exclude the replaced participant from re-
entering the study at a later date, at which point they would be re-randomised. 
 
After randomisation, all paper and electronic case report forms will utilise the participant 
study ID number, rather than personal identifiers wherever possible. 
 
5.4 Experimental study visit procedures  
Experimental study visits will take place at the NIHR Imperial Clinical Research Facility 
(CRF) at Hammersmith hospital, lasting approximately 6-7 hours (with breaks). This 
follows previous protocols which have been acceptable and well tolerated by 
participants. At each study visit participants will take their usual dose of methadone, 
undergo baseline assessments and receive a single dose of orally administered 
placebo or baclofen. Measures of safety, PK-PD, self-report questionnaires and 
adverse effects will be taken prior to, and at regular intervals following baclofen 
administration, according to section 4.3, to coincide with peak plasma concentrations, 
peak anticipated pharmacodynamic response and for up to 5 hours, allowing adequate 
rest breaks for participants. 
 
The following assessments will take place: 
5.4.1 Eligibility check 
Participants will arrive at the research centre and confirm consent. Transport will be 
arranged where appropriate. Refreshments made available throughout the day. Lunch 
will be provided. Smoking is permitted at regular intervals as required, to avoid nicotine 
withdrawal, but smoking will be avoided in the 15 minutes prior to each hourly time-
point and during the first 2 hours following dosing. Caffeine intake will be permitted 
(according to usual consumption). 
 
Upon arrival, eligibility will be checked and drug urine screen, alcohol breath and 
pregnancy tests obtained (see procedures above) 
5.4.2 Methadone Dosing 
Participants will take their usual dose of prescribed daily methadone, and the time 
noted. 
 
NB: In those receiving daily prescription methadone, given their long-term use, plasma 
levels will be at steady-state during the day. The vast majority of participants take their 
methadone in the morning, therefore on experimental visits, participants will bring their 


 
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usual methadone dose with them to the research facility, and consume it under 
observation on the premises, shortly after arrival. Maximal plasma levels of methadone 
are reached in 1.8-3.8h with half-life of ~24hrs (independent of dose, (Wolff et al., 
1993). Our previous experience is that a short delay in taking methadone is acceptable 
to participants and we do not anticipate substantial discomfort. However, to minimise 
this, the methadone will be taken as early as possible, and the gap between methadone 
and baclofen administration will be kept short (~40-60 minutes).  
5.4.3 Baclofen or Placebo Dosing & Administration 
The dose recommendation from the model will be administered approximately 1 hour 
after methadone. The dose levels are 10mg, 30mg, 60mg or 90mg, administered as 
either 1, 3, 6 or 9 tablets of baclofen respectively, or a matching number of placebo 
(vitamin D) tablets which are a very close visual match (see section 5.7).  
 
Effects of baclofen or placebo will be monitored for up to 5 hours following dosing at the 
Clinical Research Facility. Any lasting effects will be monitored at a follow-up telephone 
call the following day. 
 
Placebo or baclofen tablets will be administered with water by a nurse or study team 
member under direct supervision. Participants will not be given the chance to scrutinise 
the contents of the medication pot prior to consumption. This is a single-blind trial, 
therefore the participants will not be aware of whether they are taking placebo or 
baclofen tablets. 
 
NB Baclofen reaches peak maximum concentrations approximately 1-2 hours after oral 
dosing with 60mg (Cmax; 88-102 minutes, (Durant et al., 2018), and has an estimated 
half-life in plasma of ~3 hours after a single 60mg dose (range = 2.7-3h from 10-90mg 
baclofen). All testing will therefore be covered by baclofen’s pharmacokinetic profile. 
5.4.4 Respiratory measures 
Following baclofen administration, continuous monitoring of the patient will occur for the 
first 120 minutes.  
 
Blood gases: Pulse oximetry, capable of continuous recording, will be used for regular 
static, and periodic continuous monitoring and recording of the blood oxygen saturation 
whilst seated, or semi-supine.  
 
For safety, whilst the participant is not under direct supervision but remaining in the 
ICRF, continuous pulse oximetry will continue to be monitored at the remote nursing 
station for the first 120 min following drug administration. 
 
Capnography and/or transcutaneous CO2 measurements will be obtained at regular 
intervals, with periodic continuous monitoring and recording of ETCO2/partial pressure 
and respiratory rate via a nasal cannula. 
5.4.5 Intervention measures 
Intervention levels (0 to 4) will be utilised if marked sedation occurs (see section 3.4.3).  


 
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5.4.6 Sedation measures 
Glasgow Coma Scale (GCS) will be obtained at baseline (after methadone dosing), and 
then every hour following baclofen dosing. The GCS assesses the participant’s ability to 
open their eyes, move and speak, and has a minimum score of 3 with a maximum of 
15. 
  
National Early Warning Score 2 (NEWS2) for clinical deterioration. It is a staff rated 
aggregate scoring system (not self-report), with the magnitude of the score reflecting 
how extremely the parameter varies from the norm. The minimum score of zero and 
maximum of 20 and comprises the following 6 physiological parameters: 
1. Respiratory rate 
2. Oxygen saturation 
3. Temperature 
4. Systolic blood pressure 
5. Pulse rate 
6. Level of consciousness or new confusion (ACVPU; alert, confusion, voice, 
pain, unresponsive) score 
5.4.7 ECG measures 
An ECG to measure possible QT prolongation will be obtained at 3 timepoints; baseline 
(after methadone dosing), after anticipated peak effects (t=120min) and prior to 
discharge (approx. 5-6h post-dose). 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 taken. 
5.4.8 Vital Signs 
Under direct observation, heart rate will be measured at regular static time points whilst 
seated, or semi-supine. For safety, whilst the participant is not under direct supervision 
but remaining in the ICRF, continuous pulse oximetry will monitor heart rate at the 
remote nursing station. 
 
Blood pressure will be measured via a cuff at before and after methadone dosing, and 
at regular static time points whilst seated, or semi-supine, every hour following drug 
administration dosing. 
 
Body Temperature will be monitored as part of the MEWS score, using an aural 
thermometer. 
5.4.9 Visual analogue scales 
Visual analogue scales (VAS) will be used to assess mood and drug effects including 
drug liking, anxiety and craving which will be assessed before and after baclofen 
administration at regular time points throughout the study day – these will allow us to 
document the known central effects of baclofen if any. 
5.4.8.1 Drug effects (general) scales 
Subjective High Assessment Scale (SHAS) will be obtained at baseline, before 
and after methadone dosing, and every hour following baclofen dosing. 


 
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5.4.8.2 Drug effects & Liking scale 
Drug Effects Questionnaire (DEQ; feel, liking, dislike, high, want more) 
5.4.8.3 Other 
VAS for craving, anxiety 
5.4.10 Other questionnaires 
The Clinical Opiate Withdrawal Scale (COWS, (Wesson & Ling, 2003)) will be 
administered at baseline, and again at 2 further time-points to check that the participant 
is not in overt withdrawal. 
5.4.11 Plasma levels – Baclofen, Methadone, Growth Hormone 
Plasma concentrations of baclofen, methadone and growth hormone will be measured 
from whole blood. Blood samples of up to 10ml will be obtained at baseline and 1, 2, 3, 
5 hours after dosing, in total a maximum of 50ml blood.  
5.4.12 Adverse events 
Emergence of side effects of baclofen will be assessed as appropriate and recorded 
according to the MedDra dictionary. 
5.4.13 Actigraphy 
The wrist worn-actigraphs administered at the screening visit will be checked and re-
administered for return the following day. 
5.4.14 Debrief 
Participants will be asked about their experience of the session; whether they could 
guess whether they had placebo or drug, whether they thought it was a low or a high 
dose, and whether at any time they liked the drug effects they encountered. 
5.4.15 Discharge 
Participants will be required to remain under supervision for a period of 5 hours after 
they receive baclofen/placebo, and remain at the research facility until approved for 
discharge by the study physician. Staff will ensure that any adverse impacts etc have 
attenuated before the participant leaves. Study staff will remind participants of relevant 
study contact details, including a 24-hour mobile telephone number for the on-call study 
doctor.  
 
Where possible, study staff will arrange for a taxi to take the participant home. 
5.4.16 Emergency contact 
Provided by on-call study doctor via study mobile. 
 
5.5 Follow-up  
 
Following completion of experimental study visits, participants will be telephoned the 
day after the visit to check for the following: 
• adverse events 


 
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• complete sleep and restless legs questionnaire- Leeds Sleep Evaluation 
Questionnaire (LSEQ, (Parrott AC and Hindmarch I. 1980) 
• arrange return of questionnaires and actigraph 
• If the participant is still sedated during the call, a second follow up will 
occur later that day or the following day. 
 
The questionnaires can be completed online, or returned along with the actiwatch in a 
stamped addressed envelope or via the clinical service. 
 
Any incidental findings will be discussed with the individual and appropriate action taken 
which could include passing information to GP and/or clinical addiction team as 
required. 


 
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5.6 Schedule of events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Event 
Screening Enrolment Experimental 
Follow-up 
GENERAL 
Consent & eligibility 
x 
 
x 
 
General health 
x 
 
x 
x 
Demographics 
x 
 
  
  
CLINICAL ASSESSMENTS 
Structured clinical interview (MINI) 
x 
 
  
  
Medical examination 
x 
 
  
  
Vital statistics (height, weight) 
x 
 
  
  
Vital signs (BP, HR, SpO2) 
x 
 
x 
 
Respiratory function 
x 
 
x 
 
Blood sampling (clinical) 
(x) 
 
  
  
Urine screen (DOA & pregnancy) 
x 
 
x 
 
Breath alcohol 
x 
 
x 
Methadone administration 
  
 
x 
 
Baclofen administration 
  
 
x 
 
DRUG & ALCOHOL HISTORY 
MTD dose check 
x 
 
x 
 
TLFB (drug & alcohol use) 
x 
 
  
  
FTND 
x 
 
  
  
AUDIT 
x 
 
  
  
ASSIST (shortened) 
x 
 
  
  
SDS 
x 
 
  
  
OCDUS-H 
x 
 
  
RANDOMISATION 
Randomisation & Enrolment 
 
x 
 
  
MOOD & PERSONALITY 
BDI 
x 
 
 
  
STAI 
x 
 
  
  
SSAI 
x 
 
  
  
BIS 
x 
 
  
  
UPPS-P 
x 
 
  
  
PSQI 
x 
 
 
 
ESS 
x 
 
 
 
STATE MEASURES 
VAS drug effects (DEQ) 
  
 
x 
 
VAS craving 
x 
 
x 
 
VAS anxiety 
  
 
x 
COWS 
x 
 
x 
 
LSEQ, sleep quality 
 
 
x 
x 
Adverse events 
  
 
x 
x 
BLOOD MEASURES 
Growth hormone 
  
 
x 
  
Baclofen/Methadone 
  
 
x 
 
ACTIGRAPHY MEASURES 
Actigraphy 
 x 
x 
x 
x  
  


 
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5.6.1 Protocol events flexibility 
Whilst we will endeavour to complete all the questionnaires and tasks as detailed in the 
protocol if at the experimental visits it seems that the burden is too great on the 
participants, we will minimise this by omitting any unnecessary questions, 
questionnaires or tasks from the protocol, whilst still maintaining sufficient data to meet 
criteria for an evaluable participant, following discussion within the team as to the best 
course of action. 
 
5.7 Study medications 
Baclofen (generic) tablets are expected to be acceptable to participants and well 
tolerated. The placebo will be Vitamin D3 (generic) tablets which are not expected to 
result in any noticeable effects or mood changes and are expected to be very well 
tolerated. Vitamin D tablets provide a good visual match to the baclofen tablets. 
Participants will not be told that the placebo tablets contain vitamin D as this could also 
create expectation effects. Instead they will be told that these are ‘dummy’ pills, and we 
will check for vitamin D contraindications at screening. 
 
Participants will be randomised to receive oral baclofen (acute dose of 10, 30, 60 or 
90mg), or placebo (an equivalent number of Vitamin D tablets), in a 3:1 ratio in a single-
blind design. 
 
The dose will be recommended by the adaptive model algorithm. We will administer 
baclofen 10mg as 1 x 10mg tablets, 30mg as 3 x 10mg tablets, 60mg as 6 x 10mg 
tablets and 90mg as 9 x 10mg tablets. The placebo group will receive the same number 
of Vitamin D tablets, according to the model recommendation, up to a maximum of 6 
tablets, assuming the dose per tablet is 20 micrograms (total dose 120 micrograms or 
4800IU). 
 
Example SmPC for Vitamin D (Desunin, colecalciferol 20 micrograms/800IU) 
https://www.medicines.org.uk/emc/medicine/27007#gref 
 
5.7.1 Baclofen in licensed indication 
For baclofen, BNF recommended maximum dose is 100mg/d for licensed indication of 
spasticity.  Example SmPCs for generic baclofen can be found here: 
 
Accord UK Ltd (10mg tablets) 
https://www.medicines.org.uk/emc/product/5728/smpc 
Advanz Pharma (10mg tablets) 
https://www.medicines.org.uk/emc/product/11781/smpc 
Mylan (10mg tablets) 
https://www.medicines.org.uk/emc/product/2594/smpc 
 
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. It is an orally active g-aminobutyric acid (GABA) derivative, p-


 
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chlorophenyl-gamma aminobutyric acid. Its primary action as an antispasticity agent is 
via simulation of GABAB-receptors resulting in depression of monosynaptic and 
polysynaptic reflex transmission. Baclofen increases K+ conductance resulting in 
postsynaptic inhibition and reduces Ca2+ influx and the release probability of excitatory 
transmitters (glutamate and aspartate) causing presynaptic inhibition in the brain and 
spinal cord (Katzung, 2009). Baclofen also exerts an antinociceptive effect and may act 
at supraspinal sites producing CNS depression. Baclofen may also modulate dopamine 
release in the mesocorticolimbic system by targeting neurons in the ventral tegmental 
area (Cruz et al., 2004). 
 
Over its many years of use, baclofen has proven to be a very safe drug with few side 
effects. The main adverse effects of are somnolence, dizziness, muscle weakness, and 
headache. Baclofen has good absorption after oral administration (75%), with peak 
serum concentrations achieved in 2–4 h. It is weakly bound (30%) to plasma proteins, 
and is eliminated primarily via the kidneys, 85% as the unchanged parent compound, 
with an estimated elimination half-life of 3-4 hours. The therapeutic serum concentration 
for spasticity is 0.08 to 0.4 microgram/ml. 
5.7.2 Additional Supporting Information for the dose of baclofen 
5.7.2.1 Baclofen in Alcohol dependence 
Very high doses of baclofen have been reported for use in alcohol use disorder for 
some patients (≤300mg/d), which is 10 times higher than that used in the initial RCT in 
this indication. Meta-analyses established an efficacy signal in alcoholism with ≤60mg/d 
compared with higher doses. Baclofen doses below 30mg/d have not demonstrated 
efficacy in alcoholism. A temporary license was granted in France for this indication up 
to 80mg/d (see section 2). In addition, we have comparative data using acute doses up 
to 90mg in our healthy control and alcoholic cohort showing that doses up to and 
including 60mg in controls and up to 90mg in alcohol dependent individuals were well 
tolerated (Durant et al., 2018). NB Only 10mg doses are available in the UK, making 
planned dose escalations of 10, 30, 60 and 90mg those most practicable options.  
 
We reviewed the trials of baclofen in alcoholism to determine how they evaluated side-
effects and adverse events, as there is no universally accepted gold-standard 
assessment (Singh & Loke, 2012). A systematic review of trials of baclofen in 
alcoholism (Pierce et al., 2018) reported that 9 of the 13 published studies reported no 
serious adverse events with one study not describing any such data. Of the remaining, 
the study with the highest prevalence of adverse effects investigated the highest dose 
of baclofen  (Reynaud et al., 2017); <180mg/d)). It reported that 20 baclofen and 26 
placebo patients experienced 40 and 43 serious adverse events (e.g. hospitalisation for 
alcohol detoxification, fall, suicidal ideation, depression) but most (70%) were 
considered unrelated to study medication. The other 2 studies reported one medication 
related serious adverse event: hospitalization due to constipation (Beraha et al., 2016); 
<150mg/d) and one overdose (related to medication), two hospitalisations due to 
suicidal ideation/intoxication (possibly medication related), and one death (30mg/d, 
provisionally assessed as unrelated to medication; (Morley et al., 2018)). In all the trials, 
common side effects reported included sleepiness/drowsiness, vertigo, fatigue, dry 
mouth, headache, sleep disorders, asthenia/muscle weakness, and dizziness and 
which were more likely to be observed following higher (ie >100mg/d) doses than will be 
used in our study (Pierce et al., 2018; Rose & Jones, 2018). In summary, whilst many 


 
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patients taking baclofen will incur side-effects these are generally benign and attenuate 
within first few days (or with slower titration/dose reductions); potentially more serious 
ones include seizures, respiratory depression with sleep apnoea, severe mood 
disorders, and mental confusion/delirium and potentially coma, particularly in case of 
intoxication with alcohol or other sedative drugs or after taking a baclofen overdose (de 
Beaurepaire et al., 2019).  
 
We have been unable to find any reports that baclofen is hepatotoxic and baclofen has 
been proposed as ideal in alcoholism where liver impairment is common. The first RCT 
of baclofen in alcoholism was in patients with cirrhosis where liver function improved (G. 
Addolorato et al., 2007). A study in patients with Hepatitis C reported that baclofen was 
well tolerated and there were no differences between groups in rates of serious drug-
related adverse effects and discontinuation (Hauser et al., 2017). Thus studies and 
reports from clinical populations suggest that baclofen is well tolerated in patients with 
chronic liver disease (de Beaurepaire et al., 2019). It is recommended that baclofen not 
be used in patients with hepatic encephalopathy or hepatorenal syndrome but these are 
extremely unlikely in those undergoing community opiate detoxification as they would 
not be healthy enough (Leggio & Lee, 2017; Thursz et al., 2018) 
5.7.2.2 Baclofen dose in opiate dependence 
 
Our previously conducted pharmacokinetic-pharmacodynamic (PK/PD) study to 
investigate the sensitivity of the GABA-B system demonstrated that alcohol dependent 
participants were less sensitive to the subjective and objective effects of baclofen than 
healthy controls (Durant et al 2018), and evidence from elsewhere suggests the same 
might be true for opiate dependence (Volpi et al., 1992). 
 
Details of all previous studies (to our knowledge) investigating baclofen in opiate 
dependence are provided in Table 1 and section 2.4. Doses of baclofen ranged from 40 
to 80mg/day. No safety issues were reported, and baclofen was described as well 
tolerated with few adverse events.  
 
More specifically, Krystal et al (1992) reported that 80 mg/day of baclofen was tolerated 
without evidence of side effects in patients whose methadone was abruptly stopped. In 
the Iranian studies of opiate detox, data was not presented regarding side-effects in one 
(Akhondzadeh et al., 2000). The other reported no overall difference in side-effect 
profile with baclofen compared with clonidine however, headache, nausea and vomiting 
were seen more with baclofen and dry mouth and orthostatic hypotension more with 
clonidine (Ahmadi-Abhari et al., 2001). No difference was reported in side-effects or 
adverse events between baclofen and placebo during a trial for relapse prevention in 
opiate dependence (Assadi et al., 2003).  
5.7.3 Pharmacy and packaging 
Drugs will be stored at Hammersmith hospital (HH) pharmacy and dispensed according 
to the prescription, which will be completed by the study physician. Dispensing and 
management of drug accountability will be managed and conducted by HH Pharmacy 
according to their SOPs. Prescriptions & Drug accountability logs will be maintained by 
the research team. 


 
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5.7.3.1 Baclofen 
Baclofen (generic) will be supplied by Imperial College Healthcare NHS Trust pharmacy 
(Hammersmith Hospital). These are white, round, scored tablets. Labelling will be as 
per Annex 13 regulations and dispensed under Regulation 37 of the 2004 UK Clinical 
Trial Regulations within the hospital, according to the exemption contained therein.  
5.7.3.2 Placebo 
Placebo tablets will be vitamin D3, (colecalciferol; scored, white round tablets) that are a 
near identical match to baclofen, supplied by Imperial College Healthcare NHS Trust 
pharmacy (Hammersmith Hospital). Labelling will be as per Annex 13 regulations and 
dispensed under Regulation 37 of the 2004 UK Clinical Trial Regulations within the 
hospital, according to the exemption contained therein. 
5.7.4 Emergency Unblinding Procedure 
This is single-blind- study clinicians and researchers will be aware of the drug allocation 
that was recommended by the adaptive trial algorithm and this allocation will be stored 
within the OpenClinica Database and accessible to the research team.  
 
5.8 Study Durations  
5.8.1 Protocol in event of experimental day failure  
In the event that a participant does not attend as planned, or tests positive for alcohol or 
drugs of abuse, or is ineligible for the study day (e.g. positive covid test, illness) prior to 
baclofen administration, the experimental visit will be re-scheduled. The participant 
would retain their baclofen or placebo randomisation, and their baclofen dose allocation. 
However, depending on the length of time between the cancelled and re-scheduled 
visit, and the potential for updates to the adaptive model in the intervening time, the 
baclofen dose level may be re-allocated, according to the discretion of the Dose Setting 
Committee.  
 
In the event that a participant has been administered medication during an experimental 
study visit, and there is subsequently a problem (e.g. fire alarm, non-recoverable 
equipment malfunction), that results in significant data loss such that the participant 
does not meet criteria for an evaluable participant, with the continued consent of the 
patient the study day (including drug administration) will be repeated at another 
scheduled session (in at least 5 days’ time if participant was randomised to baclofen). 
 
In the event that a participant does not re-schedule and is considered ‘lost’, that 
participant can be replaced if required (i.e. to make total of 48 on baclofen if safety has 
not yet been established). The replacement participant should receive the same 
treatment (placebo or baclofen) of the participant that is being replaced. However, in 
this case, the baclofen dose level may be re-allocated, as informed by the current 
model based on the replacement person’s own methadone dose, and at the discretion 
of the Dose Setting Committee. 
5.8.2 Withdrawal of Participants from the Study 
Participants can initiate withdrawal from the study. Each patient that will be recruited 
has the right to withdraw from the study for any reason. All data and samples collected 
to date will be retained. Should a participant decide to withdraw from the trial, all efforts 


 
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will be made to report the reason for withdrawal as thoroughly as possible and they will 
be encouraged to continue to provide outcome data.  
5.8.3 Duration of the study period 
The duration of the study period will be approximately 2-3 weeks for participants to 
complete consent, screening, experimental study visit and follow-up. In the event of a 
longer delay between screening and experimental visit, certain screening activities may 
be repeated at the discretion of the clinical team.  
5.8.4 Flexible visits  
We wish to minimise the drop-out rates and make participation as easy and flexible for 
participants as possible (particularly opiate dependent). Therefore participants may 
decide to undertake certain screening assessments over several visits, e.g. they may 
wish to participate by phone, online video or via an in-person visit in their local addiction 
service rather than at the ICRF. Subject to the relevant HRA approvals being in place, 
flexible visits for this purpose will be permitted. 
5.8.5 Duration of the follow-up period 
The duration of the follow up period will be 1 day for all participants who will receive a 
phone call the day after the experimental study visit. 
5.8.6 Loss to follow-up 
It is anticipated that more subjects will complete initial screening assessment than the 
experimental visit. Unless participants actively withdraw participation, data will be 
retained and analysed, as appropriate. 
5.8.7 Definition of completion of the study for an individual participant 
The end of the study will be defined as the last telephone contact visit which is 1 day 
after their study visit for opiate dependent participants. This represents the end of data 
collection as defined in ethics and regulatory terms, after which, adverse events will not 
be recorded. 
5.8.8 Definition of the end of the study 
The completion of the study for regulatory purposes will be defined as the last 
telephone follow-up appointment for the last participant. 
 
6 PARTICIPANT RECRUITMENT  
6.1 Population 
Opiate dependent participants enrolled in this study will be engaged in treatment for 
their opiate dependence from a specialist community addiction service and receiving 
stable doses of opiate substitution therapy with methadone. Therefore the participants 
will be regularly attending an addiction service, receiving psychosocial support. 
Therefore participants will not be chaotic with regard to their drug/alcohol use, 
unreliable in their attendance at appointments or have substantial physical or mental 
health needs.  
 
In particular, the research team will endeavour to recruit participants from across the 
methadone-maintenance dose range, including both males and females, to maintain a 


 
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balanced design and to capture data that allows a representative assessment of safety 
across the clinical population. 
 
6.2 Number of Participants 
The sample size is not fixed. Up to a total of 64 patients are planned to be enrolled in 
the study with up to 48 patients on the experimental doses and up to 16 on placebo, as 
recommended by the trial algorithm in consultation with clinicians and the study team. 
 
The drop-out rate from the study is estimated to be approximately 20% following 
screening. We therefore anticipate screening up to 100 methadone-maintained opioid 
dependent participants for entry into the study, with ~75% eligibility rate at screening, 
and a further ~20% drop out prior to, or at the experimental session.  
 
6.2.1 Definition of successful completion 
Successful completion will be defined as those meeting criteria for an ‘evaluable patient’ 
as defined in section 3.4.7. In the event of incomplete data, we will make a decision as 
to whether an individual’s data will be included in the primary and secondary analyses 
on a case-by case basis. 
 
For primary analysis, we will endeavour to include all those who received baclofen, if 
data allows a determination of whether or not a DLT was deemed to have occurred, 
according to clinical judgement.  
 
For secondary outcomes, analyses will include those that have at least one 
measurement following drug administration.  
 
6.3 Recruitment Strategies 
Opiate dependent individuals will primarily be recruited from NHS substance misuse 
services and/or related voluntary sector services based in London and surrounding 
areas, by directed advertisement at those services, via referral, or via an investigator-
led approach at NHS trusts, voluntary sector or partner organisations via Participant 
Identification Centres (PIC) or equivalent, subsequent to relevant approvals. Increasing 
visibility of the study and additional recruitment channels may also involve widespread 
advertisement in social media, dedicated study facebook pages or social media 
presence,  and advertising on relevant websites related to addiction.  
 
All advertising webpages will contain a link to a dedicated FORWARDS study website 
and/or email address which will provide a basic resource for further information, and 
study contacts such that the study team can contact participants as appropriate. 
 
6.4 Eligibility Criteria 
6.4.1 Inclusion Criteria 
 
1. Male or female 
2. Aged over 21 
3. Willing and able to comply with protocol 


 
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4. Able to read, comprehend and record information written in English 
5. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. 
6. 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. 
7. DSM-5 diagnosis of current severe opioid use disorder 
8. Treated with methadone substitution therapy and able to maintain the same stable 
dose for screening and experimental visit. 
9. Ability to receive an acute dose of up to 90mg baclofen or up to 4800IU vitamin D 
(placebo).  
 
6.4.2 Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
1. Intoxication on any of the visits, as assessed by difficulty in walking, the slurring of 
speech, difficulty concentrating or drowsiness. This exclusion criteria would exclude 
a subject from that study day only and not the whole study, at the discretion of the 
research team. 
 
2. Positive urine drug screens or breath alcohol at screening or experimental testing 
visits. A minimum list of drugs that will be screened for include amphetamines, 
cocaine, opiates, methadone, cannabinoids and benzodiazepines. Positive results 
for methadone will be allowed for those opiate dependent participants still 
undergoing OST. Positive results for cannabinoids will be allowed given the long 
half-life of cannabinoid metabolites. This exclusion criteria would exclude a subject 
from that study day only and not the whole study, at the discretion of the research 
team. 
 
3. 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. 
 
4. 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. 
 
5. Any participant taking over 120mg/day of prescribed methadone. 
 
6. 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.  
 


 
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7. Current or past history of enduring severe mental illness e.g. psychotic disorder 
(excluding drug induced), schizophrenia, bipolar affective disorder). 
 
8. Active suicidality. 
 
9. 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. 
 
10. Participants are taking any medication that is contraindicated with baclofen or 
placebo (vitamin D3), or are hypersensitive to them or any of their excipients.   
 
11. Participants that are taking any medication that in the opinion of the investigators 
may impact on the outcome measures during the experimental session. 
 
12. Use of intermittent psychotropic medication which in the opinion of the investigators 
will interfere with subject safety or study integrity.  
 
13. End stage or acute renal failure. 
 
14. Severe chronic obstructive pulmonary disease (COPD) or Type 2 respiratory failure. 
 
15. 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. 
 
16. Oxygen saturation <92% at rest  
 
17. 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. 
 
18. Clinically significant head injury (e.g., requiring medical or surgical intervention) that 
in the opinion of the investigators, contraindicates their participation . 
 
19. Active hepatitis or HIV.  
 
20. Active peptic ulceration. 
 
21. Significant current or past medical history that, in the opinion of the investigators, 
contraindicates their participation. 
 
22. The subject has participated in a clinical trial and has received an investigational 
product within 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer) prior to the first experimental visit. 
 


 
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23. Pregnancy or breast-feeding 
 
24. Unwillingness or inability to follow the procedures outlined in the protocol. 
 
 
7 RISKS AND BENEFITS 
7.1 Ethical considerations 
 
The Chief Investigator will abide by the ethical principles underlying the Declaration of 
Helsinki (1996) and good clinical practice (GCP) guidelines on the proper conduct of 
research, and comply with research governance. 
 
Investigators will hold honorary contracts or research passports, will be trained in GCP, 
Data Protection, GDPR and will hold current DBS checks. The team includes clinically 
experienced addiction staff who can immediately deal with any issues arising from this 
study, as well as link with support from the clinical teams managing the clinical care of 
opiate dependent participants. 
 
All opiate dependent participants will be engaged with a specialist clinical service for 
their community based detoxification. They will therefore be receiving support and know 
how to access extra support if required. The risk of relapse to on-top opiate use is a 
common challenge faced by individuals in this indication. However, significant instability 
is less likely in those who are on stable doses of methadone, or those who are tapering  
or preparing to undertake detoxification. Further, if an individual feels they may relapse, 
additional support is provided and reduction in their methadone is generally suspended. 
In this case, we would wait until the risk of on-top use was reduced and their stability or 
gradual reduction in methadone dose was resumed. The clinical team will have the 
opportunity to raise with the research team if there are concerns about any participants’ 
suitability to take part in the study or change in circumstance post-screening. Further 
the PI, Prof Anne Lingford-Hughes is a Consultant addiction psychiatrist with over 20yrs 
experience in this field and the research team also have several years’ experience 
working with this population.  
7.1.1 Potential Risks 
 
No treatment is withheld from participants in this study and testing will be performed at 
times convenient to all persons.  
 
Some participants may find the long experimental study day tiring. We will endeavour to 
take all steps to ensure comfort and provide appropriate rest and sustenance during 
these procedures.  
 
In our previously completed study (Durant et al 2018) a few of our healthy volunteers 
and abstinent alcohol dependent individuals reported minor side effects to the 60mg 
dose of baclofen, primarily dizziness and, nausea. These side effects resolved and all 
participants were fit to be discharged by end of the study day. The 90mg dose resulted 
in more pronounced sedation in one healthy volunteer with mild effects still felt the 
following day so we did not proceed with testing any further healthy participants at this 
dose. No such effects were seen in the alcohol dependent group and no significant 


 
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cardiovascular effects (e.g. blood pressure, heart rate) were observed in either group. 
The model in this proposal will mitigate risks of giving such high doses if sedation is 
seen at lower baclofen doses.  
 
We are carefully monitoring for any signs of respiratory depression and such 
information will be utilised in the model to determine the next safe dose combination. 
We have enhanced assessments of possible respiratory impairment in our screening 
protocol so that anyone at risk of respiratory depression is excluded. 
 
7.1.2 Potential Benefits 
 
Research participants will not directly benefit from taking part but the information we get 
might help improve the treatment of people with opiate dependence in future. 
Participants will receive feedback if requested about all aspects of the study, but this will 
not be available until the end of the study as this is a research investigation and the 
clinical relevance of the measures taken is not proven.  
 


 
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8 STATISTICS AND DATA ANALYSIS PLAN 
 
8.1 General statistical principles 
 
No formal statistical testing will be conducted for this early phase study and no power 
calculation has been peformed; all statistical analyses for primary and secondary 
outcomes are to be viewed as exploratory.  
 
8.2 METHODS OF RANDOMISATION  
 
The randomisation schedule will be generated by Sealed Envelope, or independent 
statistician, using a 3:1 ratio (baclofen: placebo). Blocked randomisation will be used 
maintain the 3:1 ratio throughout the study.   
 
8.2 SAMPLE SIZE 
 
The sample size in Phase I is not fixed. Up to a total of 64 patients are planned to be 
enrolled in the study with up to 48 patients on the experimental baclofen doses and 16 
on placebo with a 3:1 allocation ratio. The final sample size will depend on the 
escalation/de-escalation decisions made using the trial and on the recommendation of 
the model on stopping earlier. The performance of the Bayesian design based on 48 
participants was assessed via simulations under several clinically relevant scenarios in 
terms of accuracy of the number of patients that would receive (i) their individual target 
dose combination and (ii) a combination that is safe for them in the subsequently 
planned phase 2 trial. 
 
8.3 STATISTICAL ANALYSIS PLAN 
 
8.3.1 Analysis sets 
8.3.1.1 Full analysis set 
The full analysis set includes all randomised patients. This is equivalent to the ITT 
(intent-to-treat) population. The Full analysis set will be used to summarise study 
conduct and patient disposition.  
8.3.1.2 Safety set 
The safety analysis set will consist of all subjects who are randomised and received 
study drug. Subjects in this analysis set will be used for demographic, baseline 
characteristics, and safety summaries. Patients will be grouped according to actual 
treatment received. 
8.3.1.3 DLT evaluable safety set 
The DLT evaluable safety analysis set will consist of all subjects who are randomised 
and received study drug and are evaluable for a DLT. Subjects in this analysis set will 
be used for the primary dose-combination toxicity response analysis (included in the 
Bayesian analysis model). Patients will be grouped according to actual treatment 
received. 
 


 
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The analysis set for each secondary outcome will be based on the subset of patients 
from the safety set for whom at least 1 measurable outcome has been obtained.  
 
8.3.2 Primary analysis 
The first phase I cohort (4 patients) will be randomised to 10mg of baclofen or placebo 
(3:1 allocation ratio) with subsequent planned dose escalation of baclofen up to 90mg. 
The escalation will occur only in the case of acceptable safety and tolerability at the 
next lowest dose of baclofen for the prescribed dose of methadone and if no DLTs are 
observed for the current cohort of patients. Doses of baclofen cannot be skipped. The 
relationship between the doses of baclofen and methadone and the probability of 
observing a DLT will be modelled via a 5-parameter Bayesian logistic regression model 
with an interaction parameter (Neuenschwander B, 2015). The model will be 
sequentially updated after at most every 3 patients using the DLT/no DLT data from all 
previous cohorts in the trial before making the recommendation for the next cohort.  
 
Dose escalation will be based on the review of safety data during the experimental visit 
on the DLT evaluable safety set. For each given patient with a prescribed dose of 
methadone, the doses of baclofen are deemed to be safe if the risk of dose-limiting 
toxicity (DLT) being at least 25%, is less than 25%. The recommendation of the model 
will be to assign patients in the next cohort to their individual safe doses of baclofen that 
are more likely to have a toxicity risk of between 15% and 25% according to their 
prescribed dose of methadone (subject to the escalation constraints above). The 
patients in the next cohort can receive different doses of baclofen depending on their 
individual doses of methadone and previous data contributing to the model. 
 
The model can recommend stopping the trial earlier with all doses of baclofen found to 
be safe, if the probability that the risk of toxicity at 90mg baclofen in combination with 
120mg methadone is 25% or below, is above 92.5%. The trial can be recommended to 
be stopped earlier for safety concerns if the probability that the risk of toxicity at 30mg 
baclofen in combination with 60mg methadone (the lowest clinically viable combination) 
being above 25%, is 25% or more.  
 
Further details of the specification of the 5-parameter Bayesian logistic regression 
model are provided in the detailed Statistical Analysis Plan (SAP) that will be agreed by 
the TSC. 
 
The DSC can over-rule the recommendation of the model in the light of other safety and 
tolerability information.  
 
The primary statistical analysis will be conducted in R software.  
 
8.3.3 Secondary analysis 
Descriptive statistics (means/medians, with min/max and SD/IQR or frequencies and % 
as appropriate for the data distribution) will be presented for each secondary outcome 
by time point and treatment group. Secondary outcome measures will also be 
presented graphically over time and treatment group using appropriate summary 
statistics for the data distribution. 
 
Descriptive statistics will be also presented for secondary outcomes by baclofen dose 
and gender. Correlation analyses, using Pearson or Spearmaks rank correlation 


 
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coefficient, will be conducted to explore the associations between outcomes and 
methadone dose. 
 
For repeated continuous measures linear mixed models may be used to explore the 
effects of time and group (placebo versus baclofen). Where data allows, linear mixed 
models may be extended to explore the effects of baclofen dose and methadone dose 
on secondary outcomes.  
 
Secondary outcome analysis will be conducted using SPSS, Stata or R software. 
 
8.3.4 Analysis of GABA-B sensitivity outcomes 
Analysis of PK/PD endpoints to determine GABA-B sensitivity will be analysed as 
previously described (Durant et al, 2018).  
 
8.3.5 Analysis of exploratory outcomes 
An assessment of sources of variability e.g. age, dose on PK-PD and safety outcomes 
will be made. These exploratory analyses will be described in more detail elsewhere. 
 
8.3.6 Adverse events  
Adverse events will be tabulated by treatment group (baclofen versus placebo). Where 
useful a time to event analyses will be undertaken to depict the timing of adverse events 
(using hazard plots) and display the difference in time to event curves between 
treatment groups (baclofen versus placebo) and baclofen dose group for comparative 
purpose. 
 
8.3.7 Missing data 
Every effort will be made to obtain all follow up data for all participants. Data 
summarises will be based on observed data only. Linear mixed model analyses employ 
maximum likelihood estimation and thus are efficient for handing missing outcome data 
under a missing at random (MAR) assumption. 
 
A detailed statistical analysis plan, which will describe the primary and secondary 
analyses of the trial will be developed and agreed by the TSC. 
 
9 DATA AND STUDY MANAGEMENT  
9.1 Data Monitoring & Interim Analyses 
A DMC will be convened and meet regularly to discuss study progress, recruitment 
targets and future planning. If a trial stopping rule was triggered a DMC meeting would 
be convened to review the TMG’s decision to stop/continue the trial. 
 
Quality control checking and introduction of improvement procedures for data analysis 
will be ongoing throughout data collection. The study uses the continual reassessment 
method to assess the dose-toxicity response. There is no formal plan for interim data 
analysis of secondary outcomes before the completion of the study, however data will 
be continuously monitored to determine whether data collection should continue as 
planned, or be targeted towards a particular demographic or methadone dose to 
increase precision in secondary outcomes.  


 
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9.2 Direct Access to Source Data & Documents 
In the event of an audit or study related monitoring procedure, where source documents 
and data has to be reviewed, the chief investigator will permit study related monitoring, 
which will require access to source data or documents.  
 
During the study, it will only be the Chief Investigator, the co-investigators, as well as 
the rest of the research team involved in the study, who will have access to data 
produced by the study. 
 
9.3 Data handling and record keeping 
This study and its staff will be compliant with the Data Protection Act and GDPR with 
regards to the collection, storage, processing and disclosure of personal information. It 
is under the Chief Investigator’s responsibility to be up to date and comply with the 
requirements of the law and relevant guidelines relating to security and confidentiality of 
patient or other personal data, including the need to register, when necessary, with the 
appropriate Data Protection Officer. 
 
The study team will complete a Data protection impact assessment (DPIA) according to 
data protection legislation to identify how the study will process and store data and to 
identify and minimise data protection risks. 
 
9.3.1 Personal data 
Personal contact details are required for communication with the subjects participating 
in the study. This information is held solely for communication between the researchers 
and participants.  
Information held on NHS computers is solely for the purpose of hospital booking and 
routine sample collection and analysis (e.g. for medical screening). This information is 
password protected in a similar manner to that of other hospital patients. Access to 
additional patient records is explicitly requested from participants and this is made clear 
in the Information/Consent forms. 
Each participant will be identified by a unique code number that will be used throughout 
the duration of the study. Participant names, addresses, and other contact details will 
be written in the clinical screening portion of the paper-based CRF for identification and 
contact purposes.  The clinical screening CRFs will be regarded as confidential, and 
kept in locked filing cabinets in Imperial College. The contact details will then be 
removed from the CRF and into participant notes for storage.  
Only the CI, and selected study team members will have access to anonymised codes 
and their link to personal ID. This will be kept locked in a file on site and electronically 
on secure servers accessed by research team members only (password protected). 
9.3.2 Study data management 
All data will be collected in a pseudonymised and coded manner and stored within 
paper-based CRFs and/or via electronic data capture (EDC) within purpose built 
secure-access online databases; OpenClinica and REDCap, or saved electronically on 
secure University (Imperial College) computer systems and facilities. This will ensure 


 
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the safe acquisition, storage and transmission of data. University computers and 
servers are all password protected and study data can only be accessed by the 
researchers involved in the study. 
Quality control will be conducted according to ICTU, OpenClinica, REDCap or 
FORWARDS study SOPs, as appropriate. 
9.3.3 OpenClinica 
The electronic data capture (EDC) system for collecting and entering data is 
OpenClinica on an all-in-one platform. It is fully validated and compliant with 21 Code of 
Federal Regulations (CFR) Part 11 - Electronic Records; Electronic Signatures. The 
EDC system is also ICH-GCP and ISO9001 compliant.  
 
The Imperial College Clinical Trials Unit (ICTU) will be responsible for study control; 
from eCRF design to study close-out; database build and system validation while 
OpenClinica Cloud will be responsible for hosting the data. The trial specific 
OpenClinica system is built from requirements defined by the Chief Investigator, Trial 
Statistician and Study Manager and approved by the Chief Investigator. eCRF design 
documents and all approvals will be filed in the Trial Master File (TMF). The 
OpenClinica system will be built with data validation, automatic queries, alerts and edit 
checks as defined in the study requirements.  
 
The system is capable of real-time data entry for rapid access such that the Dose 
Setting Committee can make timely updates to the adaptive Bayesian model after (at 
most) every baclofen group of 3 participants. 
 
Access permissions to OpenClinica will be managed by ICTU according to the trial 
requirements and SOPs. Data entry will be managed according to ICTU and 
FORWARDS SOPs. 
9.3.4 REDCap 
Exploratory outcomes will be captured using REDCap (Research Electronic Data 
Capture) tools hosted at Imperial College London (PA Harris, 2019, 2009). REDCap is a 
secure, web-based software platform designed to support online or offline data capture 
for clinical research studies, providing 1) an intuitive interface for validated data capture; 
2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages; and 4) 
procedures for data integration and interoperability with external sources. 
 
REDCap can be used to capture a variety of types of data including 21 CFR Part 11, 
FISMA and HIPAA compliant environment. 
9.3.5 Custodian of the Data 
The CI, Professor Anne Lingford-Hughes, will be custodian of the data. 
9.3.6 Format of Records 
Personal data and raw data formats will be stored in patient hospital notes, paper-based 
CRFs or on password protected computer systems within the study sites, as 
appropriate.  


 
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Screening data will be pseudonymised where possible, and stored in paper-based or 
eCRFs, as appropriate.  
 
Study data will be pseudonymised and stored in paper-based or eCRFs, as appropriate. 
9.3.7 Duration & Location of stored data 
Primary research data / records will be retained in their original form for a minimum of 
10 years after the study has been completed. 
 
Location of data: Data will be stored within paper-based CRFs according to local 
security procedures, electronically on secure University (Imperial College) computer 
systems and facilities or within purpose built secure-access online databases, 
OpenClinica and Redcap, as detailed above. 
 
9.4 Training and User Support 
All staff employed on the grant and all Investigators will be trained in: 
• 
GCP  
• 
Use of the assessment tools 
• 
Study standard operating procedures 
• 
Use of Study databases (OpenClinica & REDCap) 
 
All staff working directly with participants will have a CRB check, a License to attend (or 
equivalent) for the ICRF, and an honorary contract (or research passport) with Central 
and North West London (CNWL) NHS trust. 
 
10 ADVERSE EVENT REPORTING 
 
10.1 Adverse Events and Adverse Reactions 
10.1.1 Definitions 
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational medicinal product (IMP), 
whether or not considered related to the IMP. 
 
Adverse Reaction (AR): all untoward and unintended responses to an IMP related to 
any dose administered.  All AEs judged by either the reporting investigator or the 
sponsor as having reasonable causal relationship to a medicinal product qualify as 
adverse reactions.  The expression reasonable causal relationship means to convey in 
general that there is evidence or argument to suggest a causal relationship. 
 
Unexpected Adverse Reaction: an AR, the nature or severity of which is not listed in 
the reference safety information (RSI) e.g. list of expected medical events within 
investigator’s brochure for an unapproved investigational product or section 4.8 of the 
summary of product characteristics (SmPC) for an authorised product.  When the 
outcome occurs this adverse reaction should be considered as unexpected. Side effects 


 
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documented in the SmPC which occur in a more severe form than anticipated are also 
considered to be unexpected. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction: any untoward medical 
occurrence or effect that at any dose: 
• 
Results in death. 
• 
Is life-threatening – refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires hospitalisation, or prolongation of existing inpatients’ 
hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
 
Medical judgement should be exercised in deciding whether an AE/AR is serious in 
other situations.  Important AE/ARs that are not immediately life-threatening or do not 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected 
adverse reaction related to an IMP that is both unexpected and serious.   
 
10.1.2 CAUSALITY 
Most adverse events and adverse drug reactions that occur in this study, whether they 
are serious or not, will be expected treatment-related toxicities due to the drugs used in 
this study.  The assignment of the causality should be made by the investigator 
responsible for the care of the participant using the definitions in the table below. 
 
If any doubt about the causality exists the local investigator should inform the study 
coordination centre who will notify the Chief Investigators.  The pharmaceutical 
companies and/or other clinicians may be asked to advise in some cases. 
 
In the case of discrepant views on causality between the investigator and others, all 
parties will discuss the case.  In the event that no agreement is made, the MHRA will be 
informed of both points of view.  
 
 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the 
event did not occur within a reasonable time after administration of the 
trial medication).  There is another reasonable explanation for the event 
(e.g. the participant’s clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because 
the event occurs within a reasonable time after administration of the trial 
medication).  However, the influence of other factors may have 
contributed to the event (e.g. the participant’s clinical condition, other 
concomitant treatments). 


 
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Probable 
There is evidence to suggest a causal relationship and the influence of 
other factors is unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
Not 
assessable 
There is insufficient or incomplete evidence to make a clinical judgement 
of the causal relationship. 
 
10.1.3 REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the 
reporting procedures below should be followed.  Any questions concerning adverse 
event reporting should be directed to the study coordination centre in the first instance.  
A flowchart is given below to aid in the reporting procedures. 
 
10.1.4 NON SERIOUS AR/AES 
All such toxicities, whether expected or not, should be recorded in the toxicity section of 
the relevant case report form and sent to the study coordination centre within one 
month of the form being due.   
 
10.1.5 SERIOUS AR/AES 
Fatal or life threatening SAEs and SUSARs should be reported on the day that the local 
site is aware of the event.  The SAE form asks for nature of event, date of onset, 
severity, corrective therapies given, outcome and causality (i.e. unrelated, unlikely, 
possible, probably, definitely).  The responsible investigator should sign the causality of 
the event.  Additional information should be sent within 5 days if the reaction has not 
resolved at the time of reporting.   
 
SAEs 
An SAE form should be completed and sent to the study coordination centre for all 
SAEs within 24 hours. OpenClinica software facilitates notification of the SAE form via 
email. However, relapse and death or hospitalization due to substance use disorder that 
cannot reasonably be attributed to study medication, and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
SUSARs  
In the case of suspected unexpected serious adverse reactions, the staff at the site 
should:  
 
 
Complete the SAE case report form & send it immediately (within 24 
hours,), signed and dated to the study coordination centre together with 
relevant treatment forms and anonymised copies of all relevant 
investigations. 
Or 
 
Contact the study coordination centre by phone and then send the 
completed SAE form to the study coordination centre within the following 
24 hours as above. 
 
The study coordination centre will notify the MHRA, REC and the Sponsor of all 
SUSARs occurring during the study according to the following timelines; fatal and life-


 
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threatening within 7 days of notification and non-life threatening within 15 days.   All 
investigators will be informed of all SUSARs occurring throughout the study. 
 
Local investigators should report any SUSARs and /or SAEs as required by their Local 
Research Ethics Committee and/or Research & Development Office. 
 
 
 
10.2 Contact details for reporting SAEs 
 
Contact details for reporting SAEs 
jrco@imperial.ac.uk 
 
CI email (and contact details below) 
Prof Anne Lingford-Hughes 
Please send SAE forms to: anne.lingford-hughes@imperial.ac.uk 
Tel: 020 7594 8682 / Fax: 020 7594 6548 
PA: Nicole Hickey – n.hickey@ic.ac.uk, Tel: +44 (0)20 3313 4161 
 
11 REGULATORY ISSUES 
 
11.1 CTA 
This study has Clinical Trials Authorisation from the UK Competent Authority; MHRA.   
EudraCT number: 2021-002556-36 
 


 
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11.2 ETHICS APPROVAL 
The Study Coordination Centre has obtained approval from the West of Scotland REC 1 
Research Ethics Committee (REC) and Health Regulator Authority (HRA). The study 
must also receive confirmation of capacity and capability from each participating NHS 
Trust before accepting participants into the study or any research activity is carried out. 
The study will be conducted in accordance with the recommendations for physicians 
involved in research on human subjects adopted by the 18th World Medical Assembly, 
Helsinki 1964 and later revisions. 
 
11.3 COMBINED WAYS OF WORKING 
This study will be using the Combined Ways of Working Pilot scheme in order to obtain 
approvals from: MHRA, REC and HRA.  
 
11.4 CONSENT  
Consent to enter the study must be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration.  Signed participant consent should be obtained.  The right of the 
participant to refuse to participate without giving reasons must be respected.  After the 
participant has entered the trial the clinician remains free to give alternative treatment to 
that specified in the protocol at any stage if he/she feels it is in the participant’s best 
interest, but the reasons for doing so should be recorded.  In these cases the 
participants remain within the study for the purposes of follow-up and data analysis.  All 
participants are free to withdraw at any time from the protocol treatment without giving 
reasons and without prejudicing further treatment. 
 
11.5 CONFIDENTIALITY 
Participants’ identification data will be required for the registration process.  The Study 
Coordination Centre will preserve the confidentiality of participants taking part in the 
study and is registered under the Data Protection Act. However, should there be any 
concerns about risks of harm to the participants or anyone else, a clinical decision will 
be made with regard to disclosure of information and appropriate support will be 
discussed with the participant.  
 
11.6 INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study 
 
11.7 SPONSOR 
Imperial College London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.   
 
11.8 FUNDING 
This study is funded by the Medical Research Council, grant number MR/T025557/1 
(Infoed- P86340). Participants will receive compensation for taking part in the research. 
They will receive £50 for screening and £100 for a completed experimental visit, 
received either by bank transfer, or vouchers (as requested). 


 
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11.9 AUDITS AND INSPECTIONS  
The study may be subject to inspection and audit by Imperial College London/Imperial 
College Healthcare NHS Trust (delete as applicable) under their remit as Sponsor, the 
Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.  
 
11.10 Publication policy 
It is intended that the results of the study will be reported and disseminated in peer-
reviewed scientific journals, and internal reports, conference presentations, written 
feedback to study participants and consultants, and presentations to relevant 
community groups. 
 
11.11 Protocol amendments 
None 
 
12. 
TRIAL MANAGEMENT 
 
A Trial Management Group (TMG) has been appointed to oversee the FORWARDS 
grant in its entirely and meet regularly to monitor milestones and targets and will be 
responsible for overseeing the progress of the trial. 
 
A DMC and TSC will additionally be convened for oversight of trial & data management.  
 
A Trial Steering Committee (TSC) will be convened including as a minimum an 
independent Chair, independent clinician, the Chief Investigator and Trial Manager. The 
role of the TSC is to provide overall supervision of trial conduct and progress. Details of 
membership, responsibilities and frequency of meetings will be defined in a separate 
Charter. 
 
A fully independent Data Monitoring Committee (DMC) will be set up to monitor 
progress, participant safety, and any ethical issues involved in this trial. They will review 
trial progress, recruitment rates, safety, and data emerging from other trials and make 
recommendations to the TSC as to whether there are any reasons why the trial should 
not continue. The DMC membership will include independent experts in addiction 
and/or pharmacology and/or physiology and a clinical trials statistician.  A separate 
DMC Charter will be drawn up defining their responsibilities, frequency of meetings and 
reporting to the TSC. The DMC are permitted to have access to the unblinded data for 
review and any comparisons between groups where appropriate.   
 
The Dose Setting Committee (including a statistician, clinician and member of the 
research team) will be responsible for regular review of data relevant to the updating of 
the model (incidence of DLT). The trial statisticians will be responsible for the updating 
of the adaptive model.  
 
The day-to-day management of the trial will be co-ordinated by the research team.   
 
13. 
STUDY MONITORING 
 


 
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Study Monitoring at Imperial College NHS foundation trust will be conducted by the 
RGIT Clinical Trials Monitor and overseen by the RGIT Clinical Trials Manager or 
delegate, according to their SOPs. 
 
Monitoring undertaken at other research sites e.g. CNWL sites, will be undertaken by 
the research team under the responsibility of the Chief Investigator (CI) or Principal 
Investigator (PI) who will make appropriate monitoring arrangements. The Monitors will 
be appropriately trained and should have the scientific and/or clinical knowledge 
needed to monitor the trial adequately. Training records, including relevant 
qualifications, will be kept by the monitor and checked by the Chief Investigator. 
 
The monitor will be familiar with the Investigational Medicinal Product (IMP), the 
protocol, information sheet and consent form, as well as the Imperial College AHSC 
SOPs, GCP and applicable regulatory requirements 
 
13.1 
RISK ASSESSMENT 
 
A Monitoring Risk Assessment will be conducted in relation to the Colleges SOPs 
identifying the level of risk involved with this study.  
  


 
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