Extended-release Pharmacotherapy for Opioid Use Disorder (EXPO): Protocol for an Open-label Randomised Controlled Trial of Injectable Maintenance Buprenorphine With Personalised Psychosocial Intervention.
Phase: PHASE3
Conditions: Opiate Substitution Treatment
Sponsor: King's College London

 
 
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PROTOCOL FULL TITLE:  
 
Extended-release Pharmacotherapy for Opioid Use Disorder (EXPO): 
An Open Label Randomised Controlled Trial of Injectable Depot 
Maintenance Buprenorphine versus Standard-Of-Care Oral 
Maintenance Opioid Agonist/Partial Opioid Agonist Medication, with 
Personalised Psychosocial Intervention. The EXPO study. 
Protocol Short Title/Acronym 
Extended-release Pharmacotherapy for Opioid Use Disorder (EXPO)  
 
Trial Identifiers  
 
Protocol version (date): V5.1 (06/10/2021)  
 
IRAS Project ID: 255522;  
REC: London – Brighton and Sussex 
REC Reference: 19/LO/0483 
 
EudraCT number: 2018-004460-63 
 
Co-Sponsors 
King's College London (KCL) and South London & Maudsley NHS Foundation 
Trust (SLaM). 
 
Chief Investigator and Principal Investigator (contract lead for academic 
partner: SLaM) 
Mike Kelleher; South London and Maudsley NHS Foundation Trust.  
Lambeth Addictions Consortium, 12-14 Brighton Terrace, London SW9 8DG 
Telephone: 020 3228 1500; Fax: 020 3228 1585 
Email: mike.kelleher@slam.nhs.uk 
 
Lead (clinical scientific) Investigator (lead for academic partner: KCL) 
John Marsden; Addiction Sciences Building; Institute of Psychiatry, Psychology 
and Neuroscience, 4 Windsor Walk, Denmark Hill, London SE5 8AF  
Telephone: 0207 848 0830; 07710 327 876 
Email: john.marsden@kcl.ac.uk 
 
Co-Lead (clinical scientific) Investigator 
Luke Mitcheson; South London and Maudsley NHS Foundation Trust; Lambeth 
Addictions Consortium. 12-14 Brighton Terrace, Brixton, London SW9 8DG 
Telephone: 020 3228 1500; Fax: 020 3228 1585  
Email: luke.mitcheson@slam.nhs.uk  

 
 
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1. Study Synopsis 
 
Title of clinical trial 
Extended-release Pharmacotherapy for Opioid Use Disorder (EXPO): 
A Randomised Controlled Trial of Injectable Depot Buprenorphine with 
Personalised Psychosocial Intervention versus Oral Opioid 
Agonist/Partial Agonist Medication.  
Short Title/acronym 
The EXPO trial 
Protocol Version (date) 
Version 5.1 (06.10.2021) 
Trial Phase 
Phase III (CTIMP; IMP open-label, oral IMP comparators [no placebo]) 
Sponsors 
King's College London and South London & Maudsley NHS Trust 
EudraCT number 
2018-004460-63 
IRAS Project number 
255522 
NHS ethics committee  
London – Brighton and Sussex 
Medical condition  
Opioid Use Disorder (OUD; moderate-severe; DSM5) 
Primary objective  
The primary objective is a clinical superiority effectiveness contrast to 
standard of care. Reported following SPIRIT and CONSORT 
standards, the study will determine whether extended-release 
injectable depot Buprenorphine (XR-Bup) maintenance therapy for 
OUD over six months is clinically superior to standard-of-care, oral 
medication. 
 
Secondary objectives 
To explore study group differences on the following measures:  
(1) Clinical superiority of XR-Bup plus personalised Psychosocial 
Intervention (PSI; offered across the treatment phase) versus Bup/Met 
plus PSI;   
(2) Safety of XR-Bup; 
(3) Treatment retention;  
(4) OUD and CUD remission status;  
(5) Clinician rated impression of patient response to treatment;  
(6) Patient reported recovery outcomes; 
(7) Mediation of craving, work and social adjustment, and cognitive 
function on outcome. 
 
Economic Objectives  
 
To estimate the cost-effectiveness of buprenorphine extended-release 
depot injection, based on the incremental cost per quality-adjusted life 
year (QALY) gained compared with standard-of-care, oral medication. 
 
Subject to securing research support, there will be analysis of data-
registry indicators of mortality, convictions and health service utilisation 
(the later longer-term research aims). In preparation for this, 
participants will be asked for their consent.  
 
Trial design 
Multi-centre, pragmatic, open-label, phase 3, two-phase, open-label, 
randomised controlled trial. 

 
 
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Setting 
Specialist community NHS addictions treatment clinics. 
Endpoints 
Primary: Count of days abstinent from illicit/non-medical opioids during 
weeks 2 to 24 (range: 0-161 days); combining self-report information 
from Time-Line Follow-Back interview adapted from the Treatment 
Outcomes Profile and incorporating data from 12 scheduled urine drug 
screens. 
Secondary:  
To explore study group differences on the following:  
(1) Clinical superiority of XR-Bup plus PSI versus Bup/Met plus PSI.   
(2) Safety of XR-Bup; 
(3) Time (days) enrolled in study treatment (retention) to week 24;  
(4) OUD and CUD remission status (DSM5 OUD and CUD severity; 
SCID-5-RV);  
(5) Clinician rating of severity, complexity and recovery strengths: 
ADAPT;  
(6) Clinician global impression of severity and improvement): CGI-S/I;  
 (7) Count of days abstinent from cocaine and illicit/non-medical 
benzodiazepines during weeks 2 to 24 (range: 0-161 days); combining 
self-report information from Time-Line Follow-Back interview adapted 
from the Treatment Outcomes Profile and incorporating data from 12 
scheduled urine drug screens. 
(8) Frequency of opioid (H) and cocaine (C) craving experience: CEQ-
F(H) and CEQ-F(C); 
(9) Craving need and want strength for heroin and cocaine: 
VAS-N(H/C) and VAS-W(H/C);  
(10) Difficulties in Emotion Regulation (Short Form): DERS-SF; 
(11) Depression symptoms: QIDS-SR;   
(12) Work and social adjustment: WSAS; 
(13) Subjective recovery and improvement: SURE;  
(14) Patient rating of OUD severity and improvement:  PRO-S/I; (15) 
Cognitive impairment: MoCA;  
(16) Alcohol consumption: typical quantity and frequency: (ALC-QFM); 
(17) Time (days) enrolled in study treatment (retention) from week 24 to 
date of last participant randomised plus 9 months; 
(18) Semi structured, topic guided interviews after week 24 (XR-Bup, 
XR-Bup +PSI & Bup/Met +PSI treatment arms) and after 12 months of 
enrolment within the trial (XR-Bup treatment arm only);  
(19) Among participants enrolled in longer term XR-Bup treatment: 
OUD and CUD remission status (SCID-5-RV); heroin, cocaine and 
illicit/non-medical benzodiazepine use in past 90 days (TLFB; UDS); 
somatic symptoms (PHQ-15), emotion regulation (DERS-SF), 
depression and anxiety symptoms (PHQ-4) and quality of life 
(OSTQOL). 
 
Economic:  
 
Costs based on responses to the ADSUS questionnaire and the EXPO 
keyworker contact form; and QALYs calculated from EQ-5D-5L scores 
and by applying the EQ-5D-3L crosswalk value set. This has no 
implications for the sample size calculation. 

 
 
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Sample size and 
justification 
Target total N=604 
 
Group 1: XR-Bup (n=152);  
Group 2: Bup/Met (n=152);  
Group 3: XR-Bup and PSI (n=150);  
Group 4: Bup/Met and PSI (n=150). 
 
The target number of participants has been calculated using that 
required for a Poisson regression taking a baseline rate of 0.6 and 
assuming a 23% target difference in the count of days of abstinence 
from heroin over the study period of 161 days (reference study: ARC 
trial (ISRCTN69313751; 56.78% for the treatment-as-usual control 
group [i.e. assuming 17 abstinent days over a period of 28 days]).  
 
To obtain 90% power, for a Poisson regression model, with alpha at 5% 
and with 15% inflation for attrition, EXPO has a target total of 304 
participants for the statistical comparison of the primary outcome 
recorded for Group 1 and Group 2 and a target total of 300 for the 
statistical comparison of Group 3 and Group 4. 
 
The statistical analysis plan will include a sensitivity check on this 
power calculation on the assumption of a greater response for the 
control groups.  
 
Following completion of these analyses, an analysis will be done of 
Group 1 and Group 3 to estimate the effect of XR-Bup and PSI 
compared to XR-Bup). This will be an exploratory but pre-registered 
analysis.  
Participant eligibility 
criteria 
Inclusion criteria  
 
1. Aged ≥ 18 years (no upper age limit); 
2. Current diagnosis of DSM-5 OUD via SCID-5-RV (moderate-severe at 
baseline for current episode); 
3. Currently enrolled on Met (30mg/day or less) or sublingual Bup or Bup-
NX (24mg/day or less) or Esp (18mg/day or less) and in the view of the 
clinician would be able to convert to XR-Bup within 7 days post 
randomisation; 
4. Voluntarily seeking treatment and able to attend the clinic as required 
in the protocol;  
5. Able to communicate in English to level required to accept standard 
care and psychosocial intervention; 
6. Possession of a contactable personal mobile phone or landline 
telephone number and ability to nominate at least one locator individual 
with a verifiable address and a telephone number to assist with the 
arrangement of follow-up appointments; 
7. Living circumstances judged to be of sufficient stability to be able to 
engage/adhere to the study protocol; 
8. Is not pregnant (confirmed) or breast feeding and, if currently or 
intending to have potentially procreative intercourse, agrees to use a 
birth control method (either oral hormonal contraceptives, barrier 

 
 
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[condom or diaphragm], or Nexplanon implant) for the duration of the 
study. 
 
Exclusion criteria 
 
1. Clinically significant medical condition or observed abnormalities on 
physical examination or laboratory investigation, including but not limited 
to:  
(a) uncontrolled hypertension, significant heart disease (including angina 
and myocardial infarction in past 12 months), or any cardiovascular 
abnormality which is judged to be clinically significant;  
(b) severe alcohol dependence/withdrawal syndrome which is judged to 
be clinically significant and may constitute a risk to the patient's safety; 
(c) acute hepatitis taken as clinical jaundice on examination, or evidence 
of blood bilirubin level above the normal range for local reference criteria, 
or evidence of serum levels of aspartate aminotransferase, alanine 
aminotransferase levels that are more than three-times the upper limit of 
the normal range;  
2. History of allergic or adverse reactions to Bup or the proprietary 
ATRIGEL delivery system for XR-Bup (Sublocade®)*; 
3. Clinically significant or uncontrolled mental health problems (including 
but not limited to psychosis, bipolar disorder, schizoaffective disorder), 
or history or evidence of organic brain disease or dementia that may 
compromise safety or compliance with the study protocol; 
4. Current (past 30 day) suicide plan or suicide attempt in past six 
months; 
5. Current criminal justice involvement with legal proceedings, which in 
the opinion of a medically qualified investigator indicates a risk that the 
patient would fail to complete the study protocol due to re-incarceration 
or move away from the centre’s catchment area. 
6. Currently taking oral or depot naltrexone therapy or enrolment in any 
form of naltrexone therapy within 90 days prior to study screening; 
7. Any contraindication to Bup*  . 
 
*Participant is ineligible if they have any allergic or adverse reactions or 
contraindication to Buprenorphine. If participant has any allergic or 
adverse reaction or contraindication to Met or naloxone, or excipients of 
Bup-NX or Esp they can be prescribed Bup within the trial.  
 
IMP, dosage and route of 
administration 
Buprenorphine extended-release depot injection (USA Sublocade®; 
XR-Bup) is administered by subcutaneous injection into abdominal 
tissue. XR-Bup is available as a 100mg/0.5ml and 300mg/1.5ml pre-
filled syringe. In EXPO, the drug is administered as two initial doses of 
300mg given a minimum of 21 days apart, followed by 4 x 100 mg 
monthly maintenance doses.  
 
Within the regimen and if the benefits are judged to outweigh the risks: 
(1) The 100 mg maintenance dose may be increased and maintained to 
300mg if there is unsatisfactory clinical response (i.e. dose 3-6); (2) A 
300 mg maintenance dose (i.e. dose 4 and 5) may be reduced to 100 
mg according to clinical assessment; (3) Bup will be given on a rescue 

 
 
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basis for patients who do not achieve a satisfactory clinical response to 
XR-Bup. 
 
Active comparator 
product(s) 
 
(1) Bup (sublingual [tablet] Bup, or substitute 4:1 ratio Bup/naloxone 
‘Suboxone’ [Bup- NX]) usual dose 12-24mg/day; or substitute oral 
lyophilisate Espranor (Esp) usual dose 8-18mg/day) are longstanding 
standard-of-care maintenance pharmacotherapy for OUD in the NHS.  
(2) Met (oral methadone hydrochloride; usual dose 60-120mg/d), 
longstanding standard-of-care maintenance pharmacotherapy for OUD 
in the NHS.  
 
Maximum duration of 
treatment for participant 
40 months 
Electronic CRF  
InferMED MACRO (programmed by King’s Clinical Trials Unit [KCTU]) 
 
Clinical trials unit 
KCTU (on-line randomisation) 
 
 
 
Study Phases 
Data lock 1: target quarter 3, 2022 for analysis of XR-Bup vs. Bup/Met.  
Data lock 2: target quarter 3, 2022 for analysis of XR-Bup + PSI vs. 
Bup/Met + PSI. 
 
Target duration of study 
48 months  
 
Protocol Amendments 
Detailed in Section 25 of the protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2. Study Contacts 
 
Michael Kelleher (Chief Investigator [CI] and 
Principal Investigator) 
Clinical Lead Lambeth Addictions 
SLaM Drug and Alcohol Service (Lambeth) 
Lorraine Hewitt House 
12-14 Brighton Terrace, Brixton 
London SW9 8DG 
w: 020 322 81500; m: 0781 3 055 783 
email: Mike.Kelleher@slam.nhs.uk 
John Marsden (Co-Lead Investigator [Co-LI]) 
Research Lead Lambeth Addictions 
Institute of Psychiatry, Psychology & Neuroscience 
Box 48, Addiction Sciences Building 
4 Windsor Walk, London SE5 8AF 
w: 020 7848 0830; m: 07710 327 876 
f: 020 7848 5966; 
email: john.marsden@kcl.ac.uk 
Luke Mitcheson (Co-LI) 
Clinical Lead Lambeth Addictions 
SLaM Drug and Alcohol Service (Lambeth) 
Lorraine Hewitt House, 12-14 Brighton Terrace, 
Brixton, London SW9 8DG 
w: 020 322 81512 m: 0781 3 055 783 
email: Luke.Mitcheson@slam.nhs.uk 
Jatinder Bisla (EXPO Trial Manager) 
Institute of Psychiatry, Psychology & Neuroscience 
Box 48, Addiction Sciences Building 
4 Windsor Walk, London SE5 8AF 
w: 020 7848 0830; f: 020 7848 5966 
email: jatinder.bisla@kcl.ac.uk  
Zoë Hoare (Trial Statistician) 
NWORTH Clinical Trials Unit, 
School of Health Sciences, Bangor University, 
Bangor, Gwynedd, LL57 2DG; 
w: 01248 388840; 
email: z.hoare@bangor.ac.uk 
Caroline Murphy (Operational Director KCTU) 
Institute of Psychiatry, Psychology & Neuroscience 
PO64, De Crespigny Park, 
London SE5 8AF 
w: 020 7848 0532; f: 020 7848 5229 
email: caroline.murphy@kcl.ac.uk 
Angela Cape (EXPO Trial Pharmacist) 
Institute of Psychiatry, Psychology & 
Neuroscience 
PO64, De Crespigny Park, 
London SE5 8AF 
w: 020 7848 0532; f: 020 7848 5229 
email: angela.cape@kcl.ac.uk 
Joanna Kelly (Strategic Data Management Lead 
KCTU) 
Institute of Psychiatry, Psychology & Neuroscience 
PO64, De Crespigny Park, 
London SE5 8AF 
w: 020 7848 0532; f: 020 7848 5229 
email: joanna.kelly@kcl.ac.uk 
Eilish Gilvarry (Principal Investigator [PI]) 
Consultant Psychiatrist in Addictions 
Northumberland, Tyne & Wear 
NHS Foundation Trust 
Newcastle Addictions Service, Plummer Court, 
Carliol Place, Newcastle upon Tyne, NE1 6UR 
w:  0191 206 1123 (Personal Assistant) 
email: eilish.gilvarry@ntw.nhs.uk 
Ed Day (Principal Investigator) 
Consultant in Addiction Psychiatry, 
Birmingham & Solihull Mental Health 
NHS Foundation Trust 
25 Vincent Drive, Birmingham B15 2FG 
w. 0121 301 2355; f: 0121 301 2351 
email: e.j.day@bham.ac.uk 
Jonathan Dewhurst (Principal Investigator) 
Clinical Lead consultant psychiatrist 
Greater Manchester Mental Health 
NHS Foundation Trust, Chapman Barker Unit, 
Bury New Road, Prestwich, 
Manchester, M25 3BL 
w: 0161 358 1599 
email: jonathan.dewhurst@gmmh.nhs.uk 
Fiona Cowden (Principal Investigator) 
Consultant Psychiatrist 
Dundee Drug & Alcohol Recovery Service  
Constitution House 
55 Constitution Road 
Dundee, DD1 1LB 
w: 01382 424518 
email: fcowden@nhs.net 
 
Dyfrig Hughes (Health Economics Lead) 
Centre for Health Economics and Medicines  
Evaluation 
Bangor University, Bangor, Gwynedd, LL57 2PZ  
w: 01248 382950 
email: d.a.hughes@bangor.ac.uk 
 
 
 
 

 
 
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3. List of abbreviations 
 
Abbreviation   
Definition 
ADAPT  
 
Addiction Dimensions for Assessment and Personalised Treatment 
ADSUS  
 
Alcohol and Drug Service Use Schedule 
AE  
 
 
Adverse Event 
AEL 
 
 
Adverse Event Log 
ALC-QFM  
     
Alcohol - Quantity, Frequency and Maximum Consumption  
ALT  
 
 
Alanine Aminotransferase 
AMRI 
 
 
Albany Molecular Research 
AR 
 
 
Adverse Reaction  
AST  
 
 
Aspartate Aminotransferase 
ATRIGEL 
 
Proprietary Extended-Release Bup Delivery Technology 
BP  
 
 
Blood Pressure 
Bup  
 
 
Buprenorphine 
Bup-NX   
 
Buprenorphine-Naloxone (Suboxone®) 
CBT 
 
 
Cognitive Behavioural Therapy 
CDF 
 
 
Cumulative Distribution Function (for primary outcome) 
CEQ-F(H/C) 
 
Craving Experience Questionnaire (frequency version) (Heroin/Cocaine) 
CI 
 
 
Chief Investigator  
CGI-S and I 
 
Clinical Global Impression (severity and improvement) 
CHEERS  
 
Consolidated Health Economics Evaluation Reporting Standards 
COVID-19 
 
Coronavirus Disease 2019 
CRA 
 
 
Clinical Research Associate  
CRF  
 
 
Case Report Form 
CTIMP  
 
Clinical Trial of an Investigational Medical Product 
CUD  
 
 
Cocaine Use Disorder 
DERS-SF 
 
Difficulties in Emotion Regulation Scale – Short Form 
DMC 
 
 
Data Monitoring Committee 
DSM-5   
 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
DSUR 
 
 
Development Safety Update Report 
eCRF  
 
 
Electronic Case Report Form 
EDC 
 
 
Electronic Data Capture  
EEA QPPV 
 
European Economic Area Qualified Person Responsible for Pharmacovigilance 
Esp 
 
 
Espranor® 
EQ-5D-5L 
 
EurolQol Health Status (5 level) 
FDA                                    Food and Drug Administration  
GCP  
 
 
Good Clinical Practice 
HEAP   
 
Health Economics Analysis Plan 
IB                                        Investigators Brochure  
IME 
 
 
Important Medical Events  
IMP  
 
 
Investigational Medicinal Product 
IMPD  
 
 
Investigational Medicinal Product Dossier  
KCF 
 
 
Keyworker Contact Form  
KCTU 
 
 
King’s Clinical Trials Unit 
KHP-CTO 
 
King’s Health Partners – Clinical Trials Office 
LFT  
 
 
Liver Function Tests (AST, ALT, albumin and bilirubin) 
Met 
 
 
Methadone (oral) 
Mg  
 
 
Milligrams 
Mg/day  
 
Milligrams per day 
MoCA 
 
 
Montreal Cognitive Assessment  
MHRA                                 Medicines and Healthcare Product Regulatory Agency 
NICE  
 
 
National Institute for Health and Care Excellence  
OSTQOL 
 
Opioid Substitution Treatment Quality of Life scale 
OUD 
 
 
Opioid Use Disorder 
PDA                                    Percentage Days Abstinent  
PHE 
 
 
Public Health England 
PHQ-4  
 
Patient Health Questionnaire Anxiety and Depression 
PHQ-15  
 
Patient Health Questionnaire 
PI 
 
 
Principal Investigator  
PNC 
 
 
Police National Computer 

 
 
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PRO-S and I 
 
Patient Reported Outcome (severity and improvement)  
PSI 
 
 
Personalised Psychosocial Intervention 
QALY   
 
Quality-adjusted life year 
QIDS-SR 
 
Quick Inventory of Depressive Symptomatology 
QP 
 
 
Qualified Person  
REC 
 
 
Research Ethics Committee 
RR  
 
 
Relative Risk  
RSI  
 
 
Reference Safety Information   
SAE 
 
 
Serious Adverse Event  
SAP                                    Statistical Analysis Plan 
SAR  
 
 
Serious Adverse Reaction (SAR)  
SCID-5-RV 
 
Standard Clinical Interview for Dependence – Research Version (DSM-5) 
SmPC 
 
 
Summary of Product Characteristics 
SOP 
 
 
Standard Operating Procedure 
SURE 
 
 
Substance Use Recovery Evaluator 
SUSAR   
 
Suspected Unexpected Serious Adverse Reaction 
TLFB 
 
 
Timeline Follow Back  
TMG 
 
 
Trial Management Group 
TOP 
 
 
Treatment Outcomes Profile 
TSC 
 
 
Trial Steering Committee  
UAR 
 
 
Unexpected Adverse Reaction  
UDS 
 
 
Urine Drug Screen 
VAS-(N/W) 
 
Visual Analogue Craving Rating (Need/Want; 0-100 Point) 
WSAS  
 
Work and Social Adjustment Scale 
XR-Bup  
 
Extended-Release Buprenorphine (US Sublocade®; prev. RBP-60000) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Contents 
1. 
STUDY SYNOPSIS ............................................................................................... 2 
2. STUDY CONTACTS ................................................................................................... 7 
3. LIST OF ABBREVIATIONS ........................................................................................ 8 
4. INTRODUCTION ....................................................................................................... 12 
4.1 BACKGROUND ........................................................................................................ 12 
4.2 RATIONALE ............................................................................................................ 12 
5. TRIAL OBJECTIVES AND DESIGN ......................................................................... 14 
5.1. TRIAL OBJECTIVES AND PRIMARY ENDPOINT ............................................................ 14 
5.2. TRIAL DESIGN, BLINDING OVERVIEW ........................................................................ 14 
5.3. PRIMARY ENDPOINT ANALYSIS OVERVIEW ............................................................... 15 
6. TRIAL MEDICATION ................................................................................................ 15 
6.1 INVESTIGATIONAL MEDICINAL PRODUCT ................................................................... 15 
6.2 ACTIVE COMPARATORS ........................................................................................... 16 
6.3 DOSING REGIMEN ................................................................................................... 17 
6.4 IMP ADMINISTRATION ............................................................................................. 19 
6.5 IMP RISKS ............................................................................................................. 19 
6.6 TREATMENT DISCONTINUATION ............................................................................... 22 
6.7 DRUG ACCOUNTABILITY .......................................................................................... 23 
6.7.1 XR-Bup .......................................................................................................... 23 
6.7.2 Met and Bup .................................................................................................. 23 
6.8 SUPPLY, TRANSPORT AND STORAGE OF IMP ............................................................ 24 
6.8.1 XR-Bup (Sublocade®) ................................................................................... 24 
6.8.2 Active Comparators (Bup/Met) ....................................................................... 24 
6.9 CONCOMITANT MEDICATION ................................................................................... 24 
7. TAILORED PSYCHOSOCIAL INTERVENTION ....................................................... 25 
8. SELECTION AND WITHDRAWAL OF PARTICIPANTS .......................................... 26 
A MEDICALLY QUALIFIED CHIEF, PRINCIPAL OR SUB-INVESTIGATOR WILL EVALUATE THE 
FOLLOWING INCLUSION AND EXCLUSION CRITERIA: ......................................................... 26 
8.1 INCLUSION CRITERIA ............................................................................................... 26 
INCLUSION CRITERIA .................................................................................................... 26 
8.2 EXCLUSION CRITERIA ............................................................................................. 27 
8.3 SELECTION OF PARTICIPANTS ................................................................................. 27 
8.4 RANDOMISATION PROCEDURE ................................................................................ 28 
8.5 WITHDRAWAL OF PARTICIPANTS .............................................................................. 29 
8.6 END OF TRIAL DEFINITION....................................................................................... 29 
9. TRIAL PROCEDURES.............................................................................................. 29 
9.1 BY VISIT................................................................................................................. 29 
9.1.2 OPTIONAL CONSENTS ......................................................................................... 32 
9.2 ASSESSMENTS BY STUDY WEEK AND STUDY TIMELINE ............................................. 34 
9.3 LABORATORY TESTS .............................................................................................. 35 
10. ASSESSMENT OF EFFICACY ............................................................................... 35 
10.1 PRIMARY EFFICACY PARAMETER ........................................................................... 35 

 
 
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10.2 SECONDARY EFFICACY PARAMETERS .................................................................... 35 
10.3 PROCEDURES FOR ASSESSING EFFICACY PARAMETERS .......................................... 36 
10.A ASSESSMENT OF COST EFFECTIVENESS ...................................................... 36 
10.1A PRIMARY ECONOMIC PARAMETER ....................................................................... 36 
10.2A SECONDARY ECONOMIC PARAMETERS ................................................................ 37 
10.3A PROCEDURES FOR ASSESSING COST-EFFECTIVENESS PARAMETERS ..................... 37 
11. ASSESSMENT OF SAFETY ................................................................................... 38 
11.1 SPECIFICATION, TIMING AND RECORDING OF SAFETY PARAMETERS .......................... 38 
11.2 PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS ......................... 38 
11.3 TREATMENT STOPPING RULES ............................................................................... 40 
12. STATISTICS ........................................................................................................... 40 
12.1 SAMPLE SIZE........................................................................................................ 40 
12.2 STATISTICAL ANALYSIS ......................................................................................... 41 
ASSESSMENT OF EFFICACY .......................................................................................... 41 
ASSESSMENT OF COST EFFECTIVENESS ....................................................................... 42 
13. TRIAL STEERING COMMITTEE ............................................................................ 42 
14. DATA MONITORING COMMITTEE ........................................................................ 42 
15.TRIAL MANAGEMENT GROUP .............................................................................. 42 
16. DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS .................................. 43 
17. ETHICS & REGULATORY APPROVALS ............................................................... 43 
18. QUALITY ASSURANCE ......................................................................................... 43 
19. DATA HANDLING .................................................................................................. 44 
20. DATA MANAGEMENT AND DATABASE LOCK ................................................... 44 
21. PUBLICATION POLICY .......................................................................................... 44 
22. INSURANCE & INDEMNITY ................................................................................... 45 
23. FINANCIAL ASPECTS ........................................................................................... 45 
24. SIGNATURES ......................................................................................................... 46 
25. TRIAL PROTOCOL VERSION HISTORY SUMMARY ............................................ 47 
26.  REFERENCES ....................................................................................................... 52 
 
 
 

 
 
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4. Introduction  
 
4.1 Background 
 
In England, there are ~260,000 people with primary opioid use disorder (OUD) [1], with 
150,000 people enrolled in front-line standard-of-care sublingual tablet buprenorphine 
(Bup) and oral liquid methadone (Met) in 1,000 public clinics in the National Health Service 
(NHS) and third-sector services.  
 
Initially commercially developed as an analgesic, Bup is a lipophilic thebaine derivative 
with a high binding affinity at the mu-opioid receptor where it has partial agonist effects, 
and at the kappa opioid receptor where it is a competitive antagonist. Approved for 
detoxification and maintenance medication treatment for OUD, generic sublingual tablet 
Bup is available in the NHS; along with Bup combined with naloxone (Bup-NX) as 
alternatives to Met in standard-of-care treatment. In the EXPO trial, the effectiveness of 
extended-release subcutaneous injectable Bup (Sublocade®; RBP-6000 during 
development; XR-Bup herein) will be determined in comparison to standard-of-care opioid 
agonist or partial opioid agonist medication (Met or Bup; Met/Bup herein).  
 
4.2 Rationale 
 
OUD is a debilitating psychiatric condition with a high global burden of disease [1] and 
substantial social costs (£4.7 billion in England and Wales associated with drug-related 
acquisitive crime in 2010/11) [2]. Internationally, in recent years there has been a rapid 
and substantial increase in the prevalence of OUD and the rate of fatal opioid deaths [3]. 
Bup and Met are the first-line maintenance medication treatments for OUD. In the English 
public treatment system, these medications are dispensed by community pharmacists (by 
direct observation in the early phase of treatment and then for self-administration 
contingent on satisfactory progress).  
The average treatment effect from randomised controlled trials shows that Bup and Met 
supress illicit and non-medical opioid use [4,5]. In treatment systems, follow-up studies of 
these medications have reported substantial average reductions in drug use [6] and opioid 
overdose mortality [7]. Systematic review evidence from maintenance trials of Bup and 
Met for illicit OUD [5] suggests that flexible dose Met is more effective than flexible dose 
Bup maintenance at retaining patients (six trials with 837 participants; relative risk [RR] 
0.82, 95% confidence interval [CI] 0.69 to 0.96), but with no statistical difference for the 
suppression of heroin (mean difference -0.12 days, 95% CI -0.32 to 0.12). For OUD 
involving licit or illicit pharmaceutical products [6], there is no statistically significant 
difference between Bup and Met for retention (three studies, 360 participants, RR 0.69, 
95% CI 0.39 to 1.22) or suppression of non-prescribed opioid use (mean difference -1.41 
days, 95% CI -3.37 to 0.55). Observational follow-up studies suggest that retention in Bup 
and Met maintenance is associated with a reduction in the risk of fatal overdose [7,8], 
blood-borne viral infections [9] and crime [10]. 
There are three issues of concern about these two standard-of-care medications for OUD. 
Despite efforts to select the best medication and dose for each patient, many discontinue 
treatment [11]. Other patients are retained but either fail to take their prescription as 
directed [12] or continue to use illicit or non-prescribed pharmaceutical opioids (herein 

 
 
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'opioids') or relapse to pre-treatment levels. For example, in an English study of 12,745 
patients enrolled for 12-26 weeks, 64% were using opioids on 10 or more of the past 28 
days at clinical review [13]. Cocaine use disorder (particularly with the base form crack) 
[14], and co-occurring anxiety [15] and depressive disorders [16] are prevalent in the 
clinical OUD population and can moderate treatment adherence and response [17]. Family 
relationships and social networks can either support or hinder recovery [18]. 
Technological advances in the formulation of Bup have potential to address the lack of 
effectiveness for some patients. Using the polymer ATRIGEL® delivery system, Indivior 
has developed an extended-release formulation of Bup. Injected subcutaneously into 
abdominal tissue, this medication forms a depot and releases Bup for a minimum of 28 
days by diffusion and as the polymer biodegrades. Development studies of RBP-6000 
showed that a relatively high dose of Bup is stably released and this (in comparison with 
placebo Bup) is associated with attenuated craving for opioids and drug use. This 
medication (Sublocade® [XR-Bup] now approved by the Food and Drug Administration 
(FDA) and from March 2018 has been available to US prescribers. XR-Bup has the 
potential to enable patients to derive enhanced benefit from treatment – but there has 
been no head-to-head comparison to date with standard-of-care Bup and Met. This is a 
crucial comparison to inform clinical practice.  
EXPO will be a superiority evaluation. In comparison to Bup and Met, the study will 
evaluate two potential patient benefits arising from treatment with XR-Bup: (1) delivery of 
stable and effective dose of Bup to facilitate opioid blockade (and attenuate reinforcing 
effects of non-medical opioids) while giving protection against opioid overdose; and (2) by 
avoiding the need to attend for daily dosing, the facilitation of the patient's recovery 
activities and independence. As dosing of XR-Bup is done in the clinic, there will be no 
risk of medication diversion.  
Another potential avenue to enhance the medication-assisted treatment for OUD is the 
provision of adjunctive PSI. Unfortunately, a Cochrane review has concluded that no 
single PSI is effective [8]. OUD is a complex phenotype and an alternative approach is to 
use a clinical formulation to personalise (tailor) elements for a PSI that best meet the 
needs and preferences of the patient. A completed pragmatic randomised controlled trial 
by the EXPO coordinators successfully targeted Bup and Met-resistant patients with a 
tailored PSI, drawing on a toolkit of change methods indicated by a patient-collaborative, 
measurement-based care and clinical formulation model [9]. The PSI toolkit included: CBT 
for coping strategies, Contingency Management to reinforce recovery; facilitation to attend 
12-step groups; cognitive behavioural therapy (CBT)/Behavioural Activation for 
depression; and techniques to engage partners and family members in the participant's 
treatment. In this context, the EXPO co-ordinating centre will determine whether a tailored 
PSI intervention will help the patient to attenuate illicit drug use and improve their personal 
and social functioning and thereby give an adjunctive beneficial effect to XR-Bup on 
outcome. 
In summary, the EXPO study will determine the effectiveness of XR-Bup in a head-to-
head superiority comparison with Bup and Met and with an adjunctive PSI (offered during 
the 24-week treatment phase) in the pragmatic context of specialist community setting 
addiction treatment programmes in England provided by the NHS.  
The EXPO protocol will be published following the SPIRIT standard. The statistical 
analysis plans will be published on the Centre for Open Science. The results of EXPO will 
be reported in adherence with CONSORT and other relevant standards and extensions.  

 
 
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5. Trial Objectives and Design  
 
5.1. Trial objectives and primary endpoint 
 
During six months of active trial treatment, the primary objective of this superiority study 
is to determine the difference in effectiveness (in terms of reduced use of heroin and illicit 
opioids) of XR-Bup and Met or Bup. Study participation will be offered to patients already 
enrolled in Bup and Met maintenance treatment and also new admissions of patients 
seeking this treatment.  
 
With a 1-week measurement grace period from randomisation, the primary endpoint is the 
count of days abstinent from heroin and illicit opioids during six months of treatment 
combined with urine drug screen samples which are negative for non-medical opioids. 
 
5.2. Trial design, blinding overview 
 
EXPO is a pragmatic, multi-centre, open-label, superiority randomised controlled trial in 
NHS specialist addiction clinics delivering standard-of-care oral opioid medication for 
adults with OUD. The study will be implemented in five clinically recruiting sites (NHS 
trusts) across England and Scotland: in the coordinating centre in South London, the West 
Midlands, Greater Manchester, Newcastle and Tayside. The target randomised sample 
size is 604 patients. Recruitment will be in two study phases, as follows:  
 
In Phase I (all sites and with enrolment timed to start at approximately the same time), 
informed consenting participants will be allocated to one of two groups: 
 
Group 1: XR-Bup (n=152; approx. n=38 at each site) 
Group 2: Bup/Met (n=152; approx. n=38 at each site) 
 
Participants in group 2 will receive Bup or Met following the local NHS clinical process of 
medical assessment and informed by any patient expressed preference for Bup or Met. 
All participants in groups 1 and 2 will receive standard case and medication management 
with general drug counselling (fortnightly, one-to-one at the clinic; ~30 minutes). The study 
plan is to aim to commence recruitment for groups 1 and 2 in July 2019 with all participants 
completing follow-ups in Q1 2020 (n=76 participants in each NHS trust)*.   
 
During Phase 1 at the EXPO co-ordinating centre only, there will be allocation of 
participants to two additional groups: 
 
Group 3: XR-Bup + PSI (South London site only) 
Group 4: Bup/Met + PSI (South London site only) 
 
All participants in groups 3 and 4 will receive standard case/medication management and 
general drug counselling, as usual. The PSI will be a tailored PSI (adapted from the co-
ordinating centre’s successful previous trial to development this therapy (ARC Trial; 
ISRCTN69313751) and offered to participants across the treatment phase. At the co-
ordinating centre, recruitment to groups 1-4 will commence in July 2019 using a 4:1 
allocation ratio in favour of groups 1 and 2 (given local resource capacity)*.  
 

 
 
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In Phase II (co-ordinating centre only) there will be continued recruitment of groups 3 and 
4 following completion of Phase I using a 1:1 allocation ratio until target quarter 3 2021, at 
which point it is aimed that all participants will have completed this phase*.  
 
Group 3: XR-Bup + PSI (Total from Phase I and Phase II 150 South London site only) 
Group 4: Bup/Met + PSI (Total from Phase I and Phase II 150 South London site only) 
 
The senior statistician will be blinded. The junior statistician is unblinded so that reports 
can be prepared. Research and clinical team will also be unblinded.   
 
*Due to the Coronavirus 2019 (COVID-19) pandemic and slower than anticipated 
recruitment rate, recruitment into Phase I and Phase II will be completed at the same time; 
target quarter 4 2021. 
 
5.3. Primary endpoint analysis overview 
 
Analysis of EXPO primary outcome data will be done in two phases, as follows:  
 
In phase I (planned data lock: quarter 3 2020), there will be a comparison of group 1 
versus group 2. This comparison will include data from all 4 sites. In phase II (planned 
data lock: October 2021) there will be a comparison group 3 versus group 4 (data from 
the co-ordinating centre only).* 
 
Following completion of the phase I and II analysis, there will be an exploratory analysis 
of group 1 and group 3 to compare XR-Bup and XR-Bup + PSI. 
 
Further details of the statistical approach for these analyses is outlined in section 10 and 
will be specified in detail in the Statistical Analysis Plan ([SAP] to be summarised in the 
published protocol paper and on the Open Science Framework before data-lock). 
 
*Due to the Coronavirus 2019 (COVID-19) pandemic and slower than anticipated 
recruitment rate, data lock for Phase I and Phase II will be completed at the same time; 
target quarter 3 2022. 
 
 
6. Trial Medication 
 
The drugs used in the trial are controlled drugs. Sites are expected to comply with the 
storage and supply requirements set out in the Misuse of Drugs Regulations 2001 (as 
amended) and the UK Controlled Drug Regulations, in addition to the trial requirements. 
 
6.1 Investigational medicinal product 
 
Bup extended-release injection (XR-Bup in this protocol) is licenced in the USA under the 
name Sublocade®. It is used for the treatment of moderate to severe OUD in patients who 
have initiated treatment with a transmucosal Buprenorphine product. The product is 
currently unlicensed in the EU. The injection is presented as a sterile, clear, viscous, 

 
 
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colourless to yellow amber solution in a single dose, pre-filled syringe with a 19 gauge 
5/8th inch safety needle.  
Bup in XR-Bup is dissolved in the ATRIGEL® delivery system. This system delivers the 
drug at a controlled rate over a 1-month period. The depot injection provides sustained 
plasma levels of Bup sufficient to block the subjective effects of exogenous opioids after 
a single dose and even more complete blockade after two monthly doses. The product is 
available in dosage strengths of 100mg/0.5ml and 300mg/1.5ml Bup. It is administered as 
a monthly subcutaneous injection into abdominal tissue. 
Indivior will be responsible for the manufacture of the product and import into the UK. 
Sharp Clinical Services (UK) are contracted by Indivior to label and final Qualified Person 
(QP) release the product prior to distribution to investigational sites. The Simplified 
Investigational Medicinal Product Dossier (sIMPD), US Prescribing Information and 
Investigator Brochure (IB) provides further information. 
 
6.2 Active comparators  
 
The active comparator drugs sublingual Bup; (including sublingual Bup/Naloxone, 
oromucosal Bup) and oral Met will be dispensed by community pharmacies on receipt of 
a valid prescription, as per standard NHS practice. The drugs will be labelled with a normal 
dispensing label in accordance with Schedule 5 to The Medicines for Human Use 
(Marketing Authorisations etc) Regulations 1994. This activity is covered by Regulation 46 
(2) of SI 2004/1031 of the Medicines for Human Use (Clinical Trials) Regulations (as 
amended). 
Bup is licenced for the treatment of opioid use disorder. The tablets are available as 0.4mg, 
2mg and 8mg strengths. The Summary of Product Characteristics (SmPC) for Subutex® 
provides further information.  
Bup-NX (as hydrochloride) and naloxone (as hydrochloride dihydrate) sublingual tablets 
(Suboxone®) is licenced for the treatment of opioid use disorder. Suboxone® is 
manufactured by Indivior UK Limited. Buprenorphine is the active component of 
Bup/naloxone when taken sublingually. Naloxone is a deterrent to diversion and injection 
of the tablet and is prescribed in an identical fashion to Bup. Research sites are permitted 
to prescribe Bup-NX as a replacement to Bup if that is the local prescribing procedure. 
The tablets are available as 16mg/4mg, 8mg/2mg and 2mg/0.5mg strengths. The SmPC 
provides further information on this product.  
Espranor® (Esp) oral lyophilisate containing (Buprenorphine as hydrochloride) and 
aspartame is licenced for the treatment of opioid use disorder. Buprenorphine is the active 
component of Esp and administration is oromucosal. Research sites are permitted to 
prescribe Esp as a replacement to Bup if that is the local prescribing procedure. Esp oral 
lyophilisate is available in 2mg/0.5mg and 8mg/2mg strengths. The SmPC provides further 
information on this product. 
As Buprenorphine is the active component of Bup-NX and Esp they will be categorised 
under Bup within the protocol guidance and analysis between trial arms.   

 
 
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Methadone is available as a 1mg/ml solution and is licenced for the treatment of opioid 
use disorder. The SmPC provides further information on the product.  
Participant is ineligible if they have any allergic or adverse reactions or contraindication to 
Buprenorphine. If participant has any allergic or adverse reaction or contraindication to 
Met or naloxone, or excipients of Bup-NX or Esp they can be prescribed Bup within the 
trial. Participants randomised to group 2 and group 4 are permitted to change between 
the active comparator drugs whilst enrolled in the trial by following the prescribing 
guidelines as detailed in the SmPC and if there are no known allergic, adverse reactions 
or contraindications to the drug.  
 
 
6.3 Dosing regimen 
 
Bup (active sublingual comparator): The usual dose is 8-24mg/day (Esp usual dose 8-
18mg/day). Clinical practice in NHS clinics is supervised (directly observed dosing) in a 
community pharmacy followed by provision of patient self-administered 'take home' doses 
according to clinical response (i.e. informed by negative urine drug screens [UDS]; 
adherence to prescription; retention in treatment).   
 
Met (active oral comparator): The recommended dose is 60-120mg/day. Clinical 
practice in NHS clinics is supervised (directly observed dosing) in a community pharmacy 
followed by provision of patient self-administered 'take home' doses according to clinical 
response (i.e. informed by negative UDS; adherence to prescription; retention in 
treatment). 
 
In the event patients in the Met/Bup arm fail to adhere to daily dosage regime they will 
need to follow standard clinical protocol for that clinic.  
 
XR-Bup (IMP active injectable comparator): The recommended dose of Sublocade® 
(which will be adhered to in the EXPO trial) is a 300mg loading dose, administered monthly 
for the first 2 months, followed by a 100mg maintenance dose for the remaining 4 months. 
The scheduled dosing interval is 28 days and, in EXPO, the minimum interval between 
the two initial loading doses is 21 days to provide increased flexibility for the participant to  
ensure that the loading doses are achieved. All injections will be by the site investigator, 
medical practitioner, nurse, or nurse practitioner who has received training in the 
procedure. XR-Bup is for abdominal injection into adipose tissue only (not 
intramuscularly). The specific area is on the abdomen between the transpyloric and trans-
tubercular planes with adequate subcutaneous tissue below the waistline and above the 
hip bone, which is free from any lesion, mole or other skin mark.  
 
After the two 300mg loading doses, the aim is to maintain the patient on a 100mg monthly 
dose if they achieve:  
 
• 
no unsanctioned use of opioids  
• 
no clinically significant opioid withdrawal  
• 
no distressing craving for opioids and the patient is satisfied with their current dose, 
and requesting the dose be maintained at this level. 
 

 
 
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As a clinical guide, the maintenance dose should be increased from 100mg to 300mg 
under the following conditions: 
 
• 
The patient is not achieving desired treatment goals (e.g. persistent unsanctioned 
opioid use, opioid withdrawal symptoms or distressing cravings);  
• 
the patient does not report dose-related adverse events related to the 100mg dose 
(e.g. sedation or lethargy, persistent headaches, nausea); 
• 
the patient reports that 100mg is too low and they would like a dose increase, and 
there are no significant clinical safety concerns. 
 
As a clinical guide, the dose should be reduced from 300 to 100mg under the following 
conditions: 
 
• 
The patient reports XR-Bup dose-related adverse events (e.g. sedation or lethargy, 
persistent headaches, nausea); 
• 
the patient is seeking to reduce their dose in an attempt to ultimately withdraw from 
opioid agonist treatment; 
• 
the patient reports that 300mg is 'too high' and they would like a dose decrease, 
and there are no significant concerns regarding deterioration in clinical condition 
(e.g. substance use, physical or mental health symptoms) that may arise with a 
dose reduction.) 
 
On the basis of patient report and clinical judgement of the risks and benefits, rescue 
dosing of Bup can be provided at any point after the first dose of XR-Bup. This will be 
recorded as concomitant medication. 
 
Whilst maintenance doses will be routinely scheduled to occur every 28 days, flexibility 
was included in the development research for Sublocade® and this will be followed in the 
EXPO trial to accommodate patients who need to attend other appointments or have travel 
problems attending the clinic.  
In summary, the protocol allows for:  
 
(1) the second 300mg loading dose of XR-Bup to be given after a minimum of 21 days; 
(2) each planned 100mg maintenance doses can be administered up to 2 days ahead of 
the scheduled dose (i.e. 26 days since the last injection); and  
(3) all subsequent doses after the first dose to be given up to 14 days after the 28-day 
scheduled dose (i.e. to 42 days).  
 
Unexpected delays of up to 14 days are not anticipated to have any clinical impact on 
treatment response given the reported extended-release profile of the IMP. 
 
Following the 6th dose, there is an optional consent for participants who are randomised 
to XR-Bup to continue receiving doses every 28 days until the date that the last 
participant is randomised within the EXPO Trial plus 9 months. 
 
 
 
 
 
 

 
 
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In summary, the dosing schedule for EXPO is shown below: 
 
Dose  
Day 
Visit 
Window  
XR-BUP dose 
1 
1 
Baseline 
- 
300mg 
2 
28  
Week 4 
21-42 
300mg 
3 
56  
Week 8 
54-70 
100mg or 300mg 
4 
84  
Week 12 
82-98 
100mg or 300mg 
5 
112  
Week 16 
110-126 
100mg or 300mg 
6 
140 
Week 20 
138-168 
100mg or 300mg 
7 onwards 
168 
onwards 
Week 24 
onwards 
(every 
28 days) 
Up to 42 days 
since previous 
dose 
100mg or 300mg 
 
If the participant misses a scheduled maintenance of XR-Bup no adjustment in dose is 
required, if they receive this dose within 60 days of their last injection. If the participant 
does not receive an XR-Bup dose within 60 days of their last injection, the participant is 
not withdrawn from study treatment; but a clinical assessment by the principal investigator 
(PI) is needed to determine if there has been any illicit opioid use and the optimal starting 
dose. 
 
6.4 IMP administration  
 
XR-Bup will be administered by subcutaneous injection into abdominal adipose tissue by 
the site investigator, medical practitioner, nurse, or nurse practitioner who have received 
training in the procedure and are delegated to perform this task. The drug will be 
prescribed for administration following local hospital requirements. 
 
The specific area for administration is below the waist line and above the hip bone 
(specifically, in the region where the body curves at the side to about 2 inches from the 
middle of the abdomen i.e. between the transpyloric and trans tubercular planes), 
selecting a clear needle insertion point with adequate amounts of subcutaneous tissue 
that does not have excessive pigment, nodules, lesions, or hair or areas with brawny or 
fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e. with a 
belt or clothing waistband).  
 
To avoid irritation, the injection site will be recorded and rotated across four different 
injection points for subsequent doses (with the patient’s head pointing north), these will 
be, from the patient’s perspective: 
 
(1) right upper (RU); (2) left upper (LU); (3) left lower (LL) and (4) right lower (RL).  
 
A cold press can be administered for up to 10 seconds prior to the injection.  
 
6.5 IMP risks  
 
The Reference Safety Information (RSI) for all information pertaining to IMP risk for the 
XR-Bup will be set out in the manufacturer's Investigators Brochure (IB).  The SmPC will 
be the reference document for Bup/Met.  
 

 
 
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Adverse reactions (commonly associated in 5% or more of patients) receiving XR-Bup 
are: (a) constipation; (b) nausea; (c) vomiting; (d) headache; (e) fatigue; (f) increased 
hepatic enzymes; (g) injection site pain; (h) injection site pruritis. 
 
Drug-drug interactions potentially relevant to the IMP (with Bup and XR-Bup) are as 
follows: 
 
Drug Class 
Drug(s) within Class  
Clinical effect and suggested 
management 
Benzodiazepines 
and Other Central 
Nervous System 
(CNS) Depressants 
Alcohol, non‐
benzodiazepine 
sedatives/hypnotics, 
anxiolytics, 
tranquilizers, muscle 
relaxants, general 
anaesthetics, 
antipsychotics, and 
other opioids 
- Increases the risk of respiratory depression, 
profound sedation, coma, and death. 
- Use of these substances should be 
stabilised during treatment with Bup 
products. Patients should be advised of the 
danger of concomitant use of sedatives 
while participating in the trial. 
 
CYP3A4 inhibitors: 
 
Macrolide antibiotics 
(e.g. erythromycin) 
Azole‐antifungal 
agents (e.g. 
ketoconazole) 
Protease inhibitors 
(e.g. ritonavir) 
- Effects of CYP3A4 inhibitors on Bup 
exposure in participants treated with XR-
Bup have not been studied with Bup, 
however, such interactions have been 
established.  
- In the presence of CYP3A4 inhibitors, 
monitor for signs and symptoms of Bup 
toxicity or overdose. 
- Monitor for Bup withdrawal if the 
concomitant medication is discontinued 
after the patient is stable on.   
- The dose of either Bup or the CYP3A4 
inhibitor may need to be adjusted 
accordingly. 
CYP3A4 Inducers 
Rifampin 
Carbamazepine 
Phenytoin 
- Effects of CYP3A4 inducers on Bup 
exposure in participants treated with XR-
Bup have not been studied, however, 
CYP3A4 inducers may induce its 
metabolism and lead to decrease in Bup 
plasma concentrations. 
- Monitor for signs and symptoms of Bup 
toxicity or overdose, if the CYP3A4 
inducers is discontinued after the patient is 
stable on XR-Bup. The dose of either Bup 
or the CYP3A4 inducer may need to be 
adjusted accordingly. 
Antiretrovirals: Non‐
nucleoside reverse 
transcriptase 
inhibitors (NNRTIs) 
 
Efavirenz, nevirapine, 
etravirine, delavirdine 
- Significant pharmacokinetic interactions 
between NNRTIs and Bup have been 
shown, but these pharmacokinetic 
interactions did not result in any significant 
pharmacodynamic effects.  
- Monitor for increase or decrease in 
therapeutic effects of NNRTIs. 

 
 
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Antiretrovirals: 
Protease inhibitors 
(PIs) 
 
Atazanavir, ritonavir 
- Treatment with atazanavir or 
atazanavir/ritonavir may result in elevated 
levels of Bup (and the metabolite nor-
Bup). 
- If atazanavir +/- ritonavir is initiated once 
the patient is stable on XR-Bup, monitor for 
signs and symptoms of over-medication 
with Bup. If necessary, reduce XR-Bup 
dose from 300 to 100mg, or discontinue 
XR-Bup and treat with Bup to enable rapid 
dose adjustments. 
Selective serotonin 
reuptake inhibitors 
(SSRIs) 
Serotonin and 
norepinephrine 
reuptake inhibitors 
(SNRIs) 
Tricyclic 
antidepressants 
(TCAs) 
Triptans 
5‐HT3 receptor 
antagonists 
Drugs that affect the 
serotonin 
neurotransmitter 
system inhibitors  
Monoamine oxidase 
(MAO)  
e.g. mirtazapine, 
trazodone, tramadol 
e.g. linezolid and 
intravenous methylene 
blue 
- May result in serotonin syndrome in high 
doses (e.g. overdose). Monitor for signs 
and symptoms of serotonin syndrome, 
particularly during treatment initiation, and 
during dose adjustment of the serotonergic 
drug. 
 
Monoamine Oxidase 
Inhibitors (MAOIs) 
 
e.g. Phenelzine, 
tranylcypromine, 
linezolid 
- MAOI interactions with opioids may 
manifest as serotonin syndrome or opioid 
toxicity (e.g., respiratory depression, coma). 
- It is recommended that patients receiving 
Bup and MAOI should be closely 
monitored. 
Diuretics 
 
- May reduce the efficacy of diuretics by 
inducing the release of antidiuretic 
hormone. 
- Intervention: Monitor patients for signs of 
diminished diuresis and/or effects on blood 
pressure and increase the dosage of the 
diuretic as needed. 
Anticholinergic Drugs 
 
 
- May increase the risk of urinary retention 
and/or severe constipation, which may lead 
to paralytic ileus. 
- Monitor for signs of urinary retention or 
reduced gastric motility. 
Opioid antagonists  
Naltrexone, naloxone  
- Opioid antagonists should generally not be 
used outside of emergency situations in 
patients in opioid agonist treatment, 
including XR-Bup.  
- Naloxone may be administered in response 
to an opioid overdose.   

 
 
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Opioid analgesics 
Opioids 
- Bup may reduce the effects of opioid 
analgesics trough receptor blockade. 
Patients requiring analgesia should include 
non-opioid approaches (e.g. NSAIDs, 
ketamine). Opioids may be used with 
caution, but as higher doses may be 
required for analgesic effect, there may be 
a higher potential for toxicity with opioid 
administration, requiring close monitoring of 
opioid effects.  
 
 
6.6 Treatment discontinuation  
 
A participant is discontinued from the study medications for any of the following reasons:  
 
• 
Participant safety reasons, including adverse events (AEs) or significant 
concomitant illness, injury, or urgent surgeries/procedures that would, in the 
opinion of the Investigator, compromise treatment safety or deterioration in the 
patient’s clinical condition.  
• 
Participant request to discontinue study intervention. A participant is free to 
withdraw to withdraw from study intervention at any time for any reason (they do 
not need to state a reason). Their participation is to be terminated upon his/her 
request, and the reason(s) for discontinuation appropriately documented. 
• 
At the request of the Sponsor, regulatory agency, or Ethics Committee. 
• 
Pregnancy. If not terminating, participant to discuss with clinician and continue with 
oral medication or withdraw following usual practice. Participants receiving IMP will 
not receive further injections and will receive oral medication or withdrawal 
according to usual practice. 
• 
Administrative discharge due to non-adherence with site policies (e.g. violence 
towards other clients or staff). 
 
In the event of an emergency, or if clinically indicated, a decision to surgically remove 
depot (up to 14 days from injection) may be made by the CI or PI, following discussion 
with the participant. An appropriately skilled medical practitioner may perform the surgical 
procedure, as follows: 
 
1.  
Palpate the depot and surrounding area to confirm location.  
2.  
Cleanse the area with an antiseptic solution.  
3.  
Infiltration the area with local anaesthesia and wait for it to take effect.  
4.  
Cover the area with sterile drape.  
5.  
Incise the skin up to the subcutaneous tissues using a scalpel.  
6.  
Using blunt and sharp dissection, identify the plane between the depot and 
 
surrounding subcutaneous tissues. Once the plane is identified, separate the 
 
superficial 25% of the circumference of the depot with blunt dissection.  
7. 
Gently lift the incised ellipse of skin and depot with forceps.  
8. 
Once the depot is removed, ensure haemostasis, and close the skin with non-
 
absorbable sutures.  
 
Removal of the depot is to be recorded as an Important Medical Event (IME).  
 

 
 
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6.7 Drug accountability 
6.7.1 XR-Bup  
 
XR-Bup will be distributed to each site following the final QP release, and once all 
regulatory and local approvals are in place. 
The pharmacy clinical trials team must maintain accurate accountability records for XR-
Bup, including, but not limited to, the number of kits received, the number of kits dispensed 
to which patient, batch number, expiry date, and the date of the transaction, in addition to 
the quantity of unused investigational product and empty packaging returned to pharmacy 
for each patient. Trial specific prescriptions must be filed in the pharmacy trial file for audit 
purposes.  
Sites must use a transfer log to record the transfer of: 
• 
Dispensed XR-Bup from pharmacy to clinics 
• 
Return of unused syringes and empty packaging from clinics back to pharmacy 
The research team (clinic staff) must maintain accurate accountability records for XR-Bup, 
including, but not limited to, the number of kits received and administered for each 
individual patient and the date of the transaction, in addition to the number of unused kits 
returned to pharmacy. Administration records in clinics will be retained and monitored by 
the KHP-CTO during monitoring visits to ensure appropriate handling and storage of the 
IMP. 
Unused XR-Bup and empty packaging (post dose) must be returned to pharmacy by the 
research team for reconciliation on the accountability log. The returns will be verified by 
the CRA prior to disposal at site. Destruction of XR-Bup must follow the site IMP 
destruction SOP and local hospital Controlled Drugs waste management procedure. After 
the KHP-CTO monitoring of IMP accountability is complete, destruction will occur following 
CI authorisation. 
The King’s Clinical Trials Unit (KCTU) clinical trials Pharmacist will track XR-Bup trial 
supplies at investigational sites and at Sharp Clinical Services, UK. The pharmacist will 
generate orders of IMP for delivery to sites and liaise with Indivior for the shipment of 
additional stock from the USA. 
6.7.2 Met and Bup 
 
Site staff will make a copy of the script record for the FP10 written for the trial and file in 
the relevant patients notes. Accountability records are not required for the active 
comparator arm (oral Met or Bup). Research teams will check medication compliance at 
clinic visits through questioning and clinical assessments. Adherence to oral medication – 
dispensed by community retail pharmacies – will be monitored as usual in the NHS by the 
retail pharmacy and the local clinic, such that if the patient does not attend to receive or 
collect three consecutive scheduled Met or Bup doses, this will trigger the pharmacy to 
inform the clinic. This event will be recorded in the patient’s notes and should the patient 
present/contact the clinic requiring further Met or Bup, dosing will be re-started following 
the clinic’s medication screening and induction protocol. 
 

 
 
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6.8 Supply, transport and storage of IMP 
 
The Investigational Product Handling Manual gives detailed guidance on supply, transport 
and storage of IMP. 
 
6.8.1 XR-Bup (Sublocade®) 
 
XR-Bup must be stored in a locked fridge, maintaining a temperature between 2°C to 8°C.  
Appropriate storage conditions (for pharmacy and clinic fridges) must be ensured by 
completion of temperature monitoring logs.  
 
Commercial USA licenced stock (Sublocade®) will be manufactured under contract to 
Indivior by Albany Molecular Research Inc. (AMRI), Burlington, MA. The stock will be 
imported into the UK. Labelling with an annex 13 compliant label, final QP release and 
distribution to UK sites has been contracted to Sharp Clinical Services, UK. 
 
XR-Bup will be dispensed by the site pharmacy against a valid, sponsor approved clinical 
trial prescription. The dispensed XR-Bup will be transported to clinic, for the purpose of 
administration, using an appropriate transit method to maintain the cold-chain. The IMP 
transfer must be recorded on approved documentation to provide a full audit trail. Refer to 
section 6.6 of the protocol and the Investigational Product Handling Manual for further 
information. 
 
On arrival at clinic, the dispensed XR-Bup will be checked and documented as received 
before being placed in a locked, temperature controlled and monitored pharmaceutical 
refrigerator.  
 
Unused XR-Bup syringes and empty packaging will be returned to pharmacy for 
reconciliation prior to verification by the CRA. The sponsor must provide written 
permission for disposal prior to the product and empty packaging being destroyed at site. 
Participant compliance will be measured through medication dispensing records, 
attendance records and administration records.  
 
After each participant’s last visit, patients will transition to Met/Bup as appropriate 
according to local practice.   
6.8.2 Active Comparators (Bup/Met) 
 
Bup (including Bup-NX and Esp) and Met will be stored at community pharmacies in 
accordance with their SmPC’s. Temperature monitoring records are not required for these 
products. 
 
 
6.9 Concomitant Medication 
 
Each participant's use of concomitant medications will be recorded continuously but 
reviewed at week 4, 12 and 24. The Investigator will record all medication used by the 
participant. This record will include the name of the medication, the dose, dates when drug 
was started and stopped. 
 

 
 
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7. Tailored Psychosocial Intervention  
 
Convergent lines of epidemiologic and clinical research point to several behavioural 
factors which moderate Met/Bup effectiveness [10]. Addiction severity is moderator 
[11,12,13], and taking illicit drugs by injection correlates with higher levels of dependence 
and a likelihood of non-response [14]. Concurrent cocaine use and dependence is also 
common among the OUD population in the UK, and these patients tend to have poorer 
engagement with the clinic and outcome [15,16,17]. A significant minority of patients have 
co-existing chronic health and social problems which follow, precede, or are independent 
of the addictive disorder, and add complexity to clinical management [18,19,20]. The 
patient’s family relationships and social networks may also support or hinder response 
[21]. These factors are screened early in treatment.  
 
EXPO's tailored psychosocial intervention (PSI) is founded on the evidence that there are 
different reasons for non-response and that there will be no single best clinical 
intervention. The goal is to help the patient reduce the symptoms of heroin and cocaine 
addiction, to manage or attenuate concurrent health and social problems, to enhance 
engagement and to develop personal strengths and resources for recovery. The PSI has 
been successfully evaluated in a completed randomised controlled trial at the EXPO 
coordinating centre (ISRCTN number: 69313751) and further developed in a novel 
memory-focused cognitive therapy intervention (ISRCTN number: 164627831). We found 
the PSI to be well accepted and in the study. There was a relatively low level of loss to 
follow-up and all participants who withdrew from the study gave their consent for their data 
to be used in the analysis. There were no severe adverse events judged to be trial-related.   
 
The PSI is guided by a cognitive case conceptualisation assessment to develop 
collaboratively a working hypothesis of how OUD is being maintained. A micro-formulation 
will be based on recent typical (and unusual) episodes of cocaine use and will include 
contexts, triggers, physical sensations, elaborated cognition (attention, memories, beliefs, 
appraisals [emotional ‘hotspots’]), motivation, coping strategies, actions, problematic 
affective and behavioural responses, post-opioid (and other drug use) evaluations and 
problems.  
 
The EXPO PSI will be collaborative and flexible: trial psychologists will use a non-
judgemental, collaborative counselling style (adapted from Motivational Interviewing [22]) 
and graphical representations and maps (adapted from node-link mapping to facilitate 
assessment, care planning, and progress review [23]. The PSI represents a point of 
departure from a traditional manual-guided psychological therapy in which there may be 
proscription of a sequence of specific techniques, or multi-modal therapies which combine 
two or more therapies. We will use a ‘toolkit’ approach with specific change methods from 
evidence-supported therapies are chosen collaboratively with the patient and tested for 
effectiveness in the form of a rolling set of behavioural experiments.  
During development, national clinical guidelines [24] and the therapist manuals for the 
following psychological therapies:  
 
 
• 
cognitive behavioural coping and skills training (CBT [25]);   
• 
behavioural reinforcement (‘contingency management’ using a budget of £60 in 
value shop vouchers with clinic attendance and recovery activities in addition to 
the traditional drug abstinence operant reinforcer [26]; 

 
 
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• 
behavioural psychotherapy for couples to promote relationship stability and 
abstinence reinforcement [27],  
• 
Social Behaviour and Network Therapy to recruit family members and others to 
accompany the patient to PSI sessions and support their recovery [28,29]; 
• 
12-Step Facilitation Therapy for self-help group attendance [30,31]; and  
• 
CBT methods for depression to help raise awareness of automatic thoughts, 
depressive evaluations and increase activity [32]. 
 
Each PSI intervention will include two or more of these specific change techniques, with 
supporting participant informational and self-monitoring materials. The PSI intervention 
sessions will aim to take place on a weekly basis dependent on the participant and 
therapists availability for the duration of the trial. If the participant withdraws from the 
treatment, they will not be withdrawn from the PSI therapy sessions unless they wish to 
withdraw from therapy also.  A random 5% sample of session recordings per therapist will 
be independently rated using the University College London scale for rating core and 
generic (psychological) therapeutic skills [33].  
 
8. Selection and Withdrawal of Participants  
 
A medically qualified chief, principal or sub-investigator will evaluate the following 
inclusion and exclusion criteria: 
 
8.1 Inclusion criteria  
 
 
Inclusion criteria  
 
1. Aged ≥ 18 years (no upper age limit); 
2. Current diagnosis of DSM-5 OUD via SCID-5-RV (moderate-severe at baseline for 
current episode); 
3. Currently enrolled on Met (30mg/day or less) or sublingual Bup or Bup-NX (24mg/day 
or less) or Esp (18mg/day or less) and in the view of the clinician would be able to 
convert to XR-Bup within 7 days post randomisation; 
4. Voluntarily seeking treatment and able to attend the clinic as required in the protocol;  
5. Able to communicate in English to level required to accept standard care and 
psychosocial intervention; 
6. Possession of a contactable personal mobile phone or landline telephone number and 
ability to nominate at least one locator individual with a verifiable address and a 
telephone number to assist with the arrangement of follow-up appointments; 
7. Living circumstances judged to be of sufficient stability to be able to engage/adhere to 
the study protocol; 
8. Is not pregnant (confirmed) or breast feeding and, if currently or intending to have 
potentially procreative intercourse, agrees to use a birth control method (either oral 
hormonal contraceptives, barrier [condom or diaphragm], or Nexplanon implant) for the 
duration of the study. 
 
 
 

 
 
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8.2 Exclusion criteria  
 
1. Clinically significant medical condition or observed abnormalities on physical 
examination or laboratory investigation, including but not limited to:  
(a) uncontrolled hypertension, significant heart disease (including angina and myocardial 
infarction in past 12 months), or any cardiovascular abnormality which is judged to be 
clinically significant;  
(b) severe alcohol dependence/withdrawal syndrome which is judged to be clinically 
significant and may constitute a risk to the patient's safety; 
(c) acute hepatitis taken as clinical jaundice on examination, or evidence of blood 
bilirubin level above the normal range for local reference criteria, or evidence of serum 
levels of aspartate aminotransferase, alanine aminotransferase levels that are more than 
three-times the upper limit of the normal range;  
2. History of allergic or adverse reactions to Bup or the proprietary ATRIGEL delivery 
system for XR-Bup (Sublocade®)*; 
3. Clinically significant or uncontrolled mental health problems (including but not limited 
to psychosis, bipolar disorder, schizoaffective disorder), or history or evidence of organic 
brain disease or dementia that may compromise safety or compliance with the study 
protocol; 
4. Current (past 30 day) suicide plan or suicide attempt in past six months; 
5. Current criminal justice involvement with legal proceedings, which in the opinion of a 
medically qualified investigator indicates a risk that the patient would fail to complete the 
study protocol due to re-incarceration or move away from the centre’s catchment area. 
6. Currently taking oral or depot naltrexone therapy or enrolment in any form of 
naltrexone therapy within 90 days prior to study screening; 
7. Any contraindication to Bup*. 
 
*Participant is ineligible if they have any allergic or adverse reactions or contraindication 
to Buprenorphine. If participant has any allergic or adverse reaction or contraindication to 
Met or naloxone, or excipients of Bup-NX or Esp they can be prescribed Bup within the 
trial.  
 
8.3 Selection of participants  
 
All participants for EXPO will be recruited from specialist NHS addictions treatment 
programmes in community settings and already in receipt of opioid substitution therapy. 
Patients will consent prior to any screening procedures and will be randomised at a 
minimum of 24 hours post consent.  
Post- randomisation treatment is summarised as follows:  
 
Participants randomised to standard-of-care oral maintenance 
 
Participants who are allocated to oral opioid pharmacotherapy will receive Bup/Met 
according to medical screening and informed by patient preference, following each site's 
usual screening, induction/stabilisation and maintenance dosing and medication 
dispensing procedure. There will be an additional requirement to attend the clinic after 2 
weeks and then at least monthly to complete research measures and a urine drug screen 
procedure.  
 

 
 
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Met participants randomised to XR- Bup 
 
Met participants will firstly be converted to Bup by following the sites local clinical 
procedure. Once stabilised on Bup, participants will require a period of at least 3 days on 
8mg-24mg of Bup before they can receive the first dose of XR- Bup. The last dose of Bup 
is to be taken 1 day prior to the first dose of XR- Bup. Participants should receive their first 
injection of XR-Bup within 7 days of randomisation. 
 
Bup participants randomised to XR- Bup 
 
If the participant is prescribed less than 8mg of Bup there will be a minimum 3-day lead-
in on 8mg Bup prior the first dose of XR-Bup. Participants who were previously prescribed 
8mg or higher BUP can receive XR-Bup upon agreement of a suitable time with the 
participant and EXPO research team. The last dose of Bup is to be taken 1 day prior to 
the first dose of XR- Bup. Participants should receive their first injection of XR-Bup within 
7 days of randomisation.  
 
For all participants if during the transition period, the participant decides not to receive XR-
Bup or clinical judgement deems it unsuitable to continue the participant will be withdrawn 
from the trial (ITT population).  
 
8.4 Randomisation Procedure  
 
The King’s Clinical Trials Unit will oversee randomisation. This will be a secure password-
protected, web-accessed system. The system will generate an email message on 
allocation. 
  
Participants will be stratified by the following factors: 
 
(a) Site (trust and city) 
(b) Current (last 28 days) drug injecting status (yes/no) 
 
Justification for these stratification factors is as follows: (a) site is required for the random-
effects model; (b) it is expected that there will be relatively poorer outcome among 
participants who are drug injectors. The randomisation procedure will use stratified 
random blocks of varying size to ensure even allocation.  
 
Only study site staff authorised by the trial manager will be given login details to the 
randomisation system. Authorised staff will be allocated a username and password for the 
randomization system. Prior to randomisation the site needs to ensure there is capacity 
for the XR-Bup or Bup/Met for each patient.  
 
Once a patient has consented and it is confirmed that all potential medication is in place 
within the next 7 days, all baseline data collected and eligibility confirmed, the staff 
member will log into the randomization system (www.ctu.co.uk). The “help” section of the 
system has video demonstrations to aid new staff in using the system. Once randomized, 
the system automatically generates confirmation emails to key staff, with or without 
treatment allocation information, depending on their role in the study. EXPO is an open-
label (unblinded) trial, so there is no emergency code break. 

 
 
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8.5 Withdrawal of participants  
 
Participants have the right to withdraw from the study at any time for any reason. The 
investigator also has the right to withdraw patients from the study drug in the event of AE, 
SAE, SUSAR, or other reasons. Upon withdrawal from the study the patient will be asked 
to research measures (with a minimum to enable capture of the primary outcome measure 
[i.e. TLFB and UDS] and also craving measures). It is understood by all concerned that 
an excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. Participants who wish to withdraw 
from EXPO will be asked to confirm whether they are still willing to provide data. Should 
a patient decide to withdraw from the study, all efforts will be made to report the reason 
for withdrawal as thoroughly as possible.  
 
The Investigator will maintain a record of all patients who discontinue from the trial prior 
to completion; the reason(s) for trial discontinuation will be documented. If a patient 
chooses to withdraw from the trial, the Investigator should make a reasonable attempt to 
obtain and record the reason(s) for withdrawal, if possible, although the patient is not 
obligated to provide such a reason. 
 
 
8.6 End of Trial Definition 
 
The end of the trial will be deemed to occur after database lock (following completion of 
monitoring of the last patient last visit undergoing the EXPO trial).  
 
9. Trial Procedures  
 
9.1 By visit 
 
The following standardised instruments will be administered during the study: 
 
Urine drug screen (UDS; detection sensitivity: opiates: 2000ng/ml; cocaine and 
benzodiazepines: 300 ng/ml; window of detection: 72 hours; UDS procedure conducted 
each visit). A tamper-proof, instant result, immunoassay device (e.g. E-Z Split Key Cup; 
www.concateno.com) will screen for recent use of opioids, cocaine and benzodiazepines. 
The device uses a control line and a temperature sensor (required range: 92°-96 °F) to 
indicate that a valid test has been done. The UDS product for the study also includes 
measurement of Bup and Met (providing a proxy indicator of medication adherence) and 
also (meth)amphetamine and cannabis (for description and exploratory analysis).  
 
* Structured clinical interview for DSM-5 disorders – research version (SCID-5-RV 
[34]). The SCID-5-RV contains a checklist of 11 symptoms (presence or absence) to 
diagnose the severity of current OUD (mild: 2–3 symptoms; moderate: 4–5; severe: ≥6). 
The American Psychiatric Association's definition for early OUD remission will be applied 
at 3-month follow-up (i.e. without substance use disorder criteria [except] craving, using 
the “on maintenance therapy” specifier as appropriate).  

 
 
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Alcohol - Quantity, Frequency and Maximum Consumption (ALC-QFM) This 
information will be recorded using an adapted version of the Treatment Outcomes 
Profile (TOP [54]). The TOP is the standard national instrument for monitoring the 
outcomes of public substance use disorder treatment services in England.  
 
Time-Line Follow-Back (TLFB) interview for heroin, cocaine and benzodiazepine 
recorded for each day whether the participant reports using or not using these drugs. The 
TLFB, calendar-prompt interview will be adapted from the TOP.  
 
Montreal Cognitive Assessment (MoCA; [35]. The MoCA is a brief screening instrument 
for mild cognitive impairment and assesses attention, concentration, working memory, 
visuo-constructional skills, and conceptual thinking. A score of 26 is considered to reflect 
normal range functioning. An alternate version of the MoCA will be used at follow-up to 
decrease the risk of learning effects. The MoCa will be completed on 2 visits: baseline 
(version 7.1) and study week 12 (version 7.2).   
 
*Addiction Dimensions for Assessment and Personalised Treatment (ADAPT [53]). 
The ADAPT is a clinician completed 14-item instrument used for drug addiction treatment 
planning and outcome evaluation with three-subscales: opioid addiction severity, 
coexisting health and social problems, and recovery strengths.  
 
*Clinical Global Impression (CGI-S and I; [36]). The CGI is a single item clinician 
assessment of disorder severity and improvement.  
 
Craving Experience Questionnaire (CEQ-F [frequency] [56]). The CEQ-F will be 
completed for opioids (CEQ-F[H] and cocaine (CEQ-F[C]). This scale has a 14-day recall 
period and captures intensity, imagery, and intrusiveness aspects of drug craving.  
 
Visual analogue scale of maximum need (VAS-N[H/C] and want (VAS-W[H/C]). These 
single item (0-100) rating scales have a recall period of the past 14 days.  
 
Difficulties in Emotion Regulation Scale – Short Form (DERS-SF; [37]). The DERS 
The DERS is an 18 item self-report scale which records current emotional dysregulation 
in six subscales: non-acceptance, goals, impulse, aware, strategies and clarity.  
 
QIDS-SR ([39]) The QIDS-SR is a brief scale which assesses the frequency of depressive 
symptoms during in past two weeks.  
 
Work and Social Adjustment Scale (WSAS; [38]). The WSAS is a 5-item scale which 
records the extent of social functioning impairment perceived to be caused by OUD in the 
past two weeks.  
 

 
 
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Service User Recovery Evaluation (SURE; [6]). The SURE is a patient-reported 
outcome measure and is a multi-dimensional measure of perceived recovery status.  
 
Patient reported outcome measure - Status (PRO-S and I). The PRO-S is a single 7-
point item assessment of the extent to which the participant perceives the severity of their 
opioid-related problems at baseline and at follow-up.  
 
EQ-5D-5L ([39])The EQ-5D-5L is a brief generic scale which captures health status on 
five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, 
and with a 20cm vertical visual analogue scale. These responses generate health profiles 
from which health utilities can be  
calculated for economic evaluations.  
 
Alcohol and Drug Service Use Schedule (ADSUS). The ADSUS is a well-developed 
structured patient interview that records use of health, social, welfare and criminal justice 
services and crime. The ADSUS was successfully used in the ARC trial.  
 
Keyworker Contact Form (KCF). The KCF records the clinical team’s direct and indirect 
time working on EXPO. 
 
The Opioid Substitution Treatment Quality of Life scale (OSTQOL; [40]). The 
OSTQOL is a 38-item instrument assessing quality of life specific to patients in opioid 
substitution therapy across 6 subscales; personal development, mental distress, social 
contacts, material well-being, opioid substitution treatment, and discrimination.  
 
Patient Health Questionnaire- 15 (PHQ-15; [41]). The PHQ-15 is a self-administered 
somatic symptoms subscale which screens for 15 somatic symptoms that account for 
more than 90% of the physical complaints reported in the outpatient setting (exclusive of 
self-limited upper respiratory symptoms).  
 
Patient Health Questionnaire- 4 (PHQ-4; [42]). The PHQ- 4 is a 4-item inventory, rated 
on a 4-point Likert-type scale. Its purpose is to allow for very brief and accurate 
measurement of depression and anxiety. 
 
 
* The CI/ PI is able to delegate the administration of these instruments to a suitably 
trained health care professional at all visits subsequent to the baseline/screening 
assessment.  
 
 
 
 
 
 
 

 
 
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9.1.2 Optional Consents 
 
Week 24 onwards. Participants randomised to XR-Bup can continue to receive monthly 
injections as detailed in section 6.3 until the date the last participant is randomised plus 9 
months. The Trial Manager will inform study sites when this date is approaching. At week 
24 complete all research measures as detailed in the week 24 summary. Prior to the 7th 
injection at week 24 the continuing XR-Bup consent form is to be completed and 
pregnancy test recorded as negative.  Following week 24, LFT to be taken approximately 
every 6 months or as clinically indicated.  Conmeds and Adverse Events to be recorded 
at each visit that XR-Bup is administered.  
 
Exit Interview. To be conducted at the South London, Newcastle, West Midlands and 
Tayside sites with XR-Bup participants only. An additional consent will be taken from the 
participant to undertake a semi structured, topic guided interview detailing their drug use 
and experiences whilst being on the trial (based on the ADAPT). This interview can take 
place at the same time as the week 24 visit or scheduled for a time convenient to the 
participant and interviewer. Participants will be reimbursed an additional £20 for their time 
in taking part in the interview. Researchers are to follow the EXPO Exit Interview Schedule 
as a topic guide, but the interview is designed to be semi structured. Where possible, have 
the participant to do a face-to-face interview when they are coming in for their injection 
(week 28 etc) if they are continuing onto the extension phase or at a time convenient to 
them at a time after their week 24 visit. If a face-to-face interview is not possible interviews 
can be recorded over the telephone; with the call on speaker and recorded using the audio 
recorder. When starting the interview, the participant should be reminded that the interview 
will be recorded, the length of time it may last, arrangements for payment and that they 
can withdraw from the interview at any time. Audio recordings should be recorded on trust 
approved audio recorders, the interviewer who conducted the interview is responsible for 
transcribing the interviews verbatim, naming the document with the participant number for 
the trial. Original audio file recordings are to remain at the site, securely stored 
electronically as per local policy unless a Data Share Agreement is in place with the study 
sponsor. Transcripts with no personal identifiable information of the recordings will be sent 
to the study sponsor periodically upon request.  
 
Bup/Met +PSI Interview. To be conducted at the South London site only with approx. 30 
participants who are randomised to the Bup/Met +PSI arm. An additional consent will be 
taken from the participant to undertake a semi structured, topic guided interview detailing 
their drug use and experiences whilst being on the trial (based on the ADAPT). This 
interview can take place at the same time as the week 24 visit or scheduled for a time 
convenient to the participant and interviewer. Participants will be reimbursed an additional 
£20 for their time in taking part in the interview. Researchers are to follow the EXPO PSI 
Interview Schedule as a topic guide, but the interview is designed to be semi structured. 
If a face-to-face interview is not possible, interviews can be recorded over the telephone; 
with the call on speaker and recorded using the audio recorder. When starting the 
interview, the participant should be reminded that the interview will be recorded, the length 
of time it may last, arrangements for payment and that they can withdraw from the 
interview at any time. Audio recordings should be recorded on trust approved audio 
recorders, the interviewer who conducted the interview is responsible for transcribing the 
interviews verbatim, naming the document with the participant number for the trial. Original 
audio file recordings are to remain at the site, securely stored electronically as per local 

 
 
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policy unless a Data Share Agreement is in place with the study sponsor. Transcripts with 
no personal identifiable information of the recordings will be sent to the study sponsor 
periodically upon request.  
 
Extension Phase Interview. To be conducted at the South London and Newcastle sites 
with approx. 60 XR-Bup participants who consented to continue treatment after week 24 
between 12-24 months of them being randomised in the trial. An additional consent will 
be taken from the participant to undertake a semi structured; topic guided interview (based 
on the OSTQOL) and additional assessment measures as outlined in section 9.2 of this 
protocol. If a UDS is not provided at the time of the interview, the most recent UDS taken 
within routine clinical care, up to 90 days prior to the interview date, can be recorded for 
trial purposes (consent permitting). 
 
 
This interview can take place at a time convenient to the participant and interviewer. 
Participants will be reimbursed an additional £20 for their time in taking part in the 
interview. For the semi structured, topic guided section of the interview, researchers are 
to follow the EXPO Extension Phase Interview Schedule as a topic guide, but the interview 
is designed to be semi structured. If a face-to-face interview is not possible interviews can 
be recorded over the telephone; with the call on speaker and recorded using the audio 
recorder. When starting the interview, the participant should be reminded that the interview 
will be recorded, the length of time it may last, arrangements for payment and that they 
can withdraw from the interview at any time. Audio recordings should be recorded on trust 
approved audio recorders, the interviewer who conducted the interview is responsible for 
transcribing the interviews verbatim, naming the document with the participant number for 
the trial. Original audio file recordings are to remain at the site, securely stored 
electronically as per local policy unless a Data Share Agreement is in place with the study 
sponsor. Transcripts with no personal identifiable information of the recordings will be sent 
to the study sponsor periodically upon request.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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9.2 Assessments by Study Week and Study Timeline 
 
Measure  
Baseline 
Randomisation 
Ongoing 
Week 1 
Week 2~ 
Week 4 
Week 6~ 
Week 8 
Week 10~ 
Week 12 
Week 14~ 
Week 16 
Week 18~ 
Week 20 
Week 22~ 
Week 24 
Withdrawal 
Week 24 
onwards 
Ext. Phase 
Interview +++ 
Consent § 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Screening 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UDS 
 
 
 
 
X 
X X X 
X 
X X X 
X 
X X X 
X 
 
X 
LFT * 
X  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
XR-Bup** 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Bup/Met ** 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALC-QFM (TOP)*** 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
SCID-5-RV  
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
ADAPT  
X  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
CGI-S 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-I 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
CEQ-F – H*** 
X  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CEQ-F – C*** 
X  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
VAS-N (H/C)*** 
X  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
VAS-W (H/C)*** 
X  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
DERS-SF 
X  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
WSAS 
X  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
EQ-5D-5L 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
AD-SUS 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
KCF*** 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
QIDS-SR 
X  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
SURE 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PRO-S 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-I 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
MoCA*** 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
OSTQOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PHQ-4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PHQ-15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Exit Interview+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Bup/Met + PSI 
Interview++ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
TLFB 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Con Meds****  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Adverse Events Log 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Research Payments 
***** 
X 
20 
 
 
X 
10 
X 
10 
X 
10 
X
5 
X 
10 
X 
10 
X 
10 
X 
5 
X 
10 
X 
10 
X 
10 
X 
5 
X 
10 
 
 
X 
20 
 
§ screening to include pregnancy test, demographics and medical history. Participants receiving XR- Bup 
reconsented once at week 24 to continue receiving monthly injections; 
* LFT for all participants at screening; during treatment for XR-Bup participants only under protocol; 
** refer to section 6 of the protocol for guidelines; 
*** used for mediation model; 
**** ConMeds to be recorded continuously and reviewed at week 4, 12 and 24; 
***** research payments are time offset to attend the clinic to complete research measures and cover travel 
(either a £20, £10, or £5 value, as detailed per visit applicable; loaded onto a prepaid card). 

 
 
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+ Exit Interview conducted at South London, Newcastle, West Midlands and Tayside sites with XR-Bup 
participants only. Participants will be reimbursed an additional £20 for their time in taking part in the interview 
(loaded onto a prepaid card). 
++ Bup/Met +PSI Interview conducted at South London with Bup/Met +PSI participants only. Participants will 
be reimbursed an additional £20 for their time in taking part in the interview (loaded onto a prepaid card). 
+++ Extension Interview conducted at the South London and Newcastle sites with XR-Bup participants who 
consented to continue treatment after week 24 between 12-24 months of them being randomised in the trial. 
~ Due to the Coronavirus 2019 (COVID-19) pandemic and to limit health care contacts, week 2, 6, 10, 14, 18 
and 22 visits are permitted to be conducted via telephone if required. In this instance a UDS may not be 
obtained. Missed UDS due to visits being conducted by telephone are not considered a protocol deviation and 
do not have to be recorded on the deviations log however missed UDS for all other reasons should be 
recorded. All other visits are to be conducted in person at the study centre. 
 
 
9.3 Laboratory Tests 
  
Each site will determine all participants’ liver function (as defined in the inclusion/exclusion 
criteria) after consent either by conducting an LFT (serum) blood-test following their local 
laboratory procedure, or accessing this information from the participant’s hospital medical 
records if a prior LFT test result has been done and recorded within 12 weeks from the 
date of screening. During post-randomisation 6-month treatment phase, participants 
allocated to the XR-Bup arm will be asked to have further LFT testing at visits 4, 12 and 
24, or more often as judged by the CI or PI. After the post-randomisation 6-month 
treatment phase, participants who consent to continue having XR-Bup injections will be 
asked to have further LFT testing approximately every 6 months or more often as judged 
by the CI or PI.   
 
If the participant does not have their bloods taken post randomisation for any reason  (i.e., 
including but not limited to, participant refusal , they do not attend the visit or if it is not 
possible to take bloods); they may continue in the trial at the discretion of the PI or Sub 
Investigator based on their clinical judgement. Participants randomised to BUP or Met in 
the study will have LFT testing according to their local standard of care.  
 
10. Assessment of Efficacy  
 
10.1 Primary efficacy parameter   
 
With a 1-week measurement grace period from randomisation, the primary endpoint is the 
count of days abstinent from all non-medical opioids between days 8-168 (weeks 2-24; 
161 days), combined with up to 12 urine samples for opioids providing biological 
verification of 36 of the 161 days in the outcome measure. If the UDS shows positive, the 
3 days prior to the UDS will be reported as a positive and override what is reported on the 
timeline follow-back interview.  
 
10.2 Secondary Efficacy Parameters      
 
There will be 19 secondary within-study efficacy parameters:  
 
(1) Clinical superiority of XR-Bup plus PSI versus Bup/Met plus PSI using the primary 
outcome measure; 
(2) Safety measured by all adverse event reporting; 

 
 
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(3) Time (days) enrolled in study treatment (retention) to week 24;  
(4) OUD and CUD remission status (severity) measured by SCID-5-RV for DSM5;  
(5) Clinician rating of severity, complexity and recovery strengths (ADAPT);  
(6) Clinician rating of global impression (CGI-I anchored on baseline severity [CGI-S]);  
(7) Count of days abstinent from cocaine and illicit/non-medical benzodiazepines during 
weeks 2 to 24 (range: 0-161 days); combining self-report information from Time-Line 
Follow-Back interview adapted from the Treatment Outcomes Profile and incorporating 
data from 12 scheduled urine drug screens; 
(8) Craving for opioids and cocaine (CEQ-F[H] and CEQ-F[C]); 
(9) VAS-N and VAS-W craving need for heroin and cocaine; 
(10) Difficulties in Emotion Regulation – Short Form (DERS-SF); 
(11) QIDS-SR (depression rating);  
(12) WSAS (work and social adjustment); 
(13) Subjective recovery and improvement (SURE);  
(14) Subjective rating of OUD improvement (PRO-I; on baseline severity [PRO-S); 
(15) Cognitive impairment (MoCA); 
(16) Alcohol: typical quantity and frequency (ALC-QFM) 
(17) Time (days) enrolled in study treatment (retention) from week 24 to date last 
participant randomised plus 9 months; 
(18) Semi structured, topic guided interviews after week 24 (XR-Bup, XR-Bup +PSI & 
Bup/Met +PSI treatment arms) and after 12 months of enrolment within the trial (XR-Bup 
treatment arm only);  
(19) Among participants enrolled in longer term XR-Bup treatment: OUD and CUD 
remission status (SCID-5-RV); heroin, cocaine and illicit/non-medical benzodiazepine 
use in past 90 days (TLFB; UDS); somatic symptoms (PHQ-15), emotion regulation 
(DERS-SF), depression and anxiety symptoms (PHQ-4) and quality of life (OSTQOL). 
 
 
Analysis of other research measures will be specified in the statistical analysis 
plan. 
 
10.3 Procedures for assessing efficacy parameters  
 
Endpoint data collection will be gathered during 13 clinic visits using the TOP (timeline 
follow-back [TLFB] interview) and will also include recording of cocaine and non-medical 
benzodiazepines. All participants will be asked to provide a urine sample during each visit. 
If the participant does not take a UDS then all tested drugs will be taken to be positive for 
the past 3 days. 
 
10.a Assessment of Cost Effectiveness  
 
10.1a Primary Economic Parameter  
 
The primary economic endpoint will be the incremental cost per quality-adjusted life year 
(QALY) gained of injectable depot maintenance buprenorphine versus standard oral 
therapy, adopting a broad societal cost perspective. Incremental costs will be determined 
from responses to the ADSUS questionnaire and the EXPO keyworker contact form. 
QALYs will be calculated from EQ-5D-5L scores and by applying the EQ-5D-3L crosswalk 
value set. This has no implications for the sample size calculation. 

 
 
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10.2a Secondary Economic Parameters      
 
There will be 2 secondary economic parameters:  
 
(1) Health profiles (EQ-5D-5L); 
(2) Quantities of resource use (ADSUS) and total costs disaggregated by broad 
categories; 
 
10.3a Procedures for assessing cost-effectiveness parameters 
 
The cost utility analysis will consider patient QALYs and costs from a broad societal 
perspective including NHS and personal social services, productivity losses (including 
time off work because of illness), and criminal activity. This will be based on an incremental 
analysis of the mean costs and QALYs for injectable depot maintenance buprenorphine 
versus standard oral therapy.  
 
Trial participants’ direct and indirect costs will be estimated from responses to the ADSUS 
questionnaire, which includes items related to use of primary care services (including out-
of-hours services), Emergency Department and hospital care; in addition to services 
provided by local authorities, including accommodation, day care, and drop-in centres; 
and personal costs in terms of days off work, out-of-pocket expenses, time spent seeking 
healthcare, etc. Participants’ use of secondary care services will also be measured directly 
using the study CRFs. This will ensure missing data on important cost drivers are reduced 
to a minimum. The keyworker contact form will be used to record the clinical team’s direct 
and indirect time working as part of the trial. Unit costs will be obtained from routine 
hospital data (NHS reference costs) and other resources such as the British National 
Formulary for medicines, and the Personal Social Services Research Unit’s unit costs of 
health, social care [43], and criminal justice [44]. Indirect costs will be valued using the 
human-capital method, based on the average annual earnings data by sex and age group 
obtained from the Office for National Statistics. 
 
Trial participants will be asked to complete the EQ-5D-5L questionnaire at baseline, and 
weeks 12 and 24. Responses will be used to calculate 3L utilities, based on the crosswalk 
[45] which is the current recommendation by NICE. Should a EQ-5D-5L value set become 
available by the time of analysis, this will be used in a secondary analysis. 
 
 
Longer-term data linkage after end of study 
 
An analysis using data-registry indicators of mortality, convictions and health service 
utilisation (the later longer-term research aims). In preparation for this, we will ask 
participants for their consent. 
 
Subject to patient consent and securing approval from Public Health England (PHE), 
Ministry of Justice and NHS Digital, public, EXPO data will be linked to the following 
external-study measures at 3 years: This review at 3 years will be a non-CTIMP data audit 
and does not form part of the current CTIMP trial.  
 
(1) National Drug Treatment Monitoring System (total time in community and prison setting 
treatment, number of treatment journeys, treatment status at end of follow-up (in 
treatment; left successfully or unsuccessfully).  

 
 
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(2) NHS hospital episodes statistics: contact with inpatient and outpatient hospital 
services.  
 
(3) Police National Computer (net change in number of convictions before and after the 
trial by offence type. PNC: for each member of the cohort: (a) lifetime convictions history 
to point of enter into the study and nature and number of convictions (severity); (b) count 
of convictions 2 years before and after index prison discharge. All recordable offence types 
will be included where an individual was charged, then subsequently proven guilty and 
either convicted, cautioned, reprimanded or warned. The two-year observation period will 
be used to allow time for police and court processing of offences committed before 
treatment. 
 
(4) NHS Digital: NHS digital: mortality: (a) incident and date of mortality; (b) cause of 
mortality; (c) involvement of alcohol or drugs; (d) location of death. Following our previous 
work with the Office for National Statistics, case definitions will involve: ‘Mental and 
behavioural disorders due to drug use’ (ICD-10 codes: F11-F16, F18, F19) and an opioid 
was mentioned on the death certificate; or to any of the following: ‘Accidental poisoning 
by drugs, medicaments and biological substances’ (X40-X44); ‘Intentional self-poisoning 
by drugs, medicaments and biological substances’ (X60-X64); ‘Assault by drugs, 
medicaments and biological substances’ (X85); and ‘Poisoning by drugs, medicaments 
and biological substances, undetermined intent’ (Y10-Y14), where any controlled drug and 
an opioid was mentioned (and potentially referring to the same drug, such as heroin).  
 
 
 
11. Assessment of Safety  
 
11.1 Specification, timing and recording of safety parameters 
 
For participants assigned to XR-Bup, LFT (blood sampling) will be done at screening (or 
recorded from the participants medical records if an LFT procedure was done no more 
than 12 weeks before consent), and at 4-weeks, 12-weeks and end of study (24-weeks). 
Participants who consent to receive XR-Bup treatment past 6 injections, a LFT will be 
taken every 6 months.  
 
If a participant does not have their bloods taken for any reason post randomisation (i.e., 
including but not limited to, participant refusal, they do not attend the visit or if it is not 
possible to take bloods); they may continue in the trial at the discretion of the PI or Sub 
Investigator based on their clinical judgement. The CI or PI may judge that more frequent 
LFT monitoring is clinically indicated for these and other participants in the study.  
 
 
 
11.2 Procedures for recording and reporting adverse events    
 
The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amended 
Regulations 2006 gives the following definitions: 
 

 
 
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Adverse Event (AE): Any untoward medical occurrence in a subject to whom a medicinal 
product has been administered including occurrences which are not necessarily caused 
by or related to that product. 
 
Adverse Reaction (AR): Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose administered to that 
participant. 
  
Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of 
which is not consistent with the information about the medicinal product in question set 
out in the SmPC for that product (for products with a marketing authorisation), or The 
Investigator's Brochure (IB) relating to the trial in question (for any other investigational 
product). 
 
Serious adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected 
Unexpected Serious Adverse Reaction (SUSAR): Any adverse event, adverse reaction 
or unexpected adverse reaction, respectively, that results in death; is life-threatening; 
required hospitalisation or prolongation of existing hospitalisation; results in persistent or 
significant disability or incapacity; consists of a congenital anomaly or birth defect.  
 
As documented within the EXPO Trial  Investigator Brochure all SARs in the XR-Bup IMP 
groups are unexpected and will be reported as SUSARS in the study.  
 
Important Medical Events (IME) & Pregnancy Events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above 
should also be considered serious. Although not a serious adverse event, any unplanned 
pregnancy will be reported via the trial's SAE reporting system as stated below. 
 
Reporting Responsibilities: King’s College London & South London and Maudsley NHS 
Foundation Trust have delegated the delivery of the Co-sponsors’ responsibility for 
Pharmacovigilance (as defined in Regulation 5 of the Medicines for Human Use (Clinical 
Trials) Regulations 2004 to the King’s Health Partners Clinical Trials Office (KHP-CTO). 
 
All SAEs, SARs and SUSARs will be reported immediately (and certainly no later than 24 
hours) by the Investigator to the KHP-CTO and the CI will review in accordance with the 
current Pharmacovigilance Policy. The adverse event log (AEL) will be reviewed at each 
trial assessment clinic visit and at all follow-ups and following any occurrences in between 
study visits and follow-ups.  
All clinical investigators in the study will be provided with full details of possible adverse 
medical events that may result from the trial medication and/or procedure, as well as other 
possible occurrences that may not be caused by or related to that product or procedure. 
Any adverse events occurring during the trial will be recorded in the participant’s source 
data worksheet and filed in their medical records at the end of the trial. They will also be 
transcribed on to the electronic Case Record Form (eCRF).  
 
Clinicians will report, and the centre’s PI will assess, each adverse event for seriousness, 
causality (definite, probable, possible, remote, none) and intensity (mild, moderate and 
severe). The Sponsor will make the expectedness assessment against the Reference 
Safety Information section of each Investigational Medicinal Product. If the Sponsor (CI) 

 
 
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does not agree with the investigator’s causality assessment the opinion of both the 
investigator and the Sponsor will be provided with the report.  
 
The KHP-CTO Clinical Research Associate (CRA) will review the SAE once it’s received 
by email and follow up queries will be sent to the site team and CI. The original SAE form 
and documentation of event in source data will also be verified at monitoring visits. The 
information will be entered on the eCRF. The CI (or a doctor nominated by the CI) will 
review every event within one working day of the SAE form being received and determine 
whether the event was expected or unexpected. The CI may upgrade the causality of an 
event without the centre PI’s agreement.  
 
On a scheduled basis, the Data Management Committee (DMC) will review adverse event 
information. The KHP-CTO will report SUSARs to the Medicines and Healthcare Product 
Regulatory Agency (MHRA).  
 
The reporting timelines are as follows:  
 
• 
SUSARs, which are fatal, or life threatening must be reported no later than 7 days 
after the sponsor is first aware of the reaction. Any additional relevant information 
must be reported within a further 8 days. 
• 
SUSARs that are not fatal or life-threatening must be reported within 15 days of 
the sponsor first becoming aware of the reaction.  
• 
The Chief Investigator and KHP-CTO (on behalf of the co-sponsors), will submit a 
Development Safety Update Report (DSUR) relating to this trial IMP, to the MHRA 
and REC annually. 
 
Any safety concern/ safety signal raised by the DMC will be communicated by SLaM & 
KCL to Indivior European Economic Area Qualified Person Responsible for 
Pharmacovigilance (INDV EEA QPPV) at EEAQPPV@indivior.com within 24 hours of 
awareness.  
 
11.3 Treatment stopping rules 
 
EXPO may be prematurely discontinued by the Co-sponsors or Regulatory Authority on 
the basis of new safety information or for other reasons given by the DMC and TSC 
regulatory authority or ethics committee concerned. The Competent Authority and 
Research Ethics Committee (REC) will be informed within 15 days of the early termination 
of the trial. 
12. Statistics 
 
12.1 Sample size 
 
A target sample of 604 participants has been estimated for the study. The sample size 
calculation is strategic, ensuring that there is a reliable estimate of the XR-Bup versus Bup 
effect aimed to be conducted in q42020 (at the end of Phase I). The estimate of the main 
effect for XR-Bup + PSI versus Bup/Met + PSI (Phase II) has been assumed to be 
equivalent to the main effect or Phase I.  
 

 
 
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The required number of participants has been estimated using that required for a Poisson 
regression model taking a baseline rate of 0.6 and assuming a 23% target difference in 
the count of days of abstinence from heroin over the study period of 161 days. (ARC trial 
(ISRCTN69313751; 56.78% for the treatment-as-usual control i.e. assuming 17 abstinent 
days over a period of 28 days).  
 
To obtain 90% power, for a Poisson regression, with alpha at 5% and with 15% inflation 
for attrition, EXPO has a target total of 304 participants for the statistical comparison of 
the primary outcome recorded for XR-Bup and Met/Bup and a target total of 300 
participants for the statistical comparison of the primary outcome recorded for XR-Bup + 
PSI and Bup/Met + PSI. The statistical analysis plan will present a sensitivity check on this 
power calculation on the assumption of a greater response for the control groups. 
 
At each of the 5 study sites, the plan is to enrol a maximum of 76 participants for this 
comparison. This will achieve a study that is well-powered to detect a main treatment 
effect of medication [7]. At the end of Phase II (at the co-ordinating centre) there will be a 
targeted recruitment of 150 to receive XR-Bup + PSI and 150 patients to Bup/Met + PSI 
[8]. After analysis of the Phase I and Phase II contrasts, there will be an exploratory meta-
analysis, pooled data from all sites.  
 
12.2 Statistical analysis 
 
Assessment of Efficacy 
 
The Statistical Analysis Plan (SAP) - approved by the trial committees - will be published 
on the Open Science Framework (www.osf.io) and summarised in the published trial 
protocol paper. After data lock in MACRO for each phase, the statistical analysis will be 
completed in Stata and R. Pooling data from all clinical treatment sites, a mixed-effects 
multivariable regression model for the primary analysis, with covariates (sex, age, drug 
injecting status, centre and baseline score on the outcome measure), and a site-varying 
random intercept. The medication preference factor will be explored for inclusion through 
interaction tests because it is expected that many participants have a medication 
preference given past or current exposure. 
 
A maximum-likelihood multiple imputation approach will be used for the management of 
missing data with a sensitivity comparison to the complete case dataset. The cumulative 
distribution function of the primary endpoint will also be plotted for comparison purposes. 
Analyses of secondary outcomes will proceed using the same stratification and covariates 
as defined for the primary analysis model with linear (continuous outcomes) or logistic 
(binary or ordinal outcomes) regression framework. A causal mediation analysis (including 
craving, MoCa, and WSAS as mediators in separate models) will be implemented using a 
counterfactual framework to include a treatment/mediator interaction and covariates, 
based on univariable path screening, and with bias corrected bootstrapped estimates.  
 
The clinical analysis will follow the intention-to-treat principle and include all patients in the 
group to which they are allocated. Alpha will be set at 5% for the primary and secondary 
outcomes (with associated 95% confidence intervals). The distributions of scale and count 
measures may be non-normal (skewed), so test statistics and effect sizes will be 
computed following appropriate transformation (e.g. natural log to obtain a geometric 
mean).  
 

 
 
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Assessment of Cost Effectiveness 
 
The number of QALYs experienced by each participant will be calculated as the area 
under the curve, using the trapezoidal rule, and adjusted for baseline [46]. Total costs and 
QALYs will be used to calculate the incremental cost-effectiveness ratio of injectable depot 
maintenance buprenorphine versus standard oral therapy. Data that are assumed missing 
at random will be imputed using multiple imputation by chained equations as will be 
specified in the HEAP. Non-parametric bootstrapped 95% central ranges for items of 
resource use, costs and QALYs will be estimated (10,000 replicates). 
 
A range of one-way sensitivity analyses will be conducted to test whether, and to what 
extent, the incremental cost-effectiveness ratio is sensitive to key assumptions in the 
analysis (e.g. unit prices). Multivariate sensitivity analyses will be applied where interaction 
effects are suspected, and the joint uncertainty in costs and benefits will be considered 
through application of bootstrapping and estimation of cost-effectiveness acceptability 
curves [47]. Alternative scenarios will be specified in the HEAP and will include 
consideration of a narrower cost perspective (NHS +/- personal social services) to enable 
comparison with the NICE threshold range of £20,000 to £30,000 per QALY. 
 
A Health Economic Analysis Plan (HEAP) [48] (agreed prior to the analysis), will define 
the analytic steps to be undertaken. The economic findings will be reported according to 
the CHEERS guideline [49]. 
 
13. Trial Steering Committee  
 
A TSC will operate independently from the Trial Management Group (TMG), the study 
funder (Indivior), and the Co-sponsors (King’s College London and South London and 
Maudsley NHS Foundation Trust). The TSC’s key purpose will be to ensure the overall 
integrity of the study. Committee membership will be documented in the first (joint) minutes 
of the TSC and DMC.  
14. Data Monitoring Committee  
 
The DMC’s key purpose (as set out in DAMOCLES) will be defined in the DMC charter. 
Reports to the DMC will be prepared and presented by the Trial Statistician.  
 
15.Trial Management Group 
 
The TMG will be responsible for the trial’s day-to-day running and management. Chaired 
by a Senior Investigator, the membership will include: The CI, Lead (clinical scientific) 
Investigator, Co-Lead (clinical scientific Investigator), EXPO Trial Manager (secretary to 
the TMG), EXPO Trial Pharmacist, EXPO Statisticians and EXPO Co-Applicants. The 
TMG will oversee the development and operation of the study, monitor and maintain 
recruitment rates, and devise any necessary workarounds that may arise in patient 
management or the conduct of the trial, ensure that all required financial, insurance and 
indemnity arrangements are instigated, organise site agreements between each clinical 
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16. Direct Access to Source Data and Documents 
 
EXPO Investigators will permit trial-related monitoring, audits, REC review, and regulatory 
inspections by providing the Sponsors, Regulators and REC direct access to source data 
and other documents. 
17. Ethics & Regulatory Approvals 
 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki 
(1996), the principles of GCP and in accordance with all applicable regulatory 
requirements including but not limited to the Research Governance Framework and the 
Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 and any 
subsequent amendments. The protocol and related documents will be submitted via IRAS 
application for review to a REC, and to the MHRA for Clinical Trial Authorisation. EXPO 
will comply with regulations, particularly specifying pharmacovigilance reporting. 
Subsequent protocol amendments will be submitted to the REC and the Regulatory 
Authorities for approval. Progress reports and a Final Study Report will be provided to the 
REC and the Regulatory Authorities.  
 
The Senior Investigators will submit a final report at conclusion of the trial to the KHP-CTO 
(on behalf of the Cosponsor), the REC and the MHRA within the timelines defined in the 
regulations. In relation to the study’s registration and adoption: an MHRA Clinical Trial 
Authorisation application will be made. The trial will be registered with an appropriate trials 
database (e.g. clinicaltrials.gov).  
18. Quality Assurance 
 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice (GCP), and 
scientific integrity will be managed, and oversight retained, by the KHP-CTO Quality 
Team. The trial will incorporate a range of data management and quality assurance 
functions. As the data are entered online, the Trial Manager will log any queries generated 
and feed these back to the centre research workers in a timely manner. Any necessary 
alterations to entered data will be indicated clearly with an audit trail from the original point 
of data entry, to ensure that any such amendments, and the reasons for them, can be 
inspected and tracked. KHP-CTO will undertake, on behalf of the Sponsor, independent 
administrative audits of the trial master file and monitoring at all sites and pharmacies 
periodically during the trial to ensure compliance with the Medicines for Human Use 
(Clinical Trials) Regulations 2004 and its subsequent amendments. 
 
 
 
 
 
 

 
 
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19. Data Handling  
 
The Lead Investigator will act as custodian for the trial data under the General Data 
Protection Regulations. The following guidelines will be strictly adhered to: all patient data 
will be pseudo-anonymised and stored on a password protected computer; all trial data 
will be stored in line with the Medicines for Human Use (Clinical Trials) Amended 
Regulations 2006 and archived in line with the Medicines for Human Use (Clinical Trials) 
Amended Regulations 2006 as defined in the KHP-CTO Archiving SOP.  
20. Data Management and Database Lock 
 
All baseline and follow-up data will be entered on the online InferMed MACRO electronic 
data capture (EDC) system (infermed.com). This system is regulatory compliant (GCP, 
and the EC Clinical Trial Directive). An electronic case report form (eCRF) using the 
MACRO EDC will be programmed by the KCTU and hosted on a dedicated secure server. 
The eCRF system will have full audit trail, data discrepancy functionality, database lock 
functionality, and supports real time data cleaning and reporting. The Trial Manager will 
request usernames and passwords to any new researchers. Only those authorised by the 
Trial Manager will be able to use the system. 
 
After written recording, each research worker will aim to transcribe data onto the eCRF 
within one working week of a participant assessment. After completion of all follow-ups 
and prompt entry of data, the Trial Manager will review the data and resolve queries with 
sites. At the end of the trial, each centre will be supplied with their eCRF data for storage. 
This will be filed locally for any future regulatory or internal audit. 
 
Database lock for phase I will be undertaken within approximately 3 months of last patient, 
last visit and will be controlled by TMG of participants enrolled in groups 1 and 2. Database 
lock for phase II will be within approximately 3 months of last patient, last visit and will be 
controlled by TMG of participants enrolled in groups 3 and 4. 
 
21. Publication Policy  
 
A layered communication plan for the lifecycle of the trial will be developed to 
communicate material in the best format to our audiences (including service users; family 
members; policy makers; treatment commissioners; the general public; and scientific 
peers). The study will produce results and practice briefings for NHS Service and national 
stakeholder audiences. This collective activity will support the communication of results 
via high-impact general medical journals and addiction science journals.  
 
 
 
 
 
 
 

 
 
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22. Insurance & Indemnity  
 
King's College London (KCL) will provide cover under its No Fault Compensation 
Insurance, which provides for payment of damages or compensation in respect of any 
claim made by a research subject for bodily injury arising out of participation in a clinical 
trial or healthy volunteer study (with certain restrictions). The co-sponsor, South London 
and Maudsley NHS Foundation Trust, takes responsibility for ensuring that appropriate 
standards, conduct and reporting are adhered to regarding its facilities and staff involved 
with the project 
23. Financial Aspects  
 
EXPO is funded by Indivior as research grant to King's College London (KCL; Lead 
[clinical scientific] investigator, Professor John Marsden; Addictions Department), listing 
Dr Mike Kelleher as Chief Investigator and Principal Investigator (at South London and 
Maudsley NHS Trust), with sub-contracts issued by KCL to South London and Maudsley 
NHS Trust and each clinical recruitment site. The lead sponsor, KCL, will take primary 
responsibility for ensuring that the design of the study meets appropriate standards and 
that arrangements are in place to ensure appropriate conduct and reporting.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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24. Signatures 
 
 
Dr. Mike Kelleher: 
 
______________________________________  
 
_________________________ 
Chief Investigator 
 
 
 
 
 
Date 
 
 
Dr. John Marsden: 
 
______________________________________ 
 
______________________ 
Co- Lead Investigator  
 
 
 
 
Date 
 
 
Dr. Zoë Hoare: 
 
______________________________________ 
 
______________________ 
Statistician 
 
 
 
 
 
 
Date 
 
 
Prof Dyfrig Hughes: 
 
 
______________________________________  
 
_________________________ 
Health Economics Lead 
 
 
 
 
Date 
 
 
Dr. Ed Day: 
 
______________________________________  
 
_________________________ 
Principal Investigator  
 
 
 
 
Date 
 
 
Dr. Jonathan Dewhurst: 
 
______________________________________  
 
_________________________ 
Principal Investigator  
 
 
 
 
Date 
 
 
Dr Eilish Gilvarry: 
 
______________________________________  
 
_________________________ 
Principal Investigator  
 
 
 
 
Date 
 
 
Dr Fiona Cowden: 
 
______________________________________  
 
_________________________ 
Principal Investigator  
 
 
 
 
Date 
 

 
 
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25. Trial Protocol Version History Summary 
 
 
Protocol 
Version 
Number 
Issue Date 
Summary of Significant Changes 
1.2 
13.06.2019 
Clarification/expanding/amending minor instructions and details across the protocol.  
 
Section 2 
Changes to central study team and removed Sponsor Representative contract details. 
 
Section 3 
Added abbreviations. 
 
Section 4 
Background information expanded. 
 
Section 5.2  
Removal of study site and recalculation of targets. 
Senior Statistician to be blinded. Junior Statistician is unblinded to prepare reports. 
 
Section 6.1 
Condensing of information regarding Imp and that the manufacturing and importing will be 
completed by Indivior. 
 
Section 6.2 
Active Comparator arms will be dispensed by community pharmacies on receipt of a valid 
prescription, labelled with a normal dispensing label. Reference to SmPCs for oral Bup and Met. 
 
Section 6.3 
Rescue dosing of Bup can be provided at any point after the first dose of XR-Bup. This will be 
recorded as concomitant medication. 
Schedule timing of minim 21 days added for XR Bup. 
 
Section 6.6 
Guidelines on removal of XR Bup added. 
 
Section 6.7 
Clarification on the accountability of XR Bup. Pharmacy team to manage accountability, 
Sponsor approval required for all destruction.  EXPO Trial Pharmacist will manage IMP supply 
to sites. 
 
Section 6.7.2  
Accountability records not required for comparator arms within the trial as they will be dispensed 
with local pharmacy. Site staff to check compliance with local pharmacies. 
 
Section 6.7- Supply, transport and storage of IMP. Repetition of numbering amended in protocol 
version 2.0. 
Reference to the Investigational Product Handling Manual for detailed information regarding 
storage guidelines. 
Temperature monitoring not required for comparator arms. 
 
Section 8.3 
Clarification of induction procedure. 
 
Section 8.4 
Removal of stratification factors.  
 
Section 9.1 

 
 
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Amendment to research measures utilised and the timepoints of collection. 
 
Section 10.1 and 10.2 
Clarification and additional primary and secondary efficacy parameters set. 
 
Section 11.2 
All SARs in the XR-Bup IMP groups are unexpected and will be reported as SUSARS in the 
study.  
 
Amendment to sample size and statistical analysis to be conducted.  
 
Section 25 
Signatures added for Co-Lead Investigator and Trial Statistician. 
2.0 
08.01.2020 
Clarification/expanding/amending minor instructions and details across the protocol.  
 
Section2  
Addition of PI contact details. 
 
Section 5.2 
Addition of new recruiting site. 
 
Section 6.2 
Removal of Buprenorphine Naloxone- Bup-NX (Suboxone) as an active comparator. 
 
Section 6.3  
Dosing guidance for participants who consent to receive more than 6 doses of XR-Bup. 
 
Section 6.4  
Amendment of the numbering of injection sites to be consistent across guidance given, PIL, 
database. 
Cold press is authorised upon injection. 
 
Section 6.6 
Removal of XR Bup to be recorded as an Important Medical Event (IME).  
 
Section 6.8.1 
Removal of instruction that IMP can be stored at room temperature for up to 7 days prior to 
administration. 
 
Section 7.0 
Clarity and addition information on timetable of sessions and information regarding withdrawals. 
 
Section 8.1 
Reducing Met from 50mg to 30mg/day or less for inclusion into the trial. Significant change of 
wording of inclusion criterions 7 and 8. Clarity of other inclusion/exclusion criterions. 
 
Section 8.3 
Removing the induction process for participants new to treatment as all participants are to be 
already in receipt of opioid substitution therapy. Clarification of the induction process for all 
participants randomised to XR-Bup.  
 
Section 9.1 
Detailing optional consent for an Exit Interview with participants randomised to XR-Bup at South 
London recruiting centre. 
 
Section 9.2 
Adding timeline for procedures to be conducted with XR-Bup participants who consent to 
additional treatment. 
Adding timeline for Exit Interview. 
Change in payments to include payments at all visits. 
 
Section 9.3 

 
 
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Change of procedure of collection of LFT blood test as only required for XR-Bup participants. 
Use of past blood results if available at screening. 
 
Section 10.2 
Additional secondary efficacy parameters added to trial outcomes measures.  
 
Section 10.3 
Error in number of trail visits from 10 to correct number of 13. Removal of alcohol consumption 
collected as endpoint data collection. 
 
Section 11.1 
Clarity of procedure as per section 9.3. 
 
Section 12.2 
Clarify of analysis.  
 
Section 15.  
Change of membership of TMG to remove site staff. 
 
Section 24 
Signatures added for all PI’s to confirm review and approval of protocol. 
 
Section 25  
Addition of summary table of changes between protocols. 
2.1 
09.07.2020 
Section 7 
Removing instruction that the PI and lead therapist will meet weekly to discuss case 
management of non-PSI participants. 
 
Section 9.1.2 
Amendment of sub-section heading 
Exit Interview to be conducted at Newcastle, West Midlands and Tayside in addition to South 
London. 
 
Section 9.2 
Details of Exit Interview. 
 
Section 12.1 
Correction of Typographical error from 4 to 5 sites. 
 
Section 24 
Signature space for Dr Cowden PI at Tayside study centre. 
 
3.0 
22.07.2020 
Section 6.2 
Addition of Buprenorphine Naloxone [Bup-NX (Suboxone)] as an active comparator as this is 
routinely prescribed at the Tayside Site as standard of care medication for OUD. 
 
Section 9.2 
Additional details of Exit Interview. 
 
4.0 
30.09.2020 
Section 6.2 
Addition of Espranor® (Esp) as an active comparator as this is routinely prescribed at the 
Tayside Site as standard of care medication for OUD. 
Clarity that participants randomised to group 2 and group 4 are permitted to change between 
the active comparator drugs whilst enrolled in the trial by following the prescribing guidelines as 
detailed in the SmPC and if there are no known allergic, adverse reactions or contraindications 
to the drug. 
 
Section 6.3 
Esp usual daily dose separated from Bup as max daily is 18mg. 
 
Section 6.8.2 
Addition of Bup-NX and Esp. 

 
 
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Section 8.1 and 8.2 
Updated Inclusion and Exclusion Eligibility criteria to include Bup NX and Esp. 
Clarity that participant is ineligible if they have any allergic or adverse reactions or 
contraindication to Buprenorphine. If participant has any allergic or adverse reaction or 
contraindication to Met or naloxone, or excipients of Bup-NX or Esp they can be prescribed Bup 
within the trial.  
 
 
Section 11.2 
Updated reference dates for the Trial Specific Addendum to the Reference Safety Information 
for The Investigator’s Brochure (IB; RBP-6000; Indivior 06 March 2020; pages 144-153). 
 
 
 
5.0 
01.06.2021 
Section 2 
Updated clinic name at Tayside study site.  
 
Section 3 
Updated abbreviations for new terms introduced within the protocol. 
 
Section 5.2  
Caveat to document new recruitment phase timelines. 
 
Section 5.3 
Caveat to document amendment to study analysis timelines.  
 
Section 6.5 
Removal of reference to EXPO Trial Specific Addendum to Reference Safety Information as the 
Investigator Brochure has been updated to incorporate this information. Therefore, no 
requirement for the Addendum.   
 
Section 9.1 
Correction of Typo from clinician version to research version (SCID-5-RV) 
Addition of measurements OSTQOL; PHQ-15 and PHQ4. 
Confirmation that where document as clinician administered measure this can be delegated to a 
health care worker after the baseline/screening assessment.  
Exit Interview qualitative interview based on ADAPT measurement. 
Details what the Bup/Met +PSI and Extension Phase Interview comprise of 
 
Section 9.2  
Addition of timepoints for Bup/Met + PSI Interview and Extension Phase Interview. 
Due to the Coronavirus 2019 (COVID-19) pandemic and to limit health care contacts, week 2, 6, 
10, 14, 18 and 22 visits are permitted to be conducted via telephone if required. In this instance 
a UDS may not be obtained. Missed UDS due to visits being conducted by telephone are not 
considered a protocol deviation and do not have to be recorded on the deviations log however 
missed UDS for all other reasons should be recorded. All other visits are to be conducted in 
person at the study centre. 
 
Section 9.3 
Clarification that participants can continue in the trial if LFT bloods are not taken post 
randomisation based on PI/Sub Investigator clinical judgement. 
 
Section 10.2 
CUD remission status added as an efficacy parameter (previously omitted due to error but 
already approved as a measure). 
Addition of 2 secondary efficacy parameters for the measures/outcomes being collected within 
the Exit Interview, Bup/Met + PSI Interview and Extension Phase Interview. 
 
Section 11.1 
Clarification that participants can continue in the trial if LFT bloods are not taken post 
randomisation based on PI/Sub Investigator clinical judgement. 

 
 
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Section 11.2 
Removal of reference to EXPO Trial Specific Addendum to Reference Safety Information as the 
Investigator Brochure has been updated to incorporate this information. Therefore, no 
requirement for the Addendum.   
 
Section 26 
Addition of references for OSTQOL; PHQ-15 and PHQ4 and correction of reference 37. 
5.1 
06.10.2021 
Section 2 
Contact details for Health Economics Lead. 
 
Section 9.1 
EQ-5D-5L amendment to the description of the scale as used for economic evaluation. 
 
Section 10.a 
Addition of section to detail Assessment of Cost Effectiveness. 
 
Section 10.1a 
Addition of section to detail Primary Economic Parameter. 
 
Section 10.2a 
Addition of section to detail Secondary Economic Parameters. 
 
Section 10.3a 
Addition of section to detail Procedures for assessing Cost-Effectiveness Parameters. 
 
Section 12.2 
Additional details for assessment of cost effectiveness. 
 
Section 24 
Signature for Health Economics Lead added. 
 
Section 26 
References updated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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