A Pragmatic, Multi-centre, Open-label, Randomized, 12-month, Parallel Group, Superiority Study to Compare the Effectiveness of Subcutaneous Buprenorphine Depot (Sublocade®) vs Daily Sublingual Buprenorphine With Naloxone (Suboxone®) for the Treatment of Opioid Use Disorder
Phase: PHASE4
Conditions: Moderate to Severe Opioid Use Disorder
Sponsor: Royal Victoria Hospital, Canada

 
 
 
 
A pragmatic, multi-centre, open-label, 
randomized, 12-month, parallel group, 
superiority study to compare the effectiveness 
of subcutaneous buprenorphine depot 
(Sublocade®) vs daily sublingual buprenorphine 
with naloxone (Suboxone®) for the treatment 
of opioid use disorder 
 
STOP-IT  
 
Protocol version: version 4.0 (10-Aug-2022) 
Protocol version: version 3.12 (6-June-2022) 
Protocol version: version 3.1 (2-May-2022) 
Protocol version: version 3.0 (11-APR-2022) 
Protocol version: version 2.0 (02-FEB-2022) 
Original version: version 1.0 30-NOV-2021 
ClinicalTrials.gov:  
 
 
This protocol is the confidential intellectual property of the Principal Investigators and Sponsor. Acceptance implies 
an agreement not to disclose information contained herein that is not otherwise publicly available and without the 
express permission of the Principal Investigators.  

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 2 of 53 
 
Table of Contents 
 
Table of Contents ........................................................................................................................... 2 
1 
Trial Registration .................................................................................................................... 6 
1.1 
Data set .......................................................................................................................... 6 
1.2 
Glossary of abbreviations and terms .............................................................................. 8 
2 
Protocol Version ..................................................................................................................... 9 
3 
Funding ................................................................................................................................... 9 
4 
Administrative information .................................................................................................... 9 
4.1 
Investigators ................................................................................................................... 9 
4.11 
Contributions .............................................................................................................. 9 
4.2 
Rapid Access Addiction Medical (RAAM) Clinics .......................................................... 10 
4.21 
Administrative .......................................................................................................... 10 
4.22 
Sites .......................................................................................................................... 10 
4.3 
Trial sponsor ................................................................................................................. 11 
4.31 
Contact information ................................................................................................. 11 
4.32 
Administrative .......................................................................................................... 11 
4.32 
Roles and responsibilities ......................................................................................... 11 
4.32a 
Trial sponsor ..................................................................................................... 11 
4.32b 
Trial funders ..................................................................................................... 12 
4.4 
Committees .................................................................................................................. 12 
4.41 
Investigators ............................................................................................................. 12 
4.41a 
Members .......................................................................................................... 12 
4.41a 
Roles and responsibilities ................................................................................. 12 
4.42 
Trial management committee .................................................................................. 12 
4.42a 
Members .......................................................................................................... 12 
4.42b 
Roles and responsibilities ................................................................................. 12 
5 
Background and Rationale ................................................................................................... 13 
5.1 
Background .................................................................................................................. 13 
5.11 
Definition .................................................................................................................. 13 
5.12 
Epidemiology ............................................................................................................ 13 
5.13 
Treatment ................................................................................................................ 14 
5.14 
Costs ......................................................................................................................... 15 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 3 of 53 
 
5.2 
Rationale ...................................................................................................................... 16 
5.3 
Choice of Comparator .................................................................................................. 16 
6 
Hypotheses ........................................................................................................................... 17 
7 
Objectives ............................................................................................................................. 17 
7.1 
Primary ......................................................................................................................... 17 
7.2 
Secondary ..................................................................................................................... 17 
8 
Design ................................................................................................................................... 17 
9 
Study Setting ........................................................................................................................ 18 
10 
Eligibility ........................................................................................................................... 18 
10.1 
Inclusion criteria ........................................................................................................... 19 
10.2 
Exclusion criteria .......................................................................................................... 19 
11 
Interventions .................................................................................................................... 19 
11.1 
Medications .................................................................................................................. 19 
11.2 
Counselling ................................................................................................................... 20 
11.3 
Screening ...................................................................................................................... 20 
11.4 
Modifications ............................................................................................................... 20 
11.5 
Retention and adherence ............................................................................................. 21 
12 
Outcomes ......................................................................................................................... 22 
12.1 
Primary outcome measures ......................................................................................... 22 
12.11 
Opioid positivity ................................................................................................... 22 
12.11a 
Urine drug testing ............................................................................................. 23 
12.11b 
Opioid use self-reports ..................................................................................... 23 
12.12 
Healthcare utilization ........................................................................................... 24 
12.13 
Rationale for primary outcome measures ............................................................ 24 
12.2 
Secondary outcome measures ..................................................................................... 25 
12.21 
Medication satisfaction ........................................................................................ 25 
12.22 
Quality of life ........................................................................................................ 26 
12.23 
Clinic retention ..................................................................................................... 26 
12.24 
Mortality ............................................................................................................... 26 
13 
Participant timeline .......................................................................................................... 27 
14 
Sample size ....................................................................................................................... 28 
14.1 
Rationale ...................................................................................................................... 28 
14.2 
Opioid positivity ........................................................................................................... 28 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 4 of 53 
 
14.3 
Healthcare utilization ................................................................................................... 29 
14.4 
Final sample size ........................................................................................................... 30 
15 
Recruitment ..................................................................................................................... 30 
16 
Allocation ......................................................................................................................... 31 
16.1 
Sequence generation ................................................................................................... 31 
16.2 
Concealment mechanism ............................................................................................. 31 
16.3 
Implementation ............................................................................................................ 32 
17 
Masking ............................................................................................................................ 32 
18 
Data collection ................................................................................................................. 32 
18.1 
Methods ....................................................................................................................... 32 
18.11 
Routinely collected data ....................................................................................... 32 
18.11a 
Prior to induction ............................................................................................. 32 
18.11b 
During treatment .............................................................................................. 34 
18.12 
Study-specific data ............................................................................................... 35 
18.13 
Healthcare utilization ........................................................................................... 36 
18.2 
Retention ...................................................................................................................... 37 
18.21 
Strategies .............................................................................................................. 37 
18.22 
Withdrawal ........................................................................................................... 37 
19 
Data management ............................................................................................................ 38 
20 
Statistical methods ........................................................................................................... 38 
20.1 
Outcomes ..................................................................................................................... 38 
20.11 
Primary ................................................................................................................. 39 
20.11a 
Opioid positivity ............................................................................................... 39 
20.11b 
Healthcare utilization ....................................................................................... 39 
20.12 
Secondary outcomes ............................................................................................ 39 
21 
Monitoring ....................................................................................................................... 40 
21.1 
Trial management committee ...................................................................................... 40 
21.2  
Interim analysis ............................................................................................................ 40 
22 
Harms ............................................................................................................................... 40 
23 
Auditing ............................................................................................................................ 41 
23.1 
Investigator responsibilities ......................................................................................... 41 
23.2 
Coordinating centre responsibilities ............................................................................ 41 
23.3 
Site initiation ................................................................................................................ 41 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 5 of 53 
 
23.4 
Monitoring during the study ........................................................................................ 41 
23.5 
Site close-out ................................................................................................................ 42 
23.6 
Source documents ........................................................................................................ 42 
23.7 
Study treatment ........................................................................................................... 42 
23.8 
Direct access to data and documents .......................................................................... 43 
24 
Ethics approval ................................................................................................................. 43 
25 
Protocol amendments ...................................................................................................... 44 
26 
Consent ............................................................................................................................ 44 
27 
Confidentiality .................................................................................................................. 45 
28 
Declaration of Interests .................................................................................................... 45 
29 
Access to data .................................................................................................................. 45 
30 
Post-trial care ................................................................................................................... 45 
31 
Trial results and authorship ............................................................................................. 46 
32 
Reproducible research ..................................................................................................... 46 
33 
References ........................................................................................................................ 47 
34 
Appendices ....................................................................................................................... 50 
34.1 
OUD DSM-V Diagnostic Criteria for OUD ..................................................................... 50 
34.2 
Clinical Opiate Withdrawal Scale ................................................................................. 50 
34.3 
Opiate Craving Visual Analog Scale .............................................................................. 50 
34.4 
Timeline Followback questionnaire ............................................................................. 50 
34.5 
World Health Organization Quality of Life (Brief) Questionnaire ................................ 50 
34.6 
ICES Support Letter ...................................................................................................... 51 
35 
Budget .............................................................................................................................. 52 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 6 of 53 
 
1 
Trial Registration 
 
1.1 
Data set 
 
Data Category 
Information 
Primary registry and trial identifying number 
ClinicalTrials.gov  
Date of registration in primary registry 
TBD 
Secondary identifying numbers 
TBD 
Source(s) of monetary or material support 
N/A 
Primary sponsor 
Royal Victoria Regional Health Centre 
Research Institute 
Contact for public queries 
Philip Wong NP, MN [wongp@rvh.on.ca] 
Contact for scientific queries 
Giulio DiDiodato MD, PhD 
[didiodatog@rvh.on.ca] 
Royal Victoria Regional Health Centre 
Research Institute, Barrie, Canada 
Public title 
Monthly versus daily buprenorphine 
formulations for treatment of opioid use 
disorder (OUD) 
Scientific title 
A pragmatic, multi-centre, open-label, 
randomized, 12-month, parallel group, 
superiority study to compare the 
effectiveness of subcutaneous 
buprenorphine depot (Sublocade®) vs daily 
sublingual buprenorphine with naloxone 
(Suboxone®) for the treatment of opioid use 
disorder (STOP IT) 
Country of recruitment 
Canada 
Health condition/problem studied 
Agonist treatment, opioid use disorder 
Intervention 
Experimental: Sublocade® 
Active Comparator: Suboxone® 
Key Inclusion and exclusion criteria 
Ages eligible: 18 to 65 years 
Sexes eligible: Male; Female; Other 
OUD eligible: Moderate-to-severe OUD as 
defined by the Diagnostic and Statistical 
Manual of Mental Disorders – Fifth Edition 
(DSM-V) 
Induction/Stabilization therapy: Started and  
stabilized on Suboxone® (8mg/2mg to 
24mg/6mg) for ≥7 days as determined by the 
following criteria: 
1) No allergic reaction to buprenorphine, and 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 7 of 53 
 
2) Clinical Opiate Withdrawal Scale score ≤12 
(scale:0-48), and  
3) Opiate Craving Visual Analog Scale score 
≤20 (scale:0-100) 
Inclusion criteria:  
1) Written informed consent prior to 
enrolment  
2) Must have an active Ontario Health 
Insurance Plan number 
3) Contact information (telephone) available 
4) Must have drug insurance coverage for 
either medication for duration of study or 
demonstrate ability to pay for the drug out-
of-pocket 
Exclusion criteria: 
1) Receiving any investigational drug for OUD 
in previous 4 weeks 
2) Congenital long QT syndrome or QT 
prolongation at baseline 
Study type 
Interventional 
Allocation: randomized 1:1 
Intervention model: parallel assignment 
Masking: open-label 
Primary purpose: comparative effectiveness 
Date of first enrollment 
November 1, 2022 
Target sample size 
90 
Recruitment status 
Not yet started 
Primary outcome(s) 
1) Difference in proportion of relapse-free 
weeks (time-frame; 12 months) 
2) Difference in incidence rates of opioid-
related healthcare utilization (time-frame; 12 
months) 
Key secondary outcome(s) 
1) Difference in Medication Satisfaction 
Questionnaire scores 
2) Difference in World Health Organization 
Quality of Life – BREF Questionnaire scores 
3) Difference in proportion of patients who 
attend ≥80% of scheduled clinic visits 
4) Difference in opioid-related mortality 
proportions 
 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 8 of 53 
 
1.2 
Glossary of abbreviations and terms 
 
CADTH  
 
Canadian Agency for Drugs and Technologies in Health 
COWS  
 
Clinical Opiate Withdrawal Scale 
DSM-V  
 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
ICD-10-CA 
International Statistical Classification of Diseases and Related Health 
Problems, Tenth Revision, Canada 
OUD 
 
 
Opioid use disorder 
RAAM  
 
Rapid Access Addiction Medicine  
RVH 
 
 
Royal Victoria Regional Health Centre 
OAT 
 
 
Opioid agonist therapy 
ODB 
 
 
Ontario Drug Benefit 
SC-BPN-XR 
 
Monthly subcutaneous buprenorphine 
SL-BPN/NX 
 
Daily sublingual buprenorphine/naloxone 
SOPs  
 
Standard operating procedures 
VAS 
 
 
Visual analog scale 
WHOQOL-BREF 
World Health Organization Quality of Life – Brief 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 9 of 53 
 
2 
Protocol Version 
 
2021-November-30 
Original (version 1.0) 
2022-February-02 
Revised (version 2.0) 
2022-April-11 
Revised (version 3.0) 
2022-May-02 
Revised (version 3.1) 
2022-June-06 
Revised (version 3.12) 
2022-Aug-10 
Revised (version 4.0) 
3 
Funding 
 
All clinical services provided at the study sites (RAAM clinics), including staff salaries, equipment 
and consumables will be provided by the Royal Victoria Regional Health Centre.  While there is 
no funding currently available for this study, some funding may be provided by the Royal 
Victoria Regional Health Centre Foundation at some later date to support data abstraction from 
the Institute for Clinical Evaluative Sciences. 
4 
Administrative information 
 
4.1 
Investigators 
 
Philip Wong NP, MN, CNCCI (Principal Investigator) 
Nurse Practitioner 
North Simcoe Muskoka RAAM Services 
Royal Victoria Regional Health Centre 
70 Wellington St. W., Barrie, Ontario, Canada, L4N 1K4 
Email: wongp@rvh.on.ca 
Telephone: (705)728-9090 extension 24327 
 
Giulio DiDiodato MD, PhD (Research Physician/Biostatistician) 
Chief Research Scientist 
Royal Victoria Regional Health Centre 
Email: didiodatog@rvh.on.ca 
Telephone: (705)728-9090 extension 45641 
Assistant Professor 
Department of Health Research Methods, Evidence & Impact 
McMaster University 
1280 Main Street West, 2C, Hamilton, Ontario, Canada, L8S 4K1 
didiodatog@mcmaster.ca 
 
 
4.11 
Contributions 
 
PW conceived of the study. 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 10 of 53 
 
PW, GD initiated and revised the study design and protocol. 
PW, GD approved the protocol. 
 
4.2 
Rapid Access Addiction Medical (RAAM) Clinics 
 
4.21 
Administrative 
 
Brian Irving RCS, RP, CACII, CMP 
Manager, Addiction Services 
North Simcoe Muskoka RAAM Services 
Adult Mental Health Day Program & Community Treatment  
Royal Victoria Regional Health Centre 
70 Wellington St. W., Barrie, Ontario, L4N 1K4 
Email: irvingbr@rvh.on.ca 
 
Telephone: (705)728-9090 extension 24311 
 
James Shaver, MD 
North Simcoe Muskoka RAAM Services 
Medical Director, Mental Health & Addictions Program 
Royal Victoria Regional Health Centre 
70 Wellington St. W., Barrie, Ontario, L4N 1K4 
Email: shaverj@rvh.on.ca  
Telephone: (705)790-0060 
 
4.22 
Sites 
 
RAAM Clinic (Barrie) 
70 Wellington Street West, Lower Level 
Barrie, Ontario, Canada, L4N 1K4 
Telephone: (705)797-3095 
 
RAAM Clinic (Orillia) 
169 Front Street South, 1st Floor, The Common Roof 
Orillia, Ontario, Canada, L3V 4S8 
Telephone: (705)797-3095 
 
RAAM Clinic (Midland) 
287 Bayshore Drive, Second floor, Chigamik Community Health Centre 
Midland, Ontario, L4R 0B7 
Telephone: (705)797-3095 
 
RAAM Clinic (Wasaga Beach) 
14 Ramblewood Drive, Unit#202, South Georgian Bay Community Health Centre 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 11 of 53 
 
Wasaga Beach, Ontario, L9Z 0C4 
Telephone: (705)797-3095 
 
4.3 
Trial sponsor 
 
4.31 
Contact information 
 
Trial sponsor: Royal Victoria Regional Health Centre (RVH) Research institute 
Sponsor’s Reference: 119129260 RR 0001 (Charitable Registration Number) 
Contact name: Jesse McLean PhD 
Address: Health Library, Office 2218c, Royal Victoria Regional Health Centre, 201 Georgian 
Drive, Barrie, Ontario, L4M 6M2 
Telephone: 705-728-9090 extension 41350 
Email: mcleanje@rvh.on.ca  
 
4.32 
Administrative 
 
Jesse McLean PhD 
Manager, RVH Research Institute 
Royal Victoria Regional Health Centre 
Health Library, Office 2218c, 201 Georgian Drive, Barrie, Ontario, L4M 6M2 
Email: mcleanje@rvh.on.ca 
Telephone: 705-728-9090 extension 41350 
 
Christine DiMarco  
Clinical Trials Coordinator, RVH Research Institute 
Royal Victoria Regional Health Centre 
Research Office, 201 Georgian Drive, Barrie, Ontario, L4M 6M2 
Email: dimarcoc@rvh.on.ca 
Telephone: (705) 728-9090 extension 43341 
 
Kelly Cruise BHSc, CCRP 
Clinical Research Coordinator, RVH Research Institute 
Royal Victoria Regional Health Centre 
Research Office, 201 Georgian Drive, Barrie, Ontario, L4M 6M2 
Email: cruisek@rvh.on.ca 
Telephone: (705) 728-9090 extension 45639 
 
4.32 
Roles and responsibilities 
 
4.32a Trial sponsor 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 12 of 53 
 
The trial sponsor has no role in the design, analyses, interpretation of the data, writing or 
decision to report the study results.  The sponsor will support study coordination and 
execution, including informed consent, enrollment, randomization, follow-up, administering 
questionnaires, data collection and storage, and monitoring.  The study sponsor is responsible 
for taking all reasonable steps to ensure proper conduct of the clinical trial protocol, and that 
the clinical trial is performed in accordance with the International Council for Harmonisation for 
Good Clinical Practice (https://www.ich.org/page/efficacy-guidelines#6) and all applicable 
regulatory requirements.  
 
4.32b Trial funders 
 
The funding source (Royal Victoria Regional Health Centre/Royal Victoria Hospital Foundation) 
has no role in the design, execution, analyses, interpretation of the data, writing or decision to 
report the study results. 
 
4.4 
Committees  
 
4.41 
Investigators 
 
4.41a Members 
 
Principal investigator: Philip Wong  
Biostatistician: Giulio DiDiodato 
 
4.41a Roles and responsibilities 
 
Design, conduct and analysis of STOP-IT study 
Preparation of protocol and revisions 
Preparation of electronic case report forms 
Publication of study reports 
Members of the trial and data management committees 
 
4.42 
Trial management committee 
 
4.42a Members 
 
Philip Wong [Chair], Dr. Jesse McLean, Christine DiMarco, Kelly Cruise, Dr. James Shaver, Brian 
Irving 
 
4.42b Roles and responsibilities 
 
Study planning 
Serious unexpected suspected adverse events reporting 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 13 of 53 
 
Responsible for master file 
Site visits and monitoring 
Data quality and audit 
5 
Background and Rationale 
 
5.1 
Background 
 
5.11 
Definition 
 
Opioid use disorder (OUD) is defined in the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-V) as a “problematic pattern of opioid use leading to clinically 
significant impairment or distress.”1  At least 2 of 11 pre-specified criteria must be present 
within a 12-month period to fulfil the DSM-V clinical definition.  The DSM-V also uses the 
number of criteria present to categorize the severity of OUD, with mild OUD defined as having 
2-3 criteria present, moderate OUD defined as having 4-5 criteria present, and severe OUD 
defined as having ≥6 criteria present.   
 
5.12 
Epidemiology 
 
Opioid use disorder and opioid-related deaths are increasing in Ontario and Canada.2,3  
Compared to 2016, the age-adjusted opioid-related mortality rates in 2020 have increased by 
161% in Ontario to 16.5 per 100 000 population and 114% in Canada to 16.7 per 100 000 
population.  Over 90% of these deaths were non-intentional, with 87% of all deaths involving 
fentanyl or fentanyl analogues.  The majority of deaths occurred in males (75%) between the 
ages of 20 to 59 (88%).  In the North Simcoe Muskoka Local Health Integration Network, the 
study region, there were 128 opioid-related deaths in 2020, an increase of 191% from 2016.   
 
Like deaths, opioid-related healthcare utilization as measured by hospitalization and emergency 
department visits have also been increasing over the same time period.3,4  Compared to 2016, 
the age-adjusted opioid-related hospitalization rates in 2020 have increased by 19.8% in 
Ontario to 16.3 per 100 000 population and 5.9% in Canada to 17.8 per 100 000 population.  
Emergency room visits have increased by 166% during the same time period in Ontario to 84.5 
per 100 000 population.  In the North Simcoe Muskoka Local Health Integration Network, there 
were 622 emergency room visits and 128 hospitalizations that were opioid-related in 2020.  The 
majority of hospitalizations and emergency room visits occurred in males (60%) between the 
ages of 20 to 59 (73%).  The median length of hospitalization from 2016 to 2020 has remained 
unchanged at 3 days (Range 1 to 207 days), with an average cost per hospitalization of $9 626 
(CDN) (Range $26 to $296 831) (Source: The Ontario Case Costing Initiative; N=889 cases; 
Reporting period 2017 to 2018; ICD-10-CA codes F11.0 to F11.9 & T40.2; Accessed November 8, 
2021). 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 14 of 53 
 
5.13 
Treatment   
 
Opiate substitution treatment with either full (methadone) or partial (buprenorphine) opioid 
agonist therapy (OAT) has been shown to reduce self-reported opioid use or opiate positive 
urine drug tests compared to detoxification or psychological treatments.5,6  Opiate substitution 
treatment is also associated with a reduced risk of death.7,8  Relative adherence to OAT is 
highest when delivered as part of a comprehensive treatment program.6,9  Rapid access 
addiction medicine (RAAM) clinics have been established in Ontario to facilitate access to 
opiate substitution treatment as part of a comprehensive substance use disorder program.10  
 
There are 2 main opioid agonists used to treat OUD, methadone and buprenorphine.11  
Buprenorphine has been approved by Health Canada for use in OUD, and is available in 
immediate (Suboxone®) and extended-release (Sublocade®) formulations.  Monthly 
subcutaneous buprenorphine (SC-BPN-XR) has been shown to be non-inferior to daily 
sublingual buprenorphine/naloxone (SL-BPN/NX) for medication adherence and treatment 
retention.12  Other extended-release buprenorphine formulations have also demonstrated 
similar results (Table 1).13,14  The rationale for extended-release buprenorphine is to minimize 
the risk of suboptimal medication adherence, diversion, intravenous misuse and unintended 
exposures associated with buprenorphine/naloxone films and tablets.6 
 
Table 1: Summary of comparative effectiveness of extended-release versus immediate 
release buprenorphine 
 
Author 
(Country/year)  
Buprenorphine 
Time 
Period 
(weeks) 
Primary Outcome 
Effect size 
(extended vs 
immediate) 
(mean difference 
(95% CI)) 
Extended (N) 
Immediate (N) 
Rosenthal et al. 
(USA/2013) 
Implants (4 x 
80mg) (N=114) 
SL-BPN/NX (12-
16 mg/d) 
(N=119) 
24 
Mean % negative 
uds1 + self-report 
opioid use (weeks 1 
to 24) 
31% vs 33.1%  
(-2.1 (-10.7, 6.2)) 
Rosenthal et al. 
(USA/2016) 
Implants (4 x 
80mg) (N=84) 
SL-BPN/NX (≤8 
mg/d) (N=89) 
26 
Responder 
proportion2 
96.4% vs 87.6% 
(8.8% (0.009, ∞)) 
Lofwall et al. 
(USA/2018) 
SC-BPN (8-32 
mg/week) 
(weeks 1-11) 
SC-BPN (64-160 
mg/month) 
(weeks 12-24) 
(N=215) 
SL-BPN/NX (4-
24 mg/d) 
(weeks 1-11) 
SL-BPN/NX (8-
32 mg/d) 
(weeks 12-24) 
(N=213) 
24 
Mean % negative 
uds + self-report 
opioid use 
 
Responder 
proportion3 
35.1% vs 28.4% 
(6.7% (-0.1, 13.6)) 
 
 
37.0% vs 31.0% 
(3.0% (-4.0, 9.9)) 
1 uds=urine drug screen; missing uds imputed as positive; denominator was 72 uds (3 per week x 24 weeks) 
2 responder proportion defined as participant with ≥4 of 6 months with negative uds + negative self-report (uds + 
self-report scheduled every month plus 4 random uds; total 10 uds + self-reports); all patients had been on SL-
BPN/NX ≥ 12 months prior to enrollment; missing uds imputed as positive or negative with a 20% penalty for 
positive in extended-release group 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 15 of 53 
 
3 responder proportion defined as participant with ≥ 2 weeks uds/self-report negative of weeks 9-11 + uds/self-
report negative at week 12, plus ≥ 5 weeks uds/self-report negative of weeks 12-24 + uds/self-report negative 
from weeks 21-24; missing uds imputed as positive 
 
In Ontario, OAT prescriptions and prescribers have been increasing.15  Compared to 2016, 
buprenorphine prescription rates have increased by 61% to 1.91 patients per 1 000 population.  
While methadone still represents the most commonly prescribed OAT in Ontario, with a 
prescription rate of 2.88 patients per 1 000 population, its use has declined by 9% since 2016.  
The number of OAT prescribers in Ontario in 2020 was 4887, an increase of 112% from 2016.  In 
2020, 87.8% of OAT prescribers prescribed only buprenorphine (71.4%) or both buprenorphine 
and methadone (16.4%), while the remainder (12.2%) prescribed only methadone.  In the North 
Simcoe Muskoka Local Health Integration Network, buprenorphine and methadone prescription 
rates are higher than the provincial average at 2.08 and 4.13 patients per 1 000 population, 
respectively.  The number of buprenorphine only (N=259), buprenorphine and methadone 
(N=140) and methadone only (N=143) prescribers has also increased in the study region, with 
the largest increase in the buprenorphine only group (+123% from 2016 to 2020).   
 
5.14 
Costs 
 
The Canadian pharmaceutical costs of Sublocade® and Suboxone® differ substantially (Table 
2).16 
 
Table 2: Canadian costs of buprenorphine-based OAT 
 
Drug 
Health Canada 
Approval Date 
Dose 
Monthly Costs 
($CDN) 
Sublocade® 
November 21, 2018 
100 mg/0.5 ml 
300 mg/0.5 ml 
550 
550 
Suboxone® 
August 25, 2015 
2 mg/0.5 mg 
8 mg/2 mg 
72 
77 
 
The costs of both drugs are covered through the Ontario Drug Benefit (ODB) program.  
However, Sublocade® is limited for use in patients with moderate- to severe-OUD who have 
been stabilized on 8 to 24 mg/day of transmucosal buprenorphine/naloxone for at least 7 days 
and who are also receiving counselling and psychosocial supports by experienced healthcare 
providers in the diagnosis and management of OUD.  Eligibility criteria for the ODB program are 
limited to patients aged 25 years and under or 65 years and older; or are enrolled in the Ontario 
Works, Ontario Disability Support Program or Trillium Drug Program; or are receiving 
professional home and community services; or are living in a long-term home or a home for 
special care.  As a result, the majority of patients meeting criteria for Sublocade® use must pay 
for the drug out-of-pocket resulting in significant restriction to access for this population that 
has a high burden of chronic homelessness and poverty. 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 16 of 53 
 
A recent pharmacoeconomic report by the Canadian Agency for Drugs and Technologies in 
Health (CADTH) concluded that the current evidence base for supporting cost-effectiveness of 
Sublocade® over buprenorphine/naloxone is limited by the absence of studies directly 
comparing the effectiveness of the two treatments on clinically important outcomes such as 
healthcare utilization.16  Additionally, the comparative effectiveness studies reviewed in Section 
5.13 were all conducted in the United States, making inferences about Canadian settings such 
as the RAAM clinics and their clientele uncertain.  With limited evidence and significant 
uncertainty, the CADTH analysis suggested that a price reduction of at least 73% would be 
required for Sublocade® to be a cost-effective alternative to buprenorphine/naloxone.   
 
5.2 
Rationale 
 
An extended-release OAT formulation that can be safely delivered in RAAM clinics across 
Canada might prevent costly healthcare and poor outcomes in hundreds, if not, thousands of 
patients.  A real-world (pragmatic) randomised study is therefore needed to compare the 
treatment effectiveness of Sublocade® versus Suboxone® in Canadian patients attending RAAM 
clinics for OAT for moderate- to severe-OUD.  This study is needed to demonstrate the superior 
benefits of Sublocade® on important clinical outcomes such as reduced opioid and healthcare 
utilization in order to demonstrate its cost-effectiveness and justify expanded access to 
Sublocade® for this at-risk population. 
 
5.3 
Choice of Comparator 
 
According to the Canadian and Ontario guidelines for OAT, transmucosal  
buprenorphine/naloxone is the first-line treatment for moderate- to severe-OUD.6,17  
Suboxone® will be the active comparator in this study.  The medically active ingredients in 
Suboxone® are buprenorphine, a partial 𝜇-opioid receptor agonist, and naloxone, a 𝜇-opioid 
receptor antagonist.  Suboxone® (buprenorphine/naloxone) formulations approved for use in 
Canada come in sublingual tablets (SL) and soluble films (SF) in doses ranging from 2 mg/0.5 mg 
(SL/SF), 4 mg/1 mg (SF), 8 mg/2 mg (SL/SF), 12 mg/3 mg (SL/SF) and 16 mg/4 mg (SL).  Both 
formulations can be administered sublingually, but the SF can also be administered buccally.  
The usual treatment course requires induction, stabilization, and maintenance phases, with the 
ultimate goal being weaning to abstinence if possible.  For those patients attending any one of 
the study RAAM clinics who have been started on treatment with Suboxone® for moderate- to 
severe-OUD after discussion with their healthcare provider, those who have been stabilized on 
8 mg to 24 mg/day of buprenorphine for at least 7 days will be eligible to be enrolled in the 
study.  For those who are enrolled in the study and are randomly allocated to continue 
receiving Suboxone® for the remainder of the study period, their ongoing Suboxone® 
maintenance dosing will be determined by themselves and their healthcare provider through 
the usual processes of clinical care. In general, treatment with Suboxone® is directly observed 
by the pharmacist in a community pharmacy experienced with OAT during the induction and 
stabilization phases.  Once stabilized, the patient and provider can negotiate unsupervised 
Suboxone® administration through varying amounts of take-home doses during the 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 17 of 53 
 
maintenance phase.  Initially, the unsupervised intervals are short, typically one to several days, 
and depending on patient compliance with treatment that includes counselling and RAAM clinic 
visits every one to two weeks, abstinence from other non-prescription opioid and non-opioid 
substances as determined through self-report and urine drug screens, and evidence of absence 
of withdrawal symptoms, the take-home intervals may be extended.  Breakthrough doses of 
Suboxone® may also be prescribed during the maintenance phase if the patient is experiencing 
withdrawal symptoms.  It is not expected that any patient in the maintenance phase of OAT 
with either Suboxone® or Sublocade® during the 12-month study period will be ready for an 
attempted wean to abstinence. 
6 
Hypotheses 
 
In patients with moderate- to severe-OUD between the ages of 18 to 65 years old who seek 
care or are referred to one of the four RAAM clinics in the North Simcoe Muskoka Local Health 
Integrated Network for opioid-substitution therapy and are stabilized on Suboxone®, 
subsequent maintenance therapy with Sublocade® (intervention) versus Suboxone® (control) 
for a period of 12-months will be superior for reducing opioid positivity (as determined by 
proportion of negative urine drug screens and self-reports) and healthcare utilization (as 
determined by the total number of ER visits and hospital days per patient days exposure)  
7 
Objectives 
 
7.1 
Primary 
 
1) To compare the effect of Sublocade® versus Suboxone® on reducing non-prescription opioid 
utilization in patients with moderate- to severe-OUD  
 
2) To compare the effect of Sublocade® versus Suboxone® on reducing healthcare utilization in 
patients with moderate- to severe-OUD 
 
7.2 
Secondary 
 
1) To compare the effect of Sublocade® versus Suboxone® on improving patient satisfaction 
 
2) To compare the effect of Sublocade® versus Suboxone® on improving patient quality of life 
 
3) To compare the effect of Sublocade® versus Suboxone® on clinic retention 
 
4) To compare the effect of Sublocade® versus Suboxone® on patient mortality 
8 
Design 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 18 of 53 
 
The STOP-IT trial is designed as a pragmatic, multi-centre, randomised, controlled, open-label, 
superiority study with two parallel groups and primary endpoints of opioid positivity and 
healthcare utilization at 12 months after enrollment.  Randomization will be performed with a 
1:1 allocation ratio using a stratified, permuted-block group schema according to the following 
strata (no fixed ratio):   
1) RAAM clinic site (Barrie, Orillia, Midland, Wasaga Beach) 
2) Severity of OUD according to DSM-V criteria (moderate vs severe) 
9 
Study Setting 
 
The four RAAM clinics in the North Simcoe Muskoka Local Health Integrated Network will 
recruit patients for the study.  The North Simcoe Muskoka Local Health Integrated Network is a 
provincial regional health authority mandated to plan, integrate and fund local health services 
across the District of Muskoka, Simcoe County and Grey County.  This region serves a 
population of 479 471 (2015), representing 3.5% of the province of Ontario’s population.  The 
Network distributes over $880 million (CDN) in funding to 61 unique health service provider 
organizations that include 7 hospitals, 21 long-term care homes, 3 community centres, 23 
community support services and 7 community health centres.  In partnership with the Simcoe 
Muskoka District Health Unit, the Network developed the Simcoe Muskoka Opioid Strategy in 
2017 in response to the higher-than-average provincial rates of opioid-related morbidity and 
mortality being experienced in the region.18  Increased access to OAT through the RAAM clinics 
is an essential component of that strategy (p.38). 
 
The four RAAM clinics are located in the cities of Barrie, Orillia, Midland and Wasaga Beach.  
These clinics are part of a provincial strategy to remove barriers to access for addiction services 
and provide a more patient-centred model of addiction services.18  There are currently 54 
RAAM clinics located across Ontario, with the plan to continue to open new RAAM clinics across 
the province.  All the RAAM clinics are based on a similar service model.10  The four study clinics 
are owned and managed by the Royal Victoria Regional Health Centre, a 388-bed acute care 
community hospital in Barrie.  Patients can self-refer or be referred for addiction services from 
any healthcare provider.  The clinics provide voluntary outpatient services that include medical 
and psychosocial treatments for substance use disorders.  The clinics are staffed by an 
interdisciplinary team of physicians, nurse practitioners, registered nurses, registered practical 
nurses, social workers, addiction counsellors who work together to create a unique treatment 
plan for each patient.  Pharmacotherapy for alcohol and opioid use disorders is available.  The 
clinics do not provide treatment for acute or decompensated mental health illness, treatment 
for chronic pain disorders or serve as safe injection sites.  Since April 1, 2021, there have been 
801 consultations, of which 346 involved prescription and non-prescription opioid use.   
10 
Eligibility 
 
Patients must provide written, informed consent before any study procedures occur. 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 19 of 53 
 
10.1 Inclusion criteria 
 
Patients eligible for the trial must comply with all of the following at randomization: 
 
1. Ages 18 to 65 years old 
2. OAT indicated for moderate- to severe-OUD1 
3. Attend a RAAM clinic in the North Simcoe Muskoka Local Health Integrated Network for 
opiate substitution treatment  
4. Successfully completed induction and stabilization OAT with Suboxone® tablet or film defined 
as receiving 8mg/2mg to 24mg/6mg of Suboxone® for ≥7 days with no evidence of allergic 
reaction to Suboxone®, Clinical Opiate Withdrawal Scale19 (COWS) score ≤12 (scale:0-48) for 
≥24 hours, and Opiate Craving Visual Analog Scale20 (VAS) score ≤20 (scale:0-100)) for ≥24 hours 
5. Must have an active Ontario Health Insurance Plan number 
6. Must have a telephone that can receive calls, text messages or emails 
7. Must have drug insurance coverage for either medication for duration of study or 
demonstrate ability to pay for the drug out-of-pocket 
 
10.2 Exclusion criteria 
 
1. Receiving any investigational drug for OUD in previous 4 weeks 
2. Congenital long QTc syndrome or QTc prolongation at baseline by electrocardiogram (QTc 
≥450 milliseconds in men and QTc ≥470 milliseconds in women) 
3. Pregnant or lactating women 
4. Women of childbearing potential who are not using an effective and reliable method of 
contraception 
11 
Interventions 
 
11.1 Medications 
 
Eligible patients will be randomly allocated in a 1:1 ratio between Suboxone® and Sublocade®.  
Both study drugs will be provided to participants in their commercially available forms.  For 
those patients who are not eligible for drug coverage under the Ontario Drug Benefit Plan or 
other insurance plan, eligible patients must demonstrate the ability to  pay for either 
medication out-of-pocket. The commercially available drugs will be provided by the RAAM 
clinics (Sublocade®) or pharmacies (Suboxone®) as per the usual process of care.  This is an 
open-label study so no changes in labelling or packaging will take place, and both drugs will be 
stored, handled, administered and disposed of in accordance with the manufacturer’s 
recommendations and the RAAM clinics’ and pharmacies’ standard operating procedures 
(SOPs).  This is a pragmatic, comparative effectiveness study so the management of the 
participants and their medications in the RAAM clinics will be left up to the discretion of the 
RAAM healthcare personnel who have all received training and are experienced in the 
diagnosis, management and treatment of OUD. 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 20 of 53 
 
 
For eligible patients randomly allocated to Sublocade®, the first dose will be administered at 
the time of randomization (Day 0).  Sublocade® comes in two formulations, 100 mg and 300 mg 
buprenorphine doses in a pre-filled syringe.  Sublocade® administration is by subcutaneous 
injection in the abdomen.  Sublocade® is administered at intervals ≥26 days.  For patients 
randomly allocated to Sublocade®, they will receive the 300 mg dose for the first 2 months, 
followed by the 100 mg dose every month until the end of the 12-month period.  All 
Sublocade® doses will be administered in the RAAM clinics by trained personnel according to 
SOPs.  All patients receiving Sublocade® will have their vital signs monitored every 5 minutes for 
15 minutes after the injection before leaving the clinic.   
 
For eligible patients randomly allocated to Suboxone®, the first study dose will be administered 
at the time of randomization (Day 0) and will match the Suboxone® type (tablet versus film), 
route (sublingual versus buccal) and dose used for stabilization prior to study enrollment.  For 
the first 2 weeks of the study period, all Suboxone® administration will be directly observed at 
community pharmacies by trained personnel according to the usual standard of care.  
Subsequent to this period, healthcare providers and participants will develop a care plan for 
ongoing directly observed therapy vs unsupervised take-home dosing according to usual 
standard of care.  
 
11.2 Counselling 
 
For eligible patients enrolled in the study, each will receive individual patient counselling for 
addictions, mental health and trauma by trained RAAM clinic personnel at each clinic visit 
according to the usual standard of care.  In addition, each participant will be provided with links 
to community social support services.  For those participants who need it, connection to a 
primary care provider will be provided. 
 
11.3 Screening 
 
For eligible patients enrolled in the study, each will receive pregnancy screening at regular 
intervals.  Female patients of child-bearing age will also be questioned about contraceptive use, 
and counselled about the potential risks of OUD treatment in pregnancy.  Screening for illicit 
drug use will be done using a combination of a validated self-reporting tool21 and urine drug 
testing at each clinic visit.  Screening for opioid withdrawal19 and craving20 will be done at each 
clinic visit.  Weight, vital signs and mental status22 will be screened at each clinic visit.   
 
 
11.4 Modifications 
 
For eligible patients randomly allocated to Sublocade®, missed doses can be administered up to 
42 days after the last dose.  For those with longer intervals between Sublocade® doses, it will 
be up to the discretion of the RAAM clinic healthcare providers whether repeated induction 
and stabilization with Suboxone® is required, and if Sublocade® treatment should be re-

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 21 of 53 
 
initiated.  At the discretion of the RAAM clinic healthcare providers, some participants may 
receive breakthrough doses of Suboxone® and/or an increased maintenance dose of 
Sublocade® of 300 mg per month instead of 100 mg per month as clinically indicated to prevent 
opioid cravings (VAS ≥ 21) or withdrawal (COWS ≥ 5) symptoms. In some cases, Sublocade® 
doses may need to be reduced or discontinued due to adverse effects.   
 
For eligible patients randomly allocated to Suboxone®, at the discretion of the RAAM clinic 
healthcare providers, some participants may receive breakthrough doses of Suboxone® and/or 
increased maintenance doses of Suboxone® as clinically indicated to prevent opioid cravings 
(VAS ≥ 21) or withdrawal (COWS ≥ 5) symptoms.  Daily dose of Suboxone® should not exceed 24 
mg buprenorphine.  In some cases, Suboxone® doses may need to be reduced or discontinued 
due to adverse effects.  
 
For eligible patients with abnormal vital signs (a change from baseline measurements and any 
of the following: systolic blood pressure ≤ 90 mm Hg OR mean arterial blood pressure ≤ 55 mm 
Hg OR heart rate ≥ 130 beats per minute OR temperature ≥ 38.1oC OR ≤ 36oC OR respiratory 
rate ≤ 8 breaths per minute OR ≥ 30 breaths per minute or mental status (Glasgow coma scale 
≤14), RAAM healthcare personnel will investigate the causes for these abnormalities prior to 
consideration of buprenorphine dosing, and make all necessary arrangements for medical 
management of the patient. 
 
For eligible patients who have either a positive urine drug screen, illicit drug use by self-report, 
or refuse to submit to these screens, individualized patient counselling with an addictions 
counsellor will attempt to understand the underlying reasons for relapse or refusal to screen as 
per usual standard of care.  RAAM healthcare personnel will take into consideration opioid 
positivity (either positive urine drug screen or self-report) or refusal to screen prior to the 
administration of study medications. 
 
For eligible patients with a positive pregnancy test after a negative pre-enrollment test, RAAM 
healthcare personnel will counsel the patient about the potential negative effects 
(teratogenicity, neonatal opioid withdrawal syndrome) of ongoing study medication treatment, 
and the options for alternative management of OUD as per usual standard of care.  
  
11.5 Retention and adherence 
 
For eligible patients enrolled in the study, retention and adherence interventions will include: 
 
1) Phone call 2 days before each scheduled clinic visit to determine if there will be any barriers 
to attending the scheduled visit, and working on solutions to remove these barriers to maximize 
compliance with scheduled visits 
2) Assistance to complete scheduled questionnaires (quality of life and medication satisfaction) 
either in clinic or remotely 
3) Provide in-home laboratory and electrocardiographic services as needed if a patient cannot 
travel to the lab site 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 22 of 53 
 
4) Instructions about taking study tablets/films including dose timing, route, storage, and what 
to do in the event of a missed dose 
5) All participants will be provided with the RAAM clinic’s nurse practitioner’s contact number 
with instructions to call if experiencing problems possibly related to study treatment such as 
symptoms or lost pills. 
12 
Outcomes 
 
12.1 Primary outcome measures 
 
12.11 Opioid positivity 
 
Difference in proportions of relapse-free weeks (RFWs) at 12-months from the date of 
randomization, where relapse-free weeks are defined by the cumulative number of weeks 
alive during the study period in which there was a negative urine drug screen and negative 
self-report for non-prescribed opioids.  The potential number of RFWs for each patient is the 
cumulative number of weeks that the patient is alive during the 12-month study period, with a 
maximum of 48 weeks.  A week is defined as a consecutive 7-day period starting on the day of 
the week that randomization occurred.  A patient is considered to have ‘completed’ a week as 
long as they are alive for ≥ 1 day of that week.  For example, if a patient is randomized on a 
Tuesday, and subsequently dies on a Thursday of the 32nd week, the patient will have been 
considered to have been alive for 32 weeks.  The denominator used in estimating the 
proportion of RFWs will be the total number of weeks that the patient was alive during the 
study period.  Vital statistics for all participants (date and year of death) will be available 
through linkage with the Office of the Registrar General of Ontario database.23  The cumulative 
number of RFWs alive will be used as the numerator in estimating the proportion of RFWs.  
Scheduled urine drug testing and self-reports will occur every 2 weeks during the study period 
starting in week 2 from randomization. Imputation of missing data will occur for those weeks in 
which a urine drug screen/self-report was not scheduled according to the results of the 
subsequent week’s urine drug screen/self-report.  For example, if a urine drug screen/self-
report was not scheduled for week 11, but a scheduled urine drug screen/self-report was done 
on week 12 and week 12 met the criteria for a RFW, then week 11 would be imputed as a RFW 
(Figure 1).  Similarly, for weeks with scheduled urine drug screen/self-reports that are missed, 
that week and the preceding week in which there was no scheduled urine drug screen/self-
report will not be counted as RFWs (for example, see Figure 1, week 17 and 18).  In the 
hypothetical patient represented in Figure 1, 20 urine drug screens/self-reports were 
completed, with 5 positive and 15 negative urine drug screens/self-reports, resulting in 30 
cumulative RFWs over the 48-week study period, or a proportion of RFWs of 0.625. 
 
 
 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 23 of 53 
 
Figure 1: Schematic for a hypothetical participant and measurement of RFWs 
 
Variable  
Weeks 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
UDS/Self-
report1 
 
- + - - + 
- 
- 
+ 
na 
- 
- 
+ 
- 
na 
- 
- 
+ 
- 
na 
- 
na 
- 
- 
- 
RFWs 
 
2 
2 
4 
6 
6 
8 
10 
10 
10 
12 
14 
14 
16 
16 
18 
20 
20 
22 
22 
24 
24 
26 
28 
30 
1  - = negative urine drug screen (uds) and self-report , + = positive urine drug screen and/or self-report, na=not available/missing 
 
12.11a Urine drug testing 
 
The RAAM clinics perform on-site presumptive24 urine drug testing using Health Canada-
approved, lateral flow immunoassay-based point-of-care tests (Rapid Response™ Multi Drug 
Test Panel, BNTX Inc., Product code: D-1P-07).  This qualitative urine assay uses established cut-
off values for addictive substances or their metabolites to identify their presence (positive) or 
absence (negative).  The urine assay can detect the following addictive substances/metabolites:   
benzodiazepines, buprenorphine, cocaine, ethyl glucuronide, fentanyl, morphine, oxycodone, 
EDDP, hydromorphone, and methamphetamine.  In addition, the assay also measures urine pH 
and urine creatinine to screen for specimen integrity.  All results are available in 5 minutes.  All 
RAAM clinic healthcare providers must receive training and certification before use of this 
assay, and biennial re-certification is required.  Internal and procedural controls are included in 
the assay to indicate proper volume of specimen added and that wicking has occurred.  In 
addition, the Royal Victoria Regional Health Centre Laboratory Services is responsible for 
quality control checks with each new lot number prior to release to the RAAM clinics for use.  
Definitive24 urine drug testing will not be used to validate the results of any urine drug test, but 
at the discretion of the RAAM clinic healthcare providers, may be used to investigate 
discrepancies between presumptive urine drug test results and self-reports, or detect 
unexpected addictive substances not available through presumptive testing.  While urine 
sample collection is not directly observed by RAAM clinic healthcare providers, all urine 
samples must be collected during the clinic visit.  To reduce the risk of urine tampering, each 
urine sample is inspected for temperature, colour, smell and appearance in addition to 
measuring urine pH and urine creatinine.  Any urine sample that is considered substituted or 
invalid is discarded, and the patient will be imputed to have a positive urine drug test for that 
scheduled clinic visit.  Urine drug screens and self-reports will only occur on day of the 
scheduled clinic visit, and there will be no opportunity to provide a urine sample either before 
or after the scheduled clinic visit. 
 
12.11b Opioid use self-reports 
 
Opioid use self-reporting will accompany each scheduled urine drug test.24  Opioid use self-
reporting will be measured using the Timeline Followback questionnaire.25  This questionnaire 
will be administered by RAAM clinic healthcare personnel.  The questionnaire consists of asking 
patients to recall and document their use of any addictive substances in the questionnaire on 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 24 of 53 
 
any or all of the 7 days preceding the clinic visit.  A positive self-report will be defined as any 
report of the use of non-prescribed opioids in the preceding 7 days. 
 
12.12 Healthcare utilization 
 
Difference in incidence rates of healthcare days at 12-months from the date of randomization, 
where healthcare days represent the number of days alive and registered for an emergency 
room visit or admitted to an acute care or mental health facility for opioid-related harms or 
poisonings.  For each group, the incidence rate is calculated by dividing the total number of 
healthcare days by the total person days exposure over the study period.  The potential number 
of healthcare days for each patient is the number of days alive during the 12-month study 
period, with the maximum being 365 days.  Any day in which a patient is documented to have 
had an emergency room visit or is admitted to an acute care or mental health facility for any 
opioid-related harm or poisoning will be counted as a healthcare day.  To estimate the number 
of opioid-related harms and poisonings resulting in healthcare utilization, the Discharge 
Abstract Database, Ontario Mental Health Reporting System database, National Ambulatory 
Care Reporting database, Registered Persons Database, and Office of the Registrar General of 
Ontario database will be linked to each patient’s Ontario Health Insurance Plan number and the 
following opioid-related harms and poisonings International Statistical Classification of Diseases 
and Related Health Problems, Tenth Revision, Canada (ICD-10-CA) codes will be used to 
estimate the number of healthcare days utilized during the study period: Y45, F11.0-F11.9, 
T40.0-T40.4, T40.6.23  All opioid-related harms and poisonings resulting in the utilization of a 
healthcare day regardless of intent (ICD-10-CA X42 (accidental), ICD-10-CA X62 (intentional), 
and ICD-10-CA Y12 (undetermined)) will be included in the final analysis.  Only those healthcare 
days in which opioid use was considered to be influential to the ER visit or hospitalization will 
be included and are identified by the following ICD-10-CA codes: M (most responsible 
diagnosis), 1 (pre-admit comorbidity), 2 (post-admit comorbidity), W or X or Y (Service transfer 
diagnosis).  In addition, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition codes 
304.00 and 305.50 will be used to capture healthcare days for opioid-related harms and 
poisonings. 
 
12.13 Rationale for primary outcome measures 
 
While the measurement of opioid positivity during opioid substitution therapy is a consistent 
primary outcome measure used across most trials, there is no gold standard measure of 
treatment effectiveness.26  Even in the 3 trials reviewed in Table 1, each had a different 
measurement outcome for opioid positivity despite 2 of those trials being conducted by the 
same research group.  In a systematic review of outcome measures used in opioid substitution 
treatment that included 60 trials, opioid positivity was the second most commonly reported 
outcome.26  In those trials measuring opioid positivity, there were 17 different definitions, 
including a further 8 variations in measurement.  In those studies that measured opioid 
positivity using urine drug screening, it was common practice to impute opioid positivity for 
missing data, often times as a requirement for regulatory agencies for evidence of efficacy and 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 25 of 53 
 
other times as a practical matter of OAT management in the clinics.  The imputation methods 
differed across studies, with few studies ever explaining the rationale for their technique.  Urine 
drug testing was almost always accompanied by self-reports of opioid use,26 and is 
recommended as a standard of practice in opiate substitution therapy.6,24  The most commonly 
used tool to measure self-reports of opiate use was the Timeline Followback method.21  In 
those studies utilizing both urine drug testing and self-report to measure opioid positivity, 
opioid positivity was defined as any positive result in either one or both tests.  This trial will 
utilize this measure of opioid positivity because it is consistent with previous approaches 
(valid), objective, reproducible, relevant to both healthcare providers and patients with OUD, 
and has been previously demonstrated to be responsive to treatment with both drugs used in 
this trial.  
 
The choice of healthcare days as a primary outcome reflects the desire to choose a measure 
that is patient-centered, readily measured and analyzed, and reflects a patient’s holistic state 
rather than a specific symptom or arbitrary measure of effectiveness of opioid substitution 
therapy on illicit opioid use.  Healthcare days have many attractive properties: they are 
continuous, enhancing power; they can be analyzed reliably and flexibly, to account for 
different values patients may place on avoiding hospitalization; and in nearly all cases, they are 
unidirectional, in the sense that nearly all patients prefer longer lives to shorter ones, and to 
have more of those days spent outside a hospital than within.  In addition, healthcare days as a 
measure of healthcare utilization facilitate the economic valuation of the differences in the two 
treatment regimens in the trial, an important issue considering the differences in costs and the 
non-inferior outcomes previously reported for measures of illicit opioid use.  The approach 
used to measure healthcare utilization in this trial has been validated and is currently used by 
the Canadian Institute of Health Information to measure and report opioid-related harms, 
poisonings and deaths.3  This trial will utilize a measure of opioid-related harms and poisonings 
that is valid, objective, reproducible, relevant to both healthcare providers and patients with 
OUD, and should be responsive to treatment with both drugs used in this trial. 
 
12.2 Secondary outcome measures 
 
12.21 Medication satisfaction 
 
Difference in the Medication Satisfaction Questionnaire27 scores.  The questionnaire is a single-
item, global, patient-completed instrument that has been validated to measure treatment 
satisfaction, initially in patients receiving antipsychotic treatment for schizophrenia, but 
subsequently used in trials measuring satisfaction with opiate substitution treatment.  The 
question will be read aloud by the RAAM clinic healthcare providers or study personnel to the 
patient.  The question asks, “Overall, how satisfied are you with your current 
Suboxone®/Sublocade® medication?”.  The responses are on a 7-point Likert scale, ranging 
from 1=extremely dissatisfied to 7=extremely satisfied.  This questionnaire is valid, 
reproducible, relevant to both healthcare providers and patients with OUD, and has been 
shown to be responsive to opiate substitution treatment in previous studies.26,28 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 26 of 53 
 
 
12.22 Quality of life 
 
Difference in the World Health Organization Quality of Life – BREF29 scores (WHOQOL-BREF).  
The 26-item questionnaire is a validated, self-report instrument that assesses 4 domains of 
quality of life: physical health (7 items), psychological health (6 items), social relationships (3 
items) and environment (8 items).  There are also 2 items that measure overall quality of life 
and general health.  The questionnaire takes 15-20 minutes to complete.  The questionnaire 
prefaces each item, “Think about your life in the last two weeks..”.  The responses are on a 5-
point Likert scale, ranging from 1=not at all/very dissatisfied/never/very poor to 5=very 
good/very satisfied/an extreme amount/extremely/completely/always, depending on the item.  
The questionnaire is valid, reproducible, relevant to both healthcare providers and patients 
with OUD, and has been shown to be responsive to changes in quality of life across cultures, 
geography and etiology.29 
 
12.23 Clinic retention 
 
Difference in proportion of patients who attend ≥80% of scheduled clinic visits, where a clinic 
visit is defined as a scheduled visit with a RAAM clinic healthcare provider for any reason, 
including urine drug testing, medication administration, or counselling.  Clinic retention is the 
most commonly reported outcome measure in opioid substitution trials, with 46% reporting it 
as an outcome.26  However, there is no “gold standard” definition of retention, with over 16 
different methodologies used to measure retention in 28 trials of opiate substitution therapy.26  
The number of clinic visits any patient will be assigned will include those scheduled as part of 
the trial and any other visits scheduled at the discretion of the RAAM clinic healthcare 
providers.  The measure of clinic retention used in this trial is valid, objective, reproducible, 
relevant to both healthcare providers and patients with OUD, and has been shown to be 
responsive to opiate substitution therapies in previous studies.26 
 
12.24 Mortality 
 
Difference in mortality proportions, where mortality is defined as any death attributable to 
opioid use regardless of the intent.  Opioid-related deaths continue to increase year after year 
and have emerged as a public health crisis.4  Only 2 previous opiate substitution treatment 
studies measured mortality as an outcome, the latest published in 1980.26  The method used by 
the Canadian Institute for Health Information will be used to measure mortality in this study 
given its validity, reproducibility, importance to both healthcare providers and patients with 
OUD, and its responsiveness to opiate substitution therapies.3   
     
 

 
 
 
 
 
 
Page 27 of 53 
 
13 
Participant timeline 
 
 
 
 
Study Period (Weeks) 
 
 
 
-1 
0 
T1 
T2 
T3 
T4 
T5 
T6 
T7 
T8 
T9 
T10 
T11 
T12 
T13 
T14 
T15 
T16 
T17 
T18 
T19 
T20 
T21 
T22 
T23 
T24 
Activity 
C 
R 
F 
M 
R 
P 
W-1 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
Enrollment 
 
Expressed 
Consent 
N 
HCP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Screen 
Y 
HCP 
SC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
N 
HCP 
SC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
Y 
SC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
Y 
HCP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Y 
HCP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
Y 
HCP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bloodwork 
Y 
HCP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interventions 
 
Suboxone® 
Y 
HCP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sublocade® 
Y 
HCP 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Counselling 
Y 
HCP 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
RAAM clinic visit 
Y 
HCP 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pre-clinic visit 
phone call 
Y 
HCP 
SC 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Assessments 
General exam 
Y 
HCP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug test 
Y 
HCP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timeline 
Followback  
Y 
HCP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MSQ 
Y 
HCP 
SC 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
WHOQOL-BREF 
Y 
HCP 
SC 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy test 
Y 
HCP 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SAE 
Y 
HCP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
Y 
HCP 
 
Discretion of HCP 
Bloodwork 
Y 
HCP 
 
Discretion of HCP 
CRF=case report form; MRP=most responsible person; N=No; Y=Yes; HCP=healthcare provider; SC=study coordinator; EKG=electrocardiogram; MSQ=medication satisfaction questionnaire; WHOQOL-
BREF=Quality of life questionnaire; SAE=severe adverse event 

 
 
 
 
 
 
Page 28 of 53 
 
14 
Sample size 
 
14.1 Rationale 
 
The sample size was calculated on the basis of the primary hypotheses.  In the three previous 
comparative effectiveness studies between Suboxone® and Sublocade® (Table 1), the primary 
outcomes were non-inferiority with an upper margin of difference in opioid positivity of < 15%.  
None of these trials involved Canadian patients attending RAAM clinics.  As previously 
reviewed, given the significant differences in costs of Sublocade® compared to Suboxone® and 
the absence of evidence of cost-effectiveness of Sublocade® compared to Suboxone® in the 
Canadian healthcare system, it would be important to demonstrate to healthcare providers 
who advise patients that must pay out-of-pocket for their medications that the increased cost 
of Sublocade® provides clinically significant benefits to important patient-centered outcomes 
over those of less expensive OAT.  In addition, it would be important to demonstrate the same 
benefits to policy makers and insurers of the superiority of Sublocade® compared to Suboxone® 
not only in reducing rates of opioid positivity but also healthcare utilization that might offset 
the cost differential of the two drugs and provide the rationale to promote Sublocade® as an 
insured first line agent for OUD.  As such, a clinically important difference in opioid positivity 
has been selected as ≥ 15% difference for Sublocade® compared to Suboxone® given that 
previous studies had used this threshold as the upper margin for non-inferiority.  As for 
healthcare utilization, CADTH estimated that a 73% reduction in cost of Sublocade® would be 
needed to make it cost-effective for the Canadian healthcare system (see Section 5.14).  Given 
the current cost for a 12-month treatment of Sublocade® in Canada is $6600, a 73% reduction 
would translate into an annual cost of $1782, a cost reduction of $4818.  The average cost of 
healthcare utilization in Ontario for an opioid-related harm or poisoning was $9626 (Section 
5.12).  To recoup the drug costs from a reduction in healthcare utilization costs would require 
at least a 50% reduction in healthcare utilization over a 12-month period.  As such, a clinically 
important difference in healthcare utilization has been selected as ≥ 50% difference for 
Sublocade® compared to Suboxone®.  All sample size estimations were conducted using nQuery 
version 8.7.2.0 (nQuery | Platform for optimizing trial design (statsols.com); accessed 
November 17, 2021). 
 
14.2 Opioid positivity  
 
Previous studies have used a simple data generating model for opioid positivity in which the 
difference in proportions of opioid positivity, regardless of how opioid positivity was defined, 
never accounted for the clustering of repeated measures of opioid positivity by individual and 
site.  This dramatically reduces the power to detect differences in proportions of opioid 
positivity between treatment groups.  For example, for our trial to detect a difference in 
proportion of RFWs of ≥ 0.15 with a power of 80% using a Z-test (unpooled variance) 
significance level at the 2-sided ∝ level of 0.05 would require 160 patients per group if the 
comparator group’s RFWs proportion is 0.3 (estimated from Lofwall et al.12).  Contrast this to a 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 29 of 53 
 
data generating model that more appropriately accounts for clustering of opioid positivity 
observations.  In this study, a mixed model using a 3-level hierarchical design will be used to 
describe the relationship between repeated measures of opioid positivity (Level 1) obtained 
from individual patients (Level 2) recruited from 4 different RAAM clinic sites (Level 3), where 
Level 2 patients will be randomized to either Sublocade® or Suboxone®.  In addition to the 
assumption of a comparator group RFWs proportion of 0.3, if we also assume a Level 1 unit 
correlation of 0.8, a Level 2 correlation of 0.025, and an average of 5 repeated measures of 
opioid positivity per Level 2 patient over the study period, then we would need only 34 patients 
per treatment group to detect a difference in RFWs proportion of ≥ 0.15 with a power of 80% 
and a mixed model test significance level at the 2-sided ∝ level of 0.05.  Sensitivity analysis 
using different values for the variables used in the hierarchical model assumptions (Table 3) 
demonstrates that the upper range of sample sizes is consistently less than 70 per group.   
 
Table 3: Sensitivity analysis for sample size estimations needed to detect ≥ 15% difference 
between RFWs proportions between treatment groups for a mixed model test in a 3-level 
hierarchical design (Level 2 randomization) 
 
 
Scenario2 
Variable1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Power 
80 
80 
80 
80 
80 
80 
80 
80 
90 
90 
Comparator group 
RFW proportion 
0.3 
0.3 
0.3 
0.3 
0.1 
0.6 
0.3 
0.3 
0.3 
0.3 
Level 1 unit 
correlation 
0.8 
0.5 
0.99 
0.99 
0.99 
0.99 
0.8 
0.8 
0.99 
0.99 
Level 2 unit 
correlation 
0.025 
0.025 
0.1 
0.001 
0.001 
0.001 
0.025 
0.025 
0.001 
0.001 
Level 3 units 
4 
4 
4 
4 
4 
4 
3 
2 
4 
3 
Average number of 
Level 1 units per 
Level 2 units 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Sample size per 
group 
34 
24 
37 
41 
42 
38 
45 
68 
41 
54 
1 Assumptions: 2-sided ∝ level of 0.05; Difference in RFWs proportion ≥0.15; Treatment group allocation = 1:1 
2 Highlighted cells (Yellow) represent changes from preceding scenario 
 
14.3 Healthcare utilization  
 
In the only recent study that compared non-protocol-driven healthcare utilization using the 
incidence rates of healthcare days as an outcome measure among patients with OUD receiving 
opiate substitution therapy with either Sublocade® or placebo, the data demonstrated a 
combined emergency room visit or hospital day incidence rate of 2.01 healthcare days per 1 
000 patient days in the Sublocade® group versus 6.97 healthcare days per 1 000 patient days in 
the placebo group.28  These rates likely underrepresent the current rates of healthcare 
utilization in Canada as the study was conducted in 2015 and the patients included in the trial 
were residents of the United States and 60% had no medical insurance likely creating barriers 
to healthcare access and lowered rates of utilization that would not exist for Canadian patients 
who have universal and free access to acute healthcare services.  There have been no direct 
comparisons between Sublocade® and Suboxone® treatments.  As a result, a sensitivity analysis 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 30 of 53 
 
using different inputs has been conducted given that the maximum person days exposure for 
each patient is 365 days.  We also assume a worse-case scenario of loss-to-follow-up (for any 
reason) of 50% over the study period, a rate of loss-to-follow-up much higher than the 20% rate 
reported by Ling et al.28      
 
Table 4: Sensitivity analysis for attainable power to detect a range of differences in the 
incidence rates of healthcare days between treatment groups with different sample sizes 
 
 
Scenarios 
Variable1 
1 
2 
Comparator group 
incidence 
2.0 
2.4 
Group difference in 
incidence rates  
1.0 
1.2 
Sample size per group 
(patient days)2 
3650 
3650 
Power 
99 
99 
1 Incidence = total number (hospital days + emergency room visits)/1 000 patient days; Assumptions: 2-sided ∝ level of 0.05; 50% loss-to-
follow-up 
2 Sample size per group derived from a sample of 20 patients * 365 days exposure/patient * 0.5 (=50% rate of loss-to-follow-up) 
 
14.4 Final sample size 
 
In a hierarchical 3-level mixed effects model with 45 and 45 level 2 units (RAAM clinic patients) 
randomized to Suboxone® and Sublocade® in a 1:1 ratio, 4 level 3 units (RAAM clinics) in total 
and an average of 5 level 1 units (RFWs) per level 2 unit, 90.0% power is achieved to detect a 
difference in RFWs proportions of at least 0.15, where the Suboxone® and Sublocade® RFWs 
proportions are 0.3 and 0.45, respectively, assuming that the correlation between level 1 units 
in a level 2 unit is 0.8 and the correlation between level 2 units in a level 3 unit is 0.025, and the 
2-sided test is performed at the 5% significance level.  Using even a much smaller sample size 
(N=20 patients per group with 50% loss-to-follow-up over 12-month study period), a 2-sided 
comparison of two incidence rates (number of healthcare days per 1000 patient days exposure) 
with a sample size of 3650 patient days exposure per group would achieve 99% power at the 
0.05 significance level to detect a difference in incidence rates of at least 1 if the Suboxone 
®group incidence rate was 2.  
15 
Recruitment  
 
The 4 RAAM clinics serve the entire North Simcoe Muskoka Local Health Integrated Network 
region, are owned and operated by the Royal Victoria Regional Health Centre and are 
administered by the same manager and medical lead (see Section 9 for details).  
 
Each RAAM clinic will screen 100% of patients who successfully complete induction and 
stabilization with Suboxone® as this is the point at which patients might be eligible for 
enrollment and randomization.  Screening will continue until the target population is achieved.  
There will be no fixed number of patients that must be recruited from any site, only that each 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 31 of 53 
 
site will have a 1:1 allocation ratio between the treatment groups.  The expectation is that 1 to 
2 patients will be enrolled per week.  
 
The RAAM clinic healthcare providers will be responsible for expressed consent in eligible 
patients.  For those patients who provide expressed consent, the RAAM clinic healthcare 
providers will contact the study team and provide them with the patient’s name and contact 
number and inform the patient that they will be contacted by the study team to further discuss 
the study.  A study team member will contact the patient and arrange a meeting, either in 
person, telephone or videoconference, to determine eligibility and review the study and secure 
informed consent. 
 
For patients who cannot travel to a laboratory to complete their screening bloodwork or 
electrocardiogram, arrangements will be made to have the screen completed at their home 
address at no charge to the patient. 
 
Patients who are enrolled in the study at the Midland, Orillia, and Wasaga Beach RAAM clinic 
sites will now be able to receive their Sublocade® doses on-site.  Previous to this study, those 
patients would have had to travel to the Barrie RAAM clinic site to receive Sublocade®.  A taxi 
ride for this travel would be required as there is no bus or train that connects these sites, with 
the cost for a round trip in excess of $150 (CDN) (personal communication, Philip Wong). 
16 
Allocation 
 
16.1 Sequence generation 
 
Participants will be randomly assigned to either Suboxone® or Sublocade® with a 1:1 allocation 
schema as per a computer-generated randomisation schedule stratified by RAAM clinic site and 
severity of OUD (moderate versus severe by DSM-V criteria) using permuted blocks of size 6 in 
each strata.  A single block size was chosen since the next block size of 18 might be too large to 
allocate patients in a 1:1 ratio in the smaller RAAM clinics.  The block size will not be disclosed 
to ensure concealment.  Sufficient numbers of blocks will be prepared a priori to ensure 
sufficient coverage for all strata in the event that they have different sample sizes as there will 
be no a priori fixed ratio for enrollment in the different strata.   
 
16.2 Concealment mechanism 
 
The random allocation sequence will be generated using the ralloc function in STATA 17/MP for 
Mac by an independent statistician not associated with the trial.  This allocation sequence will 
be uploaded into and accessed from REDCap®,  which is an on-line, password-protected, web-
based research electronic database system stored on the PHIPA-protected servers at the Royal 
Victoria Regional Health Centre.  Allocation concealment will be ensured as the study 
coordinator will not release the randomisation code until the patient has been recruited into 
the trial, which will only take place after all baseline screening measurements have been 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 32 of 53 
 
completed.  The randomisation schedule will only be accessible by independent study 
coordinators not associated with this study to ensure that randomisation will be conducted 
without any influence of the principal investigators, RAAM healthcare providers, or other study 
personnel. 
 
16.3 Implementation 
 
Expressed consent for the study will be obtained by the RAAM clinic healthcare providers.  
Informed consent will be obtained by the study team.  All patients who give consent for 
participation and who fulfil the inclusion criteria will be randomized.  Randomization will be 
requested by the study team member who secured informed consent from an independent 
study coordinator who is not associated with the study by calling a centralized study telephone 
number.  The study coordinator will access the random allocation sequence through REDCap®, 
and then inform the study team member who secured informed consent of the treatment 
allocation for this patient.  The study team member will subsequently inform the RAAM clinic 
healthcare provider who would then provide the information about treatment allocation to the 
patient.  All RAAM clinic healthcare providers will be made aware of the treatment allocation as 
this is an open-label study. 
17 
Masking 
 
This is an open-label, pragmatic, comparative effectiveness study so neither participants nor 
RAAM healthcare providers nor study personnel, including data analysts, will be masked to the 
allocation.   
18 
Data collection 
 
18.1 Methods 
 
All data will be collected by centrally trained RAAM clinic healthcare providers and study 
personnel.  All routinely collected data will be collected by the RAAM clinic healthcare 
providers and stored in MEDITECH Expanse, the electronic health record system used across all 
the study RAAM clinics and the Royal Victoria Regional Health Centre.  This routinely collected 
data will be extracted by study personnel and stored in electronic case report forms created in 
REDCap®.30,31  All study-specific data will be collected by study personnel and stored in 
electronic case report forms created in REDCap®.   
 
18.11 Routinely collected data 
 
18.11a Prior to induction 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 33 of 53 
 
For all RAAM clinic patients with OUD who are eligible to receive any opiate substitution 
therapy, the following demographic and baseline clinical and laboratory data are collected prior 
to induction with any treatment (Table): 
 
Data 
Description 
Data type 
Demographics 
Date of birth 
Month/day/year 
Mm/dd/yyyy 
Sex at birth 
Male: Female 
Categorical 
Pregnant Yes: No 
Categorical 
Ontario health insurance plan 
number 
Unique provincial insurance 
number assigned to every 
resident 
xxxx-xxx-xxx-version code 
Ontario drug plan status 
Insured versus non-insured 
Categorical 
Residency 
Homeless; transient (< 6 
months at same address, 
couch surfing or shelter); 
stable (≥ 6 months at same 
address) 
Categorical 
Children in home Yes: No 
Categorical 
Children ages Years 
Continuous 
Telephone contact 
Yes: No 
Categorical 
Number  
(xxx)-xxx-xxxx 
Employment status1 
Full-time (≥ 40 hours per 
week for ≥ 90 days per year); 
Part-time (≤ 40 hours per 
week or ≥ 90 days per year); 
Casual (≤ 90 days per year); 
unemployed 
Categorical 
Incarceration1 
Incarceration in ≤ 12 months 
(Yes: No) 
Categorical 
Race1 
White: Non-white, non-
indigenous: Indigenous 
Categorical 
Clinical 
 
 
OUD diagnostic screen  
≥ 2 of 11 DSM-V criteria must 
be present ≤ 12 months for 
diagnosis of OUD 
Categorical: range 0 to 11:  
OUD severity DSM-V criteria of mild, 
moderate or severe OUD 
Categorical: mild (2-3 
criteria); moderate (4-5 
criteria); severe (≥6 criteria) 
Medical history 
Comorbid illness screen, 
including mental health and 
substance use  
Categorical 
Medications Prescribed 
Categorical 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 34 of 53 
 
Alcohol use Yes: No 
Categorical 
Opioid use Type: Route 
Categorical 
Other substance use Type: Route 
 
Recent substance/opioid use 
Timeline Followback 
questionnaire (assesses use 
and frequency of use of 
substances over the previous 
7 days) 
Categorical 
Hospitalization 
Substance-related ≤ 12 
months (includes emergency 
room visit, admission to 
hospital, mental health or 
detoxification facility) (Yes: 
No) 
Categorical 
General physical exam 
Vital signs; height; weight 
Continuous 
Opioid withdrawal screen ≥ 3 of the following: 
dysphoria; nausea or 
vomiting; muscle aches; 
lacrimation or rhinorrhea; 
pupillary dilation or 
piloerection or sweating; 
diarrhea; fever; insomnia; 
yawning 
Categorical; range 0-9 
Jaundice Yes: No 
Categorical 
Mental status Glasgow coma scale 
Categorical (range 3-15) 
Opiate Craving Visual Analog 
Scale 
Score ≥ 21 suggests clinically 
significant craving 
Continuous (range 0-100) 
Clinical Opiate Withdrawal 
Scale 
Score ≥ 13 suggests clinically 
significant withdrawal 
Continuous (range 0-48) 
Laboratory2 
Pregnancy 
b-hCG assay (Yes: No) 
Categorical 
Liver  
AST, ALT 
Continuous 
 
Hepatitis virus serology  
Categorical 
Urine toxicology 
Section 12.11a for 
description 
Categorical 
Renal 
Creatinine 
Continuous 
1  Employment status, incarceration and race are routinely collected in treatment studies for 
OUD as they have been identified as risk factors for outcome differences. 
2 All laboratory and electrocardiogram measurements and interpretations done at LifeLabs™ 
 
18.11b During treatment 
 
Data 
Description 
Data type 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 35 of 53 
 
Urine toxicology 
Section 12.11a for 
description 
Nominal 
Recent substance/opioid use 
Timeline Followback 
questionnaire (assesses use 
and frequency of use of 
substances over the previous 
7 days) 
Categorical 
Counselling 
Individual patient counselling 
for OUD, mental health and 
trauma 
Narrative 
General exam 
Vital signs: Glasgow coma 
scale:  
Continuous 
Pregnancy 
b-hCG assay (Yes: No) 
Categorical 
Bloodwork (optional) 
Electrolytes: Liver: Renal  
Continuous 
Buprenorphine breakthrough 
dosing 
Extra buprenorphine dosed 
for breakthrough 
Continuous 
Compliance 
Missed appointments or 
doses (Yes: No) 
Categorical 
Hospitalization1 
Any Royal Victoria Regional 
Health Centre emergency 
room visits, admissions to 
hospital or mental health or 
detoxification centre since 
previous clinic visit (Yes: No) 
Categorical 
Reason for visit/admission Opioid-related (Yes: No) 
Categorical 
Serious adverse events1 
Hospitalization (for any 
reason) 
Categorical 
Reason Opioid-related (Yes: No) 
Categorical 
1 Only hospitalization events associated with the Royal Victoria Regional Health Centre are 
accessible to the RAAM clinic healthcare providers as the clinics share the same electronic 
health record system as previously described.  All other hospitalizations would have to be self-
reported by the participants and consent for access to the health records would then need to 
be secured by the RAAM clinic healthcare providers. 
 
18.12 Study-specific data 
 
Data 
Description 
Data type 
Medication Satisfaction 
Questionnaire 
“How satisfied are you with 
your medication?” 
Categorical: Range 1-7 
WHOQOL-BREF 
26-item questionnaire 
measuring quality of life in 4 
domains: physical health; 
Continuous: Each domain 
score standardized to scores 
0 (wore) to 100 (best) 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 36 of 53 
 
psychological health; social; 
environment 
Hospitalization1 
Any Royal Victoria Regional 
Health Centre emergency 
room visits, admissions to 
hospital or mental health or 
detoxification centre since 
previous clinic visit (Yes: No) 
Categorical 
Reason for visit/admission Opioid-related (Yes: No) 
Categorical 
Serious adverse events1 
Hospitalization (for any 
reason) 
Categorical 
Reason Opioid-related (Yes: No) 
Categorical 
1 Only hospitalization events associated with the Royal Victoria Regional Health Centre are 
accessible to the RAAM clinic healthcare providers as they clinics share the same electronic 
health record system as previously described.  All other hospitalizations would have to be self-
reported by the participants and consent for access to the health records would then need to 
be secured by the RAAM clinic healthcare providers. 
 
18.13 Healthcare utilization 
 
This data (see Section 12.12) is available from the Registered Persons Database, Ontario Mental 
Health Reporting System, Discharge Abstract Database, and National Ambulatory Care 
Reporting System through the Institute for Clinical Evaluative Sciences using a data linkage with 
each patient’s unique Ontario Health Insurance Plan number. 
 
As a prescribed entity under the Personal Health Information Protection Act,32 the Institute for 
Clinical Evaluative Sciences is authorized to collect personal health information from health 
organizations without consent for the purposes of evaluation and monitoring of Ontario’s 
health system.  The Institute for Clinical Evaluative Sciences is prohibited, under its agreements 
with data providers, from contacting individuals whose information has been 
entrusted to the Institute for Clinical Evaluative Sciences. This contractual obligation restricts 
any opportunity to seek individuals’ consent for use of their information for research. 
 
The Institute for Clinical Evaluative Sciences will make available a research-ready, linked and 
risk-reduced coded dataset to the study investigators.  Although highly de-sensitized, the 
research data is presented at an individual level. Study investigators will access the Research 
Data remotely on a secure, encrypted VMware virtual desktop called the Institute for Clinical 
Evaluative Sciences Data & Analytic Virtual Environment (IDAVE). Study investigators will 
perform analyses on IDAVE using statistical software. Research Data may not be copied or 
transferred from IDAVE. Only results derived from the Research Data that have been vetted for 
re-identification risk and approved by Institute for Clinical Evaluative Sciences may be released 
from IDAVE.    
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 37 of 53 
 
18.2 Retention 
 
18.21 Strategies 
 
Once a patient is enrolled or randomized, the RAAM clinics will make every reasonable effort to 
follow the patient for the entire study period.  The RAAM clinics and their healthcare providers 
will utilize recommended clinical strategies as part of their usual standard of care to minimize 
loss-to-follow-up for any patient with OUD on opioid substitution therapy.17 
 
In addition to these strategies, the RAAM clinic healthcare providers and study personnel will: 
 
1) Direct contact by phone for each participant will take place 2 days in advance of a scheduled 
clinic visit as a reminder of the date and time of the scheduled visit, and to determine if there 
are any barriers to attendance.  Incentives such as taxi chits will be provided to participants 
who have transportation barriers to attendance.  
 
2) For those participants who require additional bloodwork or electrocardiograms, home lab 
services free-of-charge will be provided through LifeLabs™. 
 
3) The study-specific questionnaires will be completed using interviews with study personnel as 
opposed to simply asking participants to complete the questionnaires on their own to maximize 
completion rates. 
 
4) The study-specific questionnaire schedules will be flexible, with study personnel able to 
interview participants ∓ 2 weeks around the scheduled date. 
 
18.22 Withdrawal 
 
Participants may choose to withdraw from the study for any reason at any time.  As part of the 
usual standard of care, the RAAM clinic healthcare providers may also withdraw participants 
from the study for clinical reasons such as failure to comply with opiate substitution treatment, 
failure to comply with urine drug testing or self-reports of drug use, failure to attend scheduled 
clinic visits, failure to comply with birth control or becoming pregnant after enrolment, or for 
any other reason that may jeopardize the safety of the participants or others.  For those 
participants who choose to withdraw or are withdrawn by their healthcare providers, ongoing 
follow-up for the study period will continue for all outcomes measured using routinely collected 
data (such as healthcare utilization).  For outcome measures that require study-specific data, 
such as the WHOQOL-BREF questionnaire, consent will be sought to permit ongoing assessment 
for the study period.  Deviations from the study protocol (which do not result in withdrawal by 
the healthcare providers) or loss-to-follow-up for any reason will not be considered reasons for 
withdrawal from the study.    

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 38 of 53 
 
19 
Data management 
 
All routinely collected data will be entered electronically by the RAAM clinic healthcare 
providers at the RAAM clinics using the electronic health record system.  Study personnel will 
extract the relevant routinely collected data from the electronic health record system and 
record the data into the electronic case report form stored in REDCap, a password-protected,  
Personal Health Information Protection Act (PHIPA)-compliant database stored on servers at 
the Royal Victoria Regional Health Centre that is used to support all the hospital’s research 
activities and is supported and managed by the staff of the Royal Victoria Regional Health 
Centre Research Institute.  Study personnel will record study-specific data directly into the 
REDCap electronic case report form (Medication Satisfaction Questionnaire and WHOQOL-BREF 
questionnaire) or extract study-specific data from the electronic health record system 
(Healthcare utilization) and record it in REDCap.  The study personnel will access the 
questionnaires (Medication Satisfaction Questionnaire and WHOQOL-BREF questionnaire) in 
REDCap and complete them with the participants.  This may be done either in-person at the 
RAAM clinics or remotely by telephone or videoconference.   
    
When a patient is enrolled and randomized, a unique study number will be automatically 
generated in REDCap.  This unique study number, along with the patient’s name (first, middle, 
last), Ontario Health Insurance Plan number, date of birth, and unique electronic health record 
system number will be stored in a password-protected EXCEL computer file.  This study EXCEL 
file will be stored in a dedicated, password-protected electronic shared drive located on the 
Royal Victoria Regional Health Centre Personal Health Information Protection Act (PHIPA)-
compliant servers.  This EXCEL file will permit linkage to the electronic case report form to 
enable study personnel to record repeated measurements over the study period for a 
participant.  Real-time data quality rules will be implemented in REDCap that will display 
warning pop-up messages whenever the rules are violated during data entry.  These quality 
rules will minimize missing values in required fields; prevent incorrect data type entry and out 
of range data entry; identify outliers for numerical fields; and prevent invalid data entry into 
multiple choice fields.  The data quality rules will also be available to be executed at any time by 
a study monitor or study personnel.  All electronic case report form entries and edits are 
associated with an electronic audit trail that identifies the user, date and time of entry, and 
entry type.  The type of activity that study personnel may undertake in REDCap is regulated by 
privileges associated with their user identification and password.  Incremental data back-ups of 
REDCap are routinely performed twice a day, with off-site storage of the backed-up files done 
on a monthly basis.  Data status reports on missing data will be provided to the Data 
management committee on a biweekly schedule for review.  All study data will be archived in 
REDCap for 25 years and subsequently permanently destroyed. 
20 
Statistical methods 
 
20.1 Outcomes 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 39 of 53 
 
The intervention arm (Sublocade®) will be compared against the active comparator 
(Suboxone®) for all primary and secondary analyses.  All analyses will be done according to 
original patient allocation regardless of whether they received the randomized treatment or 
were compliant with the study protocol (Intention-to-treat).  All analyses will be conducted 
using STATA/MP 17.0 for Mac.    
 
20.11 Primary 
 
20.11a Opioid positivity 
 
We will use a 3-level hierarchical design to model the relapse-free weeks data where the 
observation for each week (Level 1) will be coded as binary; relapse-free week if urine drug 
screen and self-report is negative for non-prescribed opioid use, and otherwise relapse week if 
either is positive for non-prescribed opioid use.  As described in Section 12.11, imputation of 
missing data will occur for those weeks in which a urine drug screen/self-report was not 
scheduled according to the results of the subsequent week’s urine drug screen/self-report. 
Level 1 observations are clustered within individual participants (Level 2) , which are nested 
within RAAM clinic sites (Level 3).  We will analyse the outcome data using multi-level, mixed-
effects logistic regression analysis with random effects estimated for the variance in the 
intercepts of both participant and clinic levels.  The model will also include a random slope on 
the indicator for OUD severity (moderate versus severe) in the Level 2 random effects equation 
using an unstructured covariance structure between intercept and slope. We will also include 
clinic visit (week) and an interaction term between clinic visit and treatment. A sensitivity 
analysis will be conducted to compare this baseline model with an extended model that 
includes any baseline demographic or clinical variables that appear to be unbalanced at Level 1. 
The  models will be compared using the likelihood-ratio comparison test for superiority.  Post-
regression analyses using margins command will be used to estimate difference in proportions 
of RFWs between treatment groups. 
 
20.11b Healthcare utilization 
 
We will model the days of healthcare utilization as count data, with the period of follow-up 
while alive during the study period as the exposure period.  We will analyse the data using a 
Poisson regression model.  We will include an indicator for OUD severity.  We will include any 
baseline demographic or clinical variables that are unbalanced at Level 1.   
 
20.12 Secondary outcomes 
 
We will use a 3-level hierarchical design to model all the repeated measures outcomes 
(Medications Satisfaction Questionnaire and the WHOQOL-BREF) where the outcomes will be 
coded as continuous.  Level 1 observations are clustered within individual participants (Level 2), 
which are nested within RAAM clinic sites (Level 3).  We will analyse the data using multi-level, 
mixed-effects linear regression analysis with random effects estimated for the variance in the 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 40 of 53 
 
intercepts of both participant and clinic levels.  We will include a random slope on the indicator 
for OUD severity (moderate versus severe) in the Level 2 random effects equation using an 
unstructured covariance structure between intercept and slope.  We will also include clinic visit 
and an interaction term between clinic visit and treatment, along with any baseline 
demographic or clinical variables that are unbalanced at Level 1. 
 
Both clinic retention and mortality will be coded as binary outcomes.  We will conduct 
unadjusted analyses for both using a chi-squared test (with continuity correction) or Fisher’s 
exact test depending on cell sizes. 
21 
Monitoring 
 
21.1 Trial management committee 
 
This comparative effectiveness study involves the use of two opiate substitution medications 
that are Health Canada-approved for use in moderate- to severe-OUD.  In addition, the study 
RAAM clinics are accredited facilities with trained personnel in the use of both study treatments 
for the treatment of moderate- to severe-OUD.  As such, an informal trial management 
committee will be created to ensure that all privacy requirements for data collection, storage 
and dissemination are met.  In addition, this committee will meet biannually to review data 
quality, including amount and reasons for missing data, and provide guidance to investigators 
on these issues.    
 
An informal trial management committee will be created to ensure study recruitment and 
retention is optimized.  The committee will be composed of members of the study RAAM 
clinics’ administration and members of the Research Institute.  The members of the committee 
will perform quarterly audits on a random sample of 5% of enrolled participants, and these 
audits will involve, but not be limited to, the following: 
(i) Documentation of consent and consistent application of inclusion and exclusion criteria 
(ii) Adherence to study treatment allocation 
(iii) Completeness and accuracy of the electronic case report forms 
(iv) Protocol deviations and reporting 
This committee will submit quarterly reports to the data management committee as part of 
their responsibilities.  
 
21.2  Interim analysis 
 
There will be no interim analysis or premature termination of the study.   
22 
Harms 
 
In this pragmatic, comparative effectiveness study, the RAAM clinic healthcare providers will 
document adverse events that occur during the study according to their clinical judgement and 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 41 of 53 
 
usual standard of care.  The subsequent clinical decisions and actions to any adverse event will 
be left up to the discretion of the healthcare providers.  The only adverse event that will be 
considered serious will be any healthcare utilization for any reason during the 12-month study 
period, defined as any emergency room visit, admission to hospital, mental health facility or 
detoxification centre.  Screening for these events will occur with each clinic visit by soliciting the 
information from the participant but will also occur unsolicited by screening the electronic 
health record system between visits.  These healthcare utilization events will be reported to the 
Trial and Data management committees on a quarterly basis, along with the Research Ethics 
Board according to local regulatory standards.  
23 
Auditing 
 
23.1 Investigator responsibilities 
 
The investigators agree to perform the clinical trial in accordance with this clinical trial protocol, 
International Council for Harmonisation guideline for Good Clinical Practice 
(https://ichgcp.net/) and all applicable regulatory requirements.   
 
23.2 Coordinating centre responsibilities 
 
The RVH Research Institute will be responsible for taking all reasonable steps to ensure proper 
conduct of the clinical trial protocol.  
 
23.3 Site initiation 
 
Prior to the initiation of the study at each study RAAM clinic, the RVH Research Institute will be 
responsible for providing adequate training to the clinic healthcare providers and study 
personnel.  The training will cover all aspects of the study protocol and procedures and will 
include practical training on the use of the randomisation system, electronic case report forms 
and study materials such as questionnaires.  The site initiation visit will be conducted by either 
teleconference, video conference or face-to-face meetings at the participating study RAAM 
clinic.  Written and electronic materials will be supplied for study personnel and for the 
education of the study RAAM clinic healthcare providers at each site. 
 
23.4 Monitoring during the study 
 
An independent study monitor for the RVH Research Institute will visit each participating RAAM 
clinic biannually during the study period.  This will ensure that the study is conducted according 
to the protocol, good clinic practice guidelines and relevant regulatory requirements.  The main 
duty of the study monitor is to help the principal investigators and the RVH Research Institute 
maintain a high level of ethical, scientific, technical and regulatory quality throughout all 
aspects of the trial. 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 42 of 53 
 
The principal investigators, healthcare providers and study personnel will assist the study 
monitor by providing all appropriate documentation and being available to discuss the study.  
These monitoring visits will include, but not be limited to, review of the following aspects: 
 
1) Adherence to the protocol including consistency with inclusion and exclusion criteria 
2) Study treatment allocation 
3) The completeness and accuracy of the electronic case report forms and electronic medical 
records 
4) Participant recruitment 
5) Adverse event documentation and reporting 
6) Compliance with the study treatment regimen for enrolled participants 
7) Study drug storage, administration, accountability and reconciliation 
8) Compliance with regulations 
 
23.5 Site close-out 
 
At the completion of the trial, a final monitoring and close out visit will be conducted by the 
study monitor.   
 
23.6 Source documents 
 
The study monitor will check the source documents to confirm the existence of the participant 
and the integrity of the study data.  Source documents refer to the electronic medical records 
of the participants used by the study RAAM clinic healthcare providers during episodes of care 
related to the study.  Adequate and accurate source documents allow the principal 
investigators and the study monitor to verify the reliability and authenticity of data recorded on 
the electronic case report forms and ultimately to validate that the study was carried out in 
accordance with the protocol. 
 
23.7 Study treatment 
 
The principal investigator (PW) or delegate at each study RAAM clinic site will be responsible for 
receiving, inspecting and documenting Sublocade® acquired prior to placement in storage.  The 
principal investigator (PW) or delegate will inventory and acknowledge receipt of all shipments 
of the study drug.  Documentation of study drug, distribution, receipt, use and disposal will be 
kept enabling comprehensive tracking and reconciliation of all study treatments, used or 
unused. 
 
Study drug will be kept in a secure area with restricted access.  The study drug must be stored 
and handled in accordance with the manufacturer’s instructions.  The principal investigator 
(PW) or delegate will also keep accurate records of the quantities of the study drug dispensed, 
used and unused by each participant. 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 43 of 53 
 
All unused or partially used study drug should be returned to the principal investigator (PW) or 
delegate once the treatment period has ended.  The study personnel will cross check the study 
drug that are identified on the accountability log against the study drug that has been 
dispensed/administered to the participant. 
 
Following verification from the RVH Research Institute, study drug may be destroyed providing 
documentation of destruction with a complete and accurate account of study drug destroyed 
be available for verification by the study monitor and filed in the principal investigator study 
file. 
 
At the conclusion of the study, all unused study drug (which has not been allocated to a 
participant) will be destroyed unless other arrangements have been approved by the RVH 
Research Institute or RAAM clinics.  Final destruction of unallocated study drug must only occur 
following written authorisation from the RVH Research Institute or RAAM clinics.  The RVH 
Research Institute will verify that a final report of study treatment accountability is prepared 
and maintained in the principal investigator study file. 
 
23.8 Direct access to data and documents 
 
The study may be audited by Health Canada, the RVH Research Ethics Board, or qualified 
representatives of the RVH Research Institute as permitted by regulations. Therefore, access to 
medical records, other source documents and other study related files will be made available at 
all study sites for monitoring and audit purposes during the study and after its completion. 
  
Participants will not be identified by name, and confidentiality of information in medical 
records will be preserved. The confidentiality of the participant will be maintained unless 
disclosure is required by regulations. 
 
24 
Ethics approval 
 
This protocol and appendices will be reviewed and approved by the RVH Research Institute and 
the Clinical Trials Ontario-accredited RVH Research Ethics Board with respect to scientific 
content and compliance with applicable research and human subjects’ regulations. 
 
The protocol and informed consent form, other requested documents, and any subsequent 
modifications, also will be reviewed and approved by the RVH Research Ethics Board. 
 
Subsequent to initial review and approval, the RVH Research Ethics Board will review the 
protocol at least annually. The Principal investigators will make safety and progress reports to 
the RVH Research Ethics Board at least annually and within three months of study termination. 
These reports will include the total number of participants enrolled, completed the study, in 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 44 of 53 
 
follow-up, lost-to-follow-up, and withdrawn; total number of adverse events; protocol and 
informed consent deviations and modifications.  
25 
Protocol amendments 
 
All modifications to the protocol which may impact on the conduct of the study, potential 
benefit of the participant or may affect participant safety, including changes of study objectives, 
study design, participant population, sample sizes, study procedures, or significant 
administrative aspects will require a formal amendment to the protocol. Such amendments will 
be agreed upon by the Principal investigators, the RVH Research Institute, and approved by the 
RVH Research Ethics Board prior to implementation. 
 
Administrative changes of the protocol are minor corrections and/or clarifications that have no 
effect on the way the study is to be conducted. These administrative changes will be agreed 
upon by the Principal investigators, the RVH Research Institute, and will be documented in a 
Note to File to the RVH Research Ethics Board. 
26 
Consent 
 
This pragmatic, comparative effectiveness study involves the random assignment of Sublocade® 
or Suboxone® to participants who meet the Health Canada-approved indications for their use.  
This study fulfils the criteria for a low intervention clinical trial in that the drug treatments are 
Health Canada-approved, the drug treatments are being used in accordance with the terms of 
the Health Canada-marketing authorization, and any additional study-related assessments 
(Medication Satisfaction and WHOQOL-BREF questionnaires) and follow-up (12-month 
healthcare utilization) do not pose more than minimal additional risk or burden to the safety of 
the participants compared with normal clinical practice.33    As such, eligible participants will be 
briefly informed by their RAAM clinic healthcare providers about the main features of the trial 
that are not part of the usual standard of care, notably, randomisation; the Medical Satisfaction 
and WHOQOL-BREF questionnaires, and healthcare utilization follow-up at 12-months from 
enrollment.  A modified written informed consent describing only the process and rationale for 
randomization and the description, need for and schedule of the Medication Satisfaction and 
WHOQOL-BREF questionnaires will be obtained prior to enrolment by the Principal 
investigators or their nominated delegates.  The written informed consent will not contain any 
information about the study drugs, administration, side effects or duration of treatment as 
verbal consent will be obtained by the healthcare providers as part of the usual standard of 
care.33  In addition, the written informed consent will not contain any information about the 12-
month healthcare utilization follow-up as this is routinely collected data that will be de-
identified and analysed in aggregate thus posing no additional burden or risk to the safety of 
the participants.   
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 45 of 53 
 
27 
Confidentiality 
 
All participant data pertaining to the study will be stored in a computer database maintaining 
confidentiality in accordance with PHIPA regarding privacy and use of health data. When 
archiving or processing data pertaining to the investigators and/or to the participants, the RVH 
Research Institute will take all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party.  
 
The investigators will maintain the confidentiality of all study documentation and take 
measures to prevent accidental or premature destruction of these documents.  After the 
completion or discontinuation of the study the investigators will retain the study documents  
twenty-five (25) years in Canada as required by regulation. The investigators must notify the 
RVH Research Institute prior to destroying any study documents following study completion or 
discontinuation. If the investigators’ situation is such that archiving can no longer be ensured, 
the investigators will inform the RVH Research Institute, and the relevant records will be 
transferred to a mutually agreed designee.  
 
If any of the investigators retire, relocate, or otherwise withdraw from conducting the study, 
the responsibility for maintaining records may be transferred to the RVH Research Institute or 
another investigator. The RVH Research Institute must be notified of and agree to the change. 
All associated documentation must also be updated. 
 
28 
Declaration of Interests 
 
GD and PW have never received any salary support or grants, honoraria, paid consultancies or 
service on advisory boards and medical education companies, receipt of patents or patents 
pending, ownership of stocks or options from INDIVIOR. 
29 
Access to data 
 
The RVH Research Institute will oversee the intra-study data sharing process, with input from 
the Data Management Committee. 
 
The Principal Investigators will be given access to the cleaned data sets. Study data sets will be 
housed on the RVH REDCap web-site created for the study, and all data sets will be password 
protected.  The Principal Investigators will have direct access to the data sets. To ensure 
confidentiality, any data dispersed to the study RAAM clinic healthcare providers or study 
personnel will be de-identified participant information and aggregated whenever feasible. 
30 
Post-trial care 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 46 of 53 
 
Should this study provide evidence of the superior effectiveness of Sublocade® compared to 
Suboxone®, it will be critical to provide ongoing access to this drug for those study participants 
who were allocated to Sublocade® and for those who were allocated to Suboxone®.  For those 
patients who do not qualify for the Ontario Drug Benefit plan or do not have private health 
insurance to cover the ongoing costs of treatment or cannot afford to pay out-of-pocket for 
Sublocade®, discussions will be initiated with other RAAM clinic healthcare providers across 
Canada, along with federal and provincial health agencies, to encourage the bulk purchase of 
Sublocade® and provision at low or no cost to RAAM clinics for use in uninsured patients with 
OUD eligible for opiate substitution therapy with long-acting buprenorphine. 
31 
Trial results and authorship 
 
The study will be conducted in the name of the ‘STOP-IT Trial Investigators’. Overall project 
coordination and data management will be provided by the RVH Research Institute.  Study 
results will be disseminated via abstracts, trial registry, journal publication and RVH Research 
Institute and RAAM clinic websites regardless of the magnitude or direction of effect. 
  
Authorship of publications arising from the study will be consistent with current International 
Committee of Medical Journal Editors’ recommendations 
(http://www.icmje.org/recommendations/) with full credit assigned to all collaborating 
investigators, healthcare providers, study personnel and institutions. Responsibility for the 
content of manuscripts will rest with the Principal Investigators, and where listed, Philip Wong 
will be listed as first author and Giulio DiDiodato will be listed as corresponding author, with all 
other subsequent members listed alphabetically following Philip Wong and preceding Giulio 
DiDiodato. 
  
Funding bodies will be acknowledged in all publications. 
 
32 
Reproducible research 
 
The trial protocol, full study report, de-identified participant-level dataset, and statistical code 
for generating the results will be made publicly available no later than 3 years after study 
closure to an appropriate data archive for sharing purposes. 
 
 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 47 of 53 
 
33 
References 
 
 
1. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(5th ed.). (American Psychiatric Publishing, Inc., 2013). 
2. 
Ontario Agency for Health Protection and Promotion. Opioid mortality surveillance 
report: analysis of opioid-related deaths in Ontario July 2017-June 2018. (2019). 
3. 
Special Advisory Committee on the Epidemic of Opioid Overdoses. Opioid and Stimulant-
related Harms in Canada. https://health-infobase.canada.ca/substance-related-
harms/opioids-stimulants/ (2021). 
4. 
Public Health Ontario. Opioid-related Morbidity and Mortality in Ontario. 
https://www.publichealthontario.ca/en/data-and-analysis/substance-use/interactive-
opioid-tool#/trends (2021). 
5. 
Nielsen, S. et al. Opioid agonist treatment for pharmaceutical opioid dependent people. 
Cochrane database Syst. Rev. CD011117 (2016) doi:10.1002/14651858.CD011117.pub2. 
6. 
Bruneau, J. et al. Management of opioid use disorders: a national clinical practice 
guideline. Can. Med. Assoc. J. 190, E247–E257 (2018). 
7. 
Sordo, L. et al. Mortality risk during and after opioid substitution treatment: systematic 
review and meta-analysis of cohort studies. BMJ 357, j1550 (2017). 
8. 
Bahji, A., Cheng, B., Gray, S. & Stuart, H. Reduction in mortality risk with opioid agonist 
therapy: a systematic review and meta-analysis. Acta Psychiatr. Scand. 140, 313–339 
(2019). 
9. 
Galanter, M., Femino, J., Hunter, B. & Hauser, M. Buprenorphine Treatment for Opioid 
Use Disorder in Community-Based Settings: Outcome Related to Intensity of Services and 
Urine Drug Test Results. Am. J. Addict. 29, 271–278 (2020). 
10. 
Wiercigroch, D., Sheikh, H. & Hulme, J. A rapid access to addiction medicine clinic 
facilitates treatment of substance use disorder and reduces substance use. Subst. Abuse 
Treat. Prev. Policy 15, 4 (2020). 
11. 
Koehl, J. L., Zimmerman, D. E. & Bridgeman, P. J. Medications for management of opioid 
use disorder. Am. J. Heal. Pharm. 76, 1097–1103 (2019). 
12. 
Lofwall, M. R. et al. Weekly and monthly subcutaneous buprenorphine depot 
formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid 
use disorder a randomized clinical trial. JAMA Intern. Med. 178, 764–773 (2018). 
13. 
Rosenthal, R. N. et al. Buprenorphine implants for treatment of opioid dependence: 
randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction 
108, 2141–2149 (2013). 
14. 
Rosenthal, R. N. et al. Effect of buprenorphine implants on illicit opioid use among 
abstinent adults with opioid dependence treated with sublingual buprenorphine a 
randomized clinical trial. JAMA - J. Am. Med. Assoc. 316, 282–290 (2016). 
15. 
Ontario Drug Policy Research Network. Ontario Opioid Prescription Tool. 
https://odprn.ca/ontario-opioid-drug-observatory/ontario-prescription-opioid-tool/ 
(2018). 
16. 
Canadian Agency for Drugs and Technologies in Health. Pharmacoeconomic Review 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 48 of 53 
 
Report: Buprenorphine extended-release injection (Sublocade). 
https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/sr0579-sublocade-
pharmacoeconomic-review-report.pdf (2019). 
17. 
Addictions & Mental Health Ontario. Ontario Provincial Standards for Withdrawal 
Management Services: 2021 Standards Manual. https://amho.ca/wp-
content/uploads/AMHO-Final-WMS-Ontario-Provincial-Standards-for-Withdrawal-
Management-Services-September-2021-AMHO-FINAL.pdf (2021). 
18. 
Brens, C., Swoboda-Geen, C. & Gill, S. Simcoe Muskoka Opioid Strategy: An Action Plan 
for Our Communities. http://preventod.ca/Shared Documents/SMOS/SMOS Final Report 
- An Action Plan for Our Communities.pdf (2018). 
19. 
Wesson, D. R. & Ling, W. The Clinical Opiate Withdrawal Scale (COWS). J. Psychoactive 
Drugs 35, 253–259 (2003). 
20. 
McMillan, D. E. & Gilmore-Thomas, K. Stability of opioid craving over time as measured 
by visual analog scales. Drug Alcohol Depend. 40, 235–239 (1996). 
21. 
Fals-Stewart, W., O’Farrell, T. J., Freitas, T. T., McFarlin, S. K. & Rutigliano, P. The Timeline 
Followback reports of psychoactive substance use by drug-abusing patients: 
Psychometric properties. J. Consult. Clin. Psychol. 68, 134–144 (2000). 
22. 
Reith, F. C. M., Van den Brande, R., Synnot, A., Gruen, R. & Maas, A. I. R. The reliability of 
the Glasgow Coma Scale: a systematic review. Intensive Care Med. 42, 3–15 (2016). 
23. 
Institute for Clinical Evaluative Sciences. Data Dictionary. ICES Data Holdings Obligations 
for ICES Projects 
https://datadictionary.ices.on.ca/Applications/DataDictionary/Default.aspx?viewmode=
DataAccess (2021). 
24. 
Appropriate Use of Drug Testing in Clinical Addiction Medicine. J. Addict. Med. 11, 1–56 
(2017). 
25. 
Fals-Stewart, W., O’Farrell, T. J., Freitas, T. T., McFarlin, S. K. & Rutigliano, P. The Timeline 
Followback reports of psychoactive substance use by drug-abusing patients: 
Psychometric properties. Journal of Consulting and Clinical Psychology vol. 68 134–144 
(2000). 
26. 
Dennis, B. B. et al. A call for consensus in defining efficacy in clinical trials for opioid 
addiction: combined results from a systematic review and qualitative study in patients 
receiving pharmacological assisted therapy for opioid use disorder. Trials 21, 30 (2020). 
27. 
Vernon, M. K. et al. Psychometric evaluation of the Medication Satisfaction 
Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophr. Res. 118, 271–278 (2010). 
28. 
Ling, W. et al. Patient-centered Outcomes in Participants of a Buprenorphine Monthly 
Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study. J. Addict. 
Med. 13, 442–449 (2019). 
29. 
World Health Organization. The World Health Organization Quality of Life (WHOQOL). 
WHOQOL BREF (2012). 
30. 
Harris, P. A. et al. The REDCap consortium: Building an international community of 
software platform partners. J. Biomed. Inform. 95, 103208 (2019). 
31. 
Harris, P. A. et al. Research electronic data capture (REDCap)—A metadata-driven 
methodology and workflow process for providing translational research informatics 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 49 of 53 
 
support. J. Biomed. Inform. 42, 377–381 (2009). 
32. 
Ministry of Health & Long-Term Care. Personal Health Information Protection Act. 
https://www.ontario.ca/laws/statute/04p03 (2004). 
33. 
Dal-Ré, R. et al. Low risk pragmatic trials do not always require participants’ informed 
consent. BMJ 364, l1092 (2019). 
 
  
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 50 of 53 
 
 
34 
Appendices 
 
All data collection tools described in this section will be created and stored in REDCap.  The 
links to the tools are solely intended to provide the REB committee members easy access to 
the contents of these tools for their review.   
 
34.1 OUD DSM-V Diagnostic Criteria for OUD 
 
Source for review of contents: 
 
https://www.asam.org/docs/default-source/education-docs/dsm-5-dx-oud-8-28-
2017.pdf?sfvrsn=70540c2_2  
 
34.2 Clinical Opiate Withdrawal Scale 
 
Source for review of contents: 
 
https://www.mdcalc.com/cows-score-opiate-withdrawal  
 
34.3 Opiate Craving Visual Analog Scale 
 
Linear scale is 10 cm long, anchored at the left end by the phrase “no craving at all” and at the 
right end by “strongest craving ever”.  Slider is moved by the participant to mark the location 
on the linear scale that most closely measures the intensity of the strongest craving 
experienced during the previous 24 hours. 
 
34.4 Timeline Followback questionnaire 
 
Source for review of contents: 
 
https://cde.drugabuse.gov/sites/nida_cde/files/TimeLineFollowBack_2014Mar24.pdf  
 
34.5 World Health Organization Quality of Life (Brief) Questionnaire 
 
Source for review of contents: 
 
https://neurotoolkit.com/whoqol-bref/  
 
 
 
 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 51 of 53 
 
34.6 ICES Support Letter 
 
 
 
 
Monday, November 15, 2021 
 
 
Dr. Giulio DiDiodato 
Royal Victoria Regional Health Centre 
201 Georgian Drive 
Barrie, Ontario, L4M6M2 
 
Dear Dr. DiDiodato, 
 
Re: 
Confirmation of Feasibility 
 
The Institute for Clinical Evaluative Sciences (ICES) and ICES Data & Analytic Services (DAS) is pleased to provide conditional 
confirmation of feasibility for the research submitted by you and your colleagues, entitled “A pragmatic, multi-centre, open-label, 
randomized, 12-month, parallel group, superiority study to compare the effectiveness of subcutaneous buprenorphine depot 
(Sublocade®) vs daily sublingual buprenorphine with naloxone (Suboxone®) for the treatment of opioid use disorder” and the 
associated data and analytic services as outlined in Appendix A (“Research Plan”).  
 
Funding for ICES DAS comes in part through support from the Ontario Ministry of Health and Long Term Care, the Ministry of Research 
and Innovation, and the Canadian Institutes for Health Research. ICES DAS provides in-kind support for upfront consultation required 
to determine feasibility and ongoing administrative services associated with managing your research. An estimate of the total cost for 
providing your research team with virtual access to ICES data and  the analytic consultation and support for ICES to provide data cut  
and analytic services is attached.  These figures are included in Appendix B (“Services Quote”) and are intended to aid in applying for 
research funding.  Please note that this Services Quote is subject to change if there are any changes to the scope, funding or feasibility 
at any point during your engagement with ICES Data & Analytic Services. 
 
While the research meets the eligibility criteria for accessing ICES DAS, research initiation will only occur upon receipt of an approval 
letter from a valid Research Ethics Board (REB) (see Appendix C) and corresponding application. It is the responsibility of the Principal 
Investigator to complete the Research Plan in its entirety prior to submission. The REB application must include this document as 
supporting documentation in order to ensure that the REB is authorizing the intended research.  
 
ICES policy will require that the Principal Investigator confirms how and when the funds are used to support this research are derived 
from public or publicly-funded sources, that your interest in the disclosure of the data for your research purpose will not result in actual, 
perceived or potential conflict of interest. If you have any questions please contact das@ices.on.ca or 416-480-4092 (toll-free 1-844-
848-9855). 
 
Once you provide all conditional requirements ICES will provide you with an ICES Data & Analytic Services Agreement that governs the 
research and, upon execution allows the research to be activated. 
 
We look forward to working with you and your colleagues. 
 
Yours sincerely, 
 
Refik Saskin 
Staff Scientist 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 52 of 53 
 
35 
Budget 
 
All costs will be supported by in-kind funding from the Centre for Education & Research and the 
RAAM clinics. 
 
Cost Component 
Persons Involved 
Total time 
(hours) 
Cost 
per 
hour 
Total 
Cost ($) 
Study-related products & 
training 
 
 
 
 
Enrollment logs/Participant 
master files 
Randomization module 
Electronic case report form 
Standard operating 
procedures 
Training manuals 
Delegation logs 
Centre for Education 
& Research (CER) 
 
RAAM Clinic 
 
Research 
coordinator 
100 
 
 
20 
 
100 
150 
 
 
100 
 
40.50 
15 000 
 
 
2 000 
 
4 050 
Healthcare provider 
engagement & training 
Research 
coordinator 
Study nurse 
40 
20 
40.50 
48.50 
1620 
970 
Study brochures 
Study posters 
Patient instructions 
Research personnel 
business cards 
Research 
coordinator 
Study nurse 
Materials 
10 
 
10 
N/A 
40.50 
 
48.50 
N/A 
405 
 
485 
1000 
Research ethics board 
application  
Study nurse 
RAAM clinic 
40 
20 
48.50 
100 
1 940 
2 000 
Protocol review prior to 
research ethics board 
submission 
Research manager 
N/A 
N/A 
700 
Research Ethics Board Fee  
Research Ethics 
Board 
N/A 
N/A 
500 
Subtotal 
 
 
 
30 670 
Trial Management 
 
 
 
 
Eligibility screening  
Informed consent 
Enrollment 
Randomization 
Study nurse 
328 (2 hr/pt) 
48.50 
15 908 
MSQ 
WHOQOL-BREF 
UDS 
Research 
coordinator 
328 (2 
hr/patient) 
40.50 
13 284 

STOP-IT                                                                                                          VERSION 4.0 (10-Aug-2022)  
 
 
Page 53 of 53 
 
Case report form 
completion 
Research 
coordinator 
328 (2 
hr/patient) 
40.50 
13 284 
Site/data audit/close out 
Research 
coordinator 
180 (15 
hr/month) 
40.50 
7 290 
Drug storage 
Dispensation 
Study drug logs 
Pharmacist 
120 (10 
hr/month) 
72.10 
8 652 
Subtotal 
 
 
 
58 418 
Data Analysis 
 
 
 
 
Validation 
Study monitor 
20 (1 
hr/patient) 
37.50 
750 
Cleaning 
Statistical analysis 
Data report 
CER 
40 
150 
6 000 
Healthcare utilization data  
ICES 
N/A 
N/A 
12 587 
Subtotal 
 
 
 
19 337 
Report 
 
 
 
 
Publication costs (protocol 
and final publication) 
Journal fees 
N/A 
N/A 
5 000 
Subtotal 
 
 
 
5 000 
Final Costs 
 
 
 
113 425