Monthly Versus Daily Buprenorphine Formulations for Treatment of Opiate Use Disorder

Study Overview
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Brief Summary
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Opioid use disorder and opioid-related deaths are increasing across Canada. The mainstay of medical treatment includes either full (methadone) or partial (buprenorphine) opioid agonist therapy. In Canada, there are 2 buprenorphine formulations, an immediate-release (Suboxone) and extended-release(Sublocade). These treatments have been shown to be equivalent for medication adherence and treatment retention. However, Sublocade costs 8-times more, and 50% of patients must pay out-of-pocket if they prefer this treatment option. This study is needed to demonstrate the superior benefits of Sublocade on important clinical outcomes to demonstrate its cost-effectiveness and justify expanded insured access across Canada.

Detailed Description
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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. 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. Opioid use disorder and opioid-related deaths are increasing in Ontario and Canada. 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. Like deaths, opioid-related healthcare utilization as measured by hospitalization and emergency department visits have also been increasing over the same time period. 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. 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). 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. There are 2 main opioid agonists used to treat OUD, methadone and buprenorphine. 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. The Canadian pharmaceutical costs of Sublocade® and Suboxone® differ substantially , with monthly costs for Sublocade 8-fold higher than Suboxone. 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. 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 Suboxone is limited by the absence of studies directly comparing the effectiveness of the two treatments on clinically important outcomes such as healthcare utilization. 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 Suboxone. 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 for this at-risk population.

Official Title
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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

Conditions
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Moderate to Severe Opioid Use Disorder

Intervention / Treatment
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* Drug: Extended Release Subcutaneous Buprenorphine
* Drug: Immediate Release Sublingual Buprenorphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18 to 65 years old OAT indicated for moderate- to severe-OUD Attend a RAAM clinic in the North Simcoe Muskoka Local Health Integrated Network for opiate substitution treatment 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 Scale (COWS) score ≤12 (scale:0-48) for ≥24 hours, and Opiate Craving Visual Analog Scale (VAS) score ≤20 (scale:0-100)) for ≥24 hours Must have an active Ontario Health Insurance Plan number Must have a telephone that can receive calls, text messages or emails 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: Receiving any investigational drug for OUD in previous 4 weeks Congenital long QTc syndrome or QTc prolongation at baseline by electrocardiogram (QTc ≥450 milliseconds in men and QTc ≥470 milliseconds in women) Pregnant or lactating women Women of childbearing potential who are not using an effective and reliable method of contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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): RAAM clinic site (Barrie, Orillia, Midland, Wasaga Beach) Severity of OUD according to DSM-V criteria (moderate vs severe)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extended-release subcutaneous buprenorphine (SC-BPN-XR)<br>For eligible patients randomly allocated to SC-BPN-XR, the first dose will be administered at the time of randomization (Day 0). SC-BPN-XR comes in two formulations, 100 mg and 300 mg buprenorphine doses in a pre-filled syringe. SC-BPN-XR administration is by subcutaneous injection in the abdomen. SC-BPN-XR is administered at intervals ≥26 days. For patients randomly allocated to SC-BPN-XR, 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 SC-BPN-XR doses will be administered in clinics by trained personnel. All patients receiving SC-BPN-XR will have their vital signs monitored every 5 minutes for 15 minutes after the injection before leaving the clinic. | Drug: Extended Release Subcutaneous Buprenorphine<br>* Monthly subcutaneous injections of long-acting buprenorphine<br>* Other names: Sublocade;|
| Active Comparator: Immediate-release sublingual buprenorphine/naloxone (SL-BPN/NX)<br>For eligible patients randomly allocated to SL-BPN/NX, the first study dose will be administered at the time of randomization (Day 0) and will match the SL-BPN/NX 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 SL-BPN/NX 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. | Drug: Immediate Release Sublingual Buprenorphine<br>* Daily sublingual fast-acting buprenorphine<br>* Other names: Suboxone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | every 7 days for 12 months | 
| 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. Only those healthcare days in which opioid use was considered to be influential to the ER visit or hospitalization will be included in the final analysis. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Medication Satisfaction | Difference in the Medication Satisfaction Questionnaire 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. | Every 6 weeks starting on week 6 after randomization for 12 months | 
| Quality of Life Score | Difference in the World Health Organization Quality of Life - BREF 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. | At time of randomization (baseline), then week 12, week 24 and week 36 | 
| 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. 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. | 12 months | 
| Mortality | Difference in mortality proportions, where mortality is defined as any death attributable to opioid use regardless of the intent. | 12 months |