Comparing Outpatient Treatment Retention Among Individuals Using Fentanyl Randomized to Low-dose and Direct-to-inject Buprenorphine Initiation (COPILOT)

Improving Buprenorphine Initiation Among Individuals With Opioid Use Disorder Using Fentanyl

The goal of this pragmatic randomized controlled trial is to compare treatment outcomes of two strategies for initiating buprenorphine treatment (low-dose initiation and direct-to-inject) in adults with opioid use disorder (OUD) who use fentanyl. This study aims to:

1. Compare effectiveness of each strategy on treatment retention in a real world, clinical setting, and
2. Assess differences between strategies in patient-reported outcomes, including withdrawal symptoms, cravings, drug use, treatment satisfaction, and overall acceptability.

Participants will:

1. Be randomized to initiate buprenorphine via a low-dose initiation or direct-to-inject protocol at an outpatient buprenorphine clinic,
2. Keep a diary of craving and withdrawal symptoms for the first 7 days after initiation, and
3. Visit the outpatient clinic 7, 30, and 90 days after initiation for urinary drug screen and follow-up surveys.

Study Overview

• Status: Not yet recruiting
• Conditions: Opioid Use Disorder; Fentanyl
• Intervention / Treatment: Drug: Sublingual Buprenorphine (SUBOXONE, Zubsolv, or generic tablets); Drug: Injectable buprenorphine

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Leslie W Suen, MD; Phone Number: 628-206-6007; Email: leslie.suen@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94103
      • San Francisco Outpatient Buprenorphine Induction Clinic
      • Contact: Tricia Wright, MD; Phone Number: 628-754-9201; Email: Tricia.Wright@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years of age at Visit 1.
• Documentation of an OUD diagnosis as evidenced by meeting two or more of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) Criteria for Opioid Use Disorder
• Self-reported daily use of fentanyl ≥ 5 out of the past 7 days at baseline,
• Fentanyl-positive urine drug screening at baseline,
• Interest in stopping or reducing fentanyl use,
• Publicly insured through San Francisco Medicaid or Medicare and therefore able receive buprenorphine prescription dispensing through Community Behavioral Health Services (CBHS) Pharmacy

Exclusion Criteria:

• Currently nursing, pregnant, or anticipating pregnancy in the next 6 months
• Methadone-positive urine drug screening at baseline
• Buprenorphine-positive urine drug screening at baseline
• Be unable to provide any locator or contact information at least one contact in addition to themselves
• Any pending legal action that could prevent participation in study activities
• Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data (e.g., acute psychosis), or cognitive impairment (e.g., dementia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low-dose initiation (LDI); Participants start 0.5mg sublingual buprenorphine (Subutex) and gradually increase by 0.5-1.0mg daily for 7 days	Drug: Sublingual Buprenorphine (SUBOXONE, Zubsolv, or generic tablets); Starting dose (0.5mg) of sublingual buprenorphine tablets in blister packs (Brixadi or Sublocade) on day 1, followed by 0.5-1.0mg daily increases in week 1 and maintenance dosing based on shared decision-making with provider; Other Names: Suboxone; Low-dose buprenorphine initiation; Buprenorphine blister packs
Experimental: Direct-to-inject (DTI); Participants receive 8-32mg long-acting injectable buprenorphine (Brixadi or Sublocade) on day 1, followed by monthly injections as discussed with the provider	Drug: Injectable buprenorphine; Starting dose (8-32mg) of long-acting injectable buprenorphine (Brixadi or Sublocade) on day 1, followed by monthly maintenance doses (e.g., 128mg Brixadi or 300mg Sublocade); Other Names: Sublocade; Brixadi; Direct-to-inject; Long-acting injectable buprenorphine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Continuous retention in outpatient buprenorphine treatment by day 90	Receiving continuous treatment with buprenorphine sublingual prescriptions or injections administrations during the 90 days of follow up post-randomization as intended-to-treat. A period without buprenorphine treatment ≥8 days will be considered treatment discontinuation. Number of days of continuous treatment with the site clinician prescribing sublingual or injectable buprenorphine treatment during the 90 days post-randomization among RCT participants	90 days
Self-reported protocol satisfaction at day 7	Patient-reported satisfaction with buprenorphine initiation protocol measured by Likert-scale satisfaction survey administered on day 7 follow-up visit	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Per protocol and as-treated retention in outpatient buprenorphine treatment at day 90	Similar to the primary intention to treat analysis, though we will be analyzing data and individuals based on actual protocol received and treated, rather than assigned treatment at randomization	90 days
Successful buprenorphine initiation within first 7 days	Defined as successfully completing buprenorphine initiation. For LDI treatment arm, this means self-reported completion of initiation "blister pack" during Days 1-6 at clinical follow up and pick up of buprenorphine refill based on prescription data. For DTI, this means administration of initial weekly BRIXADI injection and subsequent monthly BRIXADI or SUBLOCADE buprenorphine injection within 7 days of the initial weekly injection.	7 days
Fentanyl use during days 1-7 determiend by urinary drug screen	Concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by urinary drug screen at day 7 follow-up visit.	7 days
Fentanyl use during days 8-30 determined by urinary drug screen	Concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by urinary drug screen at day 30 follow-up visit.	30 days
Fentanyl use during days 31-90 determined by urinary drug screen	Concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by urinary drug screen at day 90 follow-up visit.	90 days
Self-reported concurrent fentanyl use during days 1-7	Concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 7 follow-up visit.	7 days
Self-reported concurrent fentanyl use during days 8-30	Concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 30 follow-up visit.	30 days
Self-reported concurrent fentanyl use during days 31-90	Concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 90 follow-up visit.	90 days
Self-reported number of days of fentanyl use in first 7 days	Number of days of concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 7 follow-up visit.	7 days
Self-reported number of days of concurrent fentanyl use during first 30 days	Number of days of concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 30 follow-up visit.	30 days
Self-reported number of days of concurrent fentanyl use during days 31-90	Number of days of concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 90 follow-up visit.	90 days
Baseline withdrawal symptoms, measured with COWS	At baseline, a Clinical Opioid Withdrawal Score (COWS) survey will be administered and confirmed with the prescribing clinician.	0 days
Standardized self-reported daily withdrawal symptom severity over days 1-7 by SOWS	During each of the first 7 days, participants will rate the severity of withdrawal symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Subjective Opioid Withdrawal Scale [SOWS] (from 0-4, with 0 being not at all and 4 being extreme) to assess for subjective withdrawal symptoms to minimize participant burden while ensuring reliable data capture.	7 days
Standardized self-reported peak withdrawal symptom severity during days 1-7 by SOWS	During each of the first 7 days, participants will rate the severity of withdrawal symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Subjective Opioid Withdrawal Scale [SOWS] (from 0-4, with 0 being not at all and 4 being extreme) to assess for subjective withdrawal symptoms to minimize participant burden while ensuring reliable data capture. We will calculate peak withdrawal symptoms during the 7-day period.	7 days
Standardized self-reported daily craving symptom severity over days 1-7 by VAS	During each of the first 7 days, participants will rate the severity of craving symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Visual Analog Scale [VAS] (from 0-100, with 0 being none at all and 100 being strongest craving ever) to assess for subjective craving symptoms to minimize participant burden while ensuring reliable data capture.	7 days
Standardized self-reported peak craving symptom severity during days 1-7 by VAS	During each of the first 7 days, participants will rate the severity of craving symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Visual Analog Scale [VAS] (from 0-100, with 0 being none at all and 100 being strongest craving ever) to assess for subjective craving symptoms to minimize participant burden while ensuring reliable data capture. We will calculate the peak craving severity during the first 7 days.	7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall number of adverse events in each arm within 30 days, and by relatedness to study intervention	Number of adverse events within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.	30 days
Number of serious adverse events in each arm in 30 days, and by relatedness to the study intervention	Number of serious adverse events within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.	30 days
Number of ED visits and hospital admissions in each arm in 30 days, and by relatedness to study intervention	Number of emergency department visits and hospital admissions within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.	30 days
Number of fatal opioid overdose events occurring during the 90-day follow-up period, by study arm	Documented deaths due to opioid overdose during the 90-day follow-up period will be identified through the EHR and, if available, linkage to external death records.	90 days
Treatment Fidelity and Protocol Adherence	Study staff will track whether the assigned LDI or DTI protocol was delivered as intended, including any deviations from the dosing schedule or logistical challenges encountered	90 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Leslie W Suen, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Noel M, Abbs E, Suen L, Samuel L, Dobbins S, Geier M, Soran CS. The Howard Street Method: A Community Pharmacy-led Low Dose Overlap Buprenorphine Initiation Protocol for Individuals Using Fentanyl. J Addict Med. 2023 Jul-Aug 01;17(4):e255-e261. doi: 10.1097/ADM.0000000000001154. Epub 2023 Feb 17.
• Rosenwohl-Mack S, Suen LW, Logan AA, Peterson D, Snyder HR. Outpatient Initiation of 7-Day Injectable Buprenorphine: A Direct-to-Inject Case Series. Subst Use Addctn J. 2025 Oct;46(4):1064-1069. doi: 10.1177/29767342251330412. Epub 2025 Apr 4.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: February 20, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Medication for opioid use disorder; Low-dose initiation; Buprenorphine initiation; Direct-to-inject initiation; Outpatient treatment for opioid use disorder
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Drug Combinations; Naloxone; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Buprenorphine, Naloxone Drug Combination; Buprenorphine; Sublocade
• Other Study ID Numbers: 1K23DA060329-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared outside of this study's research team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No