Buprenorphine-Fentanyl Interaction Study

NCT03747341 | Completed Phase 1

• 3 other identifiers: INDV-6000-1012017-004858-42CHDR1754
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

An increase in overdose deaths has been attributed to widespread access to fentanyl and carfentanyl. The study is designed to determine if buprenorphine can change the respiratory depression response to intravenous (IV) fentanyl.

Conditions

Healthy; Opioid Use

Outcome Measures

Primary Outcomes (1)

• Changes in peak ventilatory depression will be measured.

  Peak ventilatory depression (change in minute ventilation) will be calculated based on a 1-minute average of the ventilation data of each individual subject/patient. For buprenorphine or placebo, absolute changes and percentage changes are calculated from the baseline value. For fentanyl, absolute changes and percentage changes for each bolus are calculated from the baseline value and from the pre-fentanyl baseline value immediately before the first fentanyl bolus

  6 hours (during study drug infusion)

Secondary Outcomes (2)

• Number (percentage) of subjects who experience apnoea for each fentanyl dose during the placebo treatment vs. the buprenorphine treatment

  6 hours

• Number (percentage) of subjects who require stimulation for breathing for each fentanyl dose during the placebo treatment vs. the buprenorphine treatment.

  6 hours

Study Arms (7)

Part A (Healthy Participants): Placebo-Buprenorphine Low

EXPERIMENTAL

Three treatment periods consisting of 3 days each of investigational treatment * 1=placebo + fentanyl, * 2=low dose buprenorphine + fentanyl, * 3 (optional)=low dose buprenorphine only Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.075, 0.15, 0.25 and 0.35 mg/70 kg. Each dosing period was followed by 10-17 days of washout.

Drug: Buprenorphine Injectable Solution - Part A; Drug: Placebo - Parts A + B; Drug: Fentanyl - Part A; Drug: Ondansetron - Parts A + B

Part A (Healthy Participants): Placebo-Buprenorphine High

EXPERIMENTAL

Three treatment periods consisting of 3 days each of investigational treatment * 1=placebo + fentanyl, * 2=high dose buprenorphine + fentanyl, * 3 (optional)=high dose buprenorphine only Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.075, 0.15, 0.25 and 0.35 mg/70 kg. Each dosing period was followed by 10-17 days of washout.

Drug: Buprenorphine Injectable Solution - Part A; Drug: Placebo - Parts A + B; Drug: Fentanyl - Part A; Drug: Ondansetron - Parts A + B

Part A (Healthy Participants): Buprenorphine Low-Placebo

EXPERIMENTAL

Three treatment periods consisting of 3 days each of investigational treatment * 1=low dose buprenorphine + fentanyl, * 2=placebo + fentanyl, * 3 (optional)=low dose buprenorphine only Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.075, 0.15, 0.25 and 0.35 mg/70 kg. Each dosing period was followed by 10-17 days of washout.

Drug: Buprenorphine Injectable Solution - Part A; Drug: Placebo - Parts A + B; Drug: Fentanyl - Part A; Drug: Ondansetron - Parts A + B

Part A (Healthy Participants): Buprenorphine High-Placebo

EXPERIMENTAL

Three treatment periods consisting of 3 days each of investigational treatment * 1=high dose buprenorphine + fentanyl, * 2=placebo + fentanyl, * 3 (optional)=high dose buprenorphine only Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.075, 0.15, 0.25 and 0.35 mg/70 kg. Each dosing period was followed by 10-17 days of washout.

Drug: Buprenorphine Injectable Solution - Part A; Drug: Placebo - Parts A + B; Drug: Fentanyl - Part A; Drug: Ondansetron - Parts A + B

Part B (Opioid-Tolerant): Placebo-Buprenorphine Low

EXPERIMENTAL

Opioid-tolerant participants in Part B undergo a washout of their own opioids during which these were replaced with oral oxycodone, and continue at stable doses of oxycodone from at least 48 hours before Period 1 to the end of Period 2. Two treatment periods: * 1=placebo (Day 1), * 2=low dose buprenorphine + fentanyl (Day 3) Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.25, 0.35, 0.5 and 0.7 mg/70 kg.

Drug: Placebo - Parts A + B; Drug: Ondansetron - Parts A + B; Drug: Buprenorphine Injectable Solution - Part B; Drug: Fentanyl - Part B; Drug: Oxycodone - Part B

Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

EXPERIMENTAL

Opioid-tolerant participants in Part B undergo a washout of their own opioids during which these were replaced with oral oxycodone, and continue at stable doses of oxycodone from at least 48 hours before Period 1 to the end of Period 2. Two treatment periods: * 1=placebo (Day 1), * 2=mid dose buprenorphine + fentanyl (Day 3) Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.25, 0.35, 0.5 and 0.7 mg/70 kg.

Drug: Placebo - Parts A + B; Drug: Ondansetron - Parts A + B; Drug: Buprenorphine Injectable Solution - Part B; Drug: Fentanyl - Part B; Drug: Oxycodone - Part B

Part B (Opioid-Tolerant): Placebo-Buprenorphine High

EXPERIMENTAL

Opioid-tolerant participants in Part B undergo a washout of their own opioids during which these were replaced with oral oxycodone, and continue at stable doses of oxycodone from at least 48 hours before Period 1 to the end of Period 2. Two treatment periods: * 1=placebo (Day 1), * 2=high dose buprenorphine + fentanyl (Day 3) Fentanyl was administered as a bolus over 90 seconds in escalating doses of 0.25, 0.35, 0.5 and 0.7 mg/70 kg.

Drug: Placebo - Parts A + B; Drug: Ondansetron - Parts A + B; Drug: Buprenorphine Injectable Solution - Part B; Drug: Fentanyl - Part B; Drug: Oxycodone - Part B

Interventions

Buprenorphine Injectable Solution - Part A DRUG

Buprenorphine intravenous (IV) injection given as a primed-continuous infusion. Low Dose: initial bolus (0.05 mg/70 kg) administered over 15 minutes and infusion continued (0.02 mg/70 kg/hour infusion rate) to complete 360 minutes of administration targeting 0.2 ng/ml. High Dose: initial bolus (0.125 mg/70 kg) administered over 15 minutes and infusion continued (0.05 mg/70 kg/hour infusion rate) to complete 360 minutes of administration targeting 0.5 ng/ml. Administration of buprenorphine was flexible and infusion rates were selected to target approximately 25 to 50% respiratory depression.

Also known as: TEMGESIC®

Part A (Healthy Participants): Buprenorphine High-Placebo; Part A (Healthy Participants): Buprenorphine Low-Placebo; Part A (Healthy Participants): Placebo-Buprenorphine High; Part A (Healthy Participants): Placebo-Buprenorphine Low

Placebo - Parts A + B DRUG

0.9% normal saline for IV administration was used as placebo matching the buprenorphine formulation and administration.

Part A (Healthy Participants): Buprenorphine High-Placebo; Part A (Healthy Participants): Buprenorphine Low-Placebo; Part A (Healthy Participants): Placebo-Buprenorphine High; Part A (Healthy Participants): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine High; Part B (Opioid-Tolerant): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

Fentanyl - Part A DRUG

Participant received up to four fentanyl doses: 0.075, 0.15, 0.25, and 0.35 mg/70 kg in Periods 1 and 2. Fentanyl boluses were administered over 90 seconds by dose escalation +2hr, +3hr, +4hr and +5hr after starting administration of buprenorphine/ placebo. Administration of fentanyl was flexible and bolus doses were selected to elicit moderate to more severe respiratory depression with apnoea ≥20 seconds.

Part A (Healthy Participants): Buprenorphine High-Placebo; Part A (Healthy Participants): Buprenorphine Low-Placebo; Part A (Healthy Participants): Placebo-Buprenorphine High; Part A (Healthy Participants): Placebo-Buprenorphine Low

Ondansetron - Parts A + B DRUG

A non-investigational intervention administered as an infusion prior to investigation intervention. 4 mg of ondansetron was administered to manage the expected gastrointestinal side effect (nausea, vomiting) to buprenorphine.

Part A (Healthy Participants): Buprenorphine High-Placebo; Part A (Healthy Participants): Buprenorphine Low-Placebo; Part A (Healthy Participants): Placebo-Buprenorphine High; Part A (Healthy Participants): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine High; Part B (Opioid-Tolerant): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

Buprenorphine Injectable Solution - Part B DRUG

Buprenorphine intravenous (IV) injection given as a primed-continuous infusion. Low Dose: initial bolus (0.25 mg/70 kg) administered over 15 minutes and infusion continued (0.1 mg/70 kg/hour infusion rate) to complete 360 minutes of administration targeting 1 ng/ml. Mid Dose: initial bolus (0.5 mg/70 kg) administered over 15 minutes and infusion continued (0.2 mg/70 kg/hour infusion rate) to complete 360 minutes of administration targeting 2 ng/ml. High Dose: initial bolus (1.25 mg/70 kg) administered over 15 minutes and infusion continued (0.5 mg/70 kg/hour infusion rate) to complete 360 minutes of administration targeting 5 ng/ml.

Also known as: TEMGESIC®

Part B (Opioid-Tolerant): Placebo-Buprenorphine High; Part B (Opioid-Tolerant): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

Fentanyl - Part B DRUG

Participant received up to four fentanyl doses: 0.25, 0.35, 0.5, and 0.7 mg/70 kg in Periods 1 and 2. Fentanyl boluses were administered over 90 seconds by dose escalation +2hr, +3hr, +4hr and +5hr after starting administration of buprenorphine/ placebo.

Part B (Opioid-Tolerant): Placebo-Buprenorphine High; Part B (Opioid-Tolerant): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

Oxycodone - Part B DRUG

All opioid-tolerant participants in Part B were transitioned to oral oxycodone at least 48 hours before Period 1 to ensure washout of the participants' regular opioids and a stable dose of oxycodone with an adequate bridging schedule reached. Oxycodone is a non-investigational intervention.

Part B (Opioid-Tolerant): Placebo-Buprenorphine High; Part B (Opioid-Tolerant): Placebo-Buprenorphine Low; Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid

Eligibility Criteria

• Age: 18 Years - 55 Years
• Gender Eligibility Details: For Part A, at least 5 subjects of each sex will be included in the population. For Part B, at least 3 patients of each sex will be included
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Part A-Healthy Subjects:
• Signed the informed consent form (ICF) and able to comply with study requirements and restrictions
• Age 18- 45, inclusive years for this part
• Women of childbearing potential must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception through at least 3 months after last dose of study drug
• Body Mass Index (BMI) 18-30 kg/m\^2, inclusive
• Healthy as defined by the Investigator
• No history of substance use disorder
• No current use of any central nervous system (CNS) depressants
• Part B-Opioid-tolerant patients
• Signed the ICF and able to comply with study requirements and restrictions
• Age 18 - 55 years inclusive
• Same as #3 above
• BMI 18-32 kg/m\^2
• Opioid tolerant patients administered opioids at daily doses greater than or equal to 90 mg oral morphine equivalents
• Stable as defined by the Investigator

You may not qualify if:

• Part A
• History of risk factors of Torsades de Pointes or an electrocardiogram (ECG) demonstrating a Fridericia's corrected QT interval (QTcF) \> 450 msec in males and QTcF \> 470 msec in females at screening;
• Currently meet the criteria for diagnosis of substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria on any substance;
• Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
• Current smokers and those who have smoked within the last 6 months;
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 6 months;
• Consume, on average, \> 20 units/week of alcohol in men and \> 13 units/week of alcohol in women; (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);
• Previous treatment with any prescribed medications (including all types of vaccines) or over-the-counter (OTC) medications within 14 days or 5 half-lives (whichever is longer) prior to first study treatment administration;
• Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;
• Require ongoing prescription or OTC medications that are clinically relevant cytochrome (CYP) P450 3A4 or CYP P450 2C8 inducers or inhibitors;
• Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
• History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;
• Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg prior to Day 1;
• History or presence of allergic response to buprenorphine or fentanyl;
• Subjects who have demonstrated allergic reactions which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial;

Sponsors & Collaborators

• Indivior Inc.: lead

Study Sites (1)

Center for Human Drug Research

Leiden, The Netherlands, Netherlands

Location

Related Publications (2)

• Olofsen E, Algera MH, Moss L, Dobbins RL, Groeneveld GJ, van Velzen M, Niesters M, Dahan A, Laffont CM. Modeling buprenorphine reduction of fentanyl-induced respiratory depression. JCI Insight. 2022 May 9;7(9):e156973. doi: 10.1172/jci.insight.156973.

  PMID: 35316224 BACKGROUND

• Moss LM, Algera MH, Dobbins R, Gray F, Strafford S, Heath A, van Velzen M, Heuberger JAAC, Niesters M, Olofsen E, Laffont CM, Dahan A, Groeneveld GJ. Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PLoS One. 2022 Jan 27;17(1):e0256752. doi: 10.1371/journal.pone.0256752. eCollection 2022.

  PMID: 35085249 RESULT

MeSH Terms

Interventions

Buprenorphine

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Geert J Groeneveld

  Center for Human Drug Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will be blinded to treatment with buprenorphine or placebo during Periods 1 and 2 in Part A only.
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A is a 3 period study in approximately 18 healthy subjects. Subjects will be randomized in a 1:1 ratio to 2 treatment sequences determined by the order in which they receive buprenorphine or placebo (periods 1 and 2). An optional open-label Period 3 may be conducted in which subjects will receive buprenorphine only. Part B is an open label study of approximately 8 opioid tolerant patients. All will undergo a washout of their own opioids which will be replaced with oral oxycodone and continue at stable doses from at least 48 hours prior to Period 1 to the end of Period 2. All will receive placebo plus fentanyl during Period 1 and buprenorphine plus fentanyl during Period 2.

Study Record Dates

• First Submitted: November 16, 2018
• First Posted: November 20, 2018
• Study Start: March 22, 2018
• Primary Completion: January 4, 2019
• Study Completion: January 4, 2019
• Last Updated: March 13, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)