HealthyPhase 1NCT03747341
Buprenorphine-Fentanyl Interaction Study
A Phase 1 study testing Buprenorphine Injectable Solution - Part A, Fentanyl - Part A and Ondansetron - Parts A + B in people with Healthy and Opioid Use, run by Indivior Inc. at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy, Opioid Use
- What is being tested?
- Buprenorphine Injectable Solution - Part A, Fentanyl - Part A and Ondansetron - Parts A + B
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteNetherlands
- Study dates
- 22 Mar 2018to 4 Jan 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
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- 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
- No current use of any CNS depressants, besides opioids, for 5 half-lives of the product before first study drug administration
Who cannot join
- 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;
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- 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;
- Estimated glomerular filtration rate <60 mL/min as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation;
- Anaemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;
- Positive serology tests for human immunodeficiency virus (HIV), hepatitis B (HBsAg), or hepatitis C (HepC);
- Aspartate transaminase (AST) or alanine transaminase (ALT) levels >1.5 times the upper limit of normal at screening;
- Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;
- Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
- Part B
- Same as Part A #1
- Currently meet the criteria for diagnosis of moderate or severe substance use disorder according to the DSM-5 criteria on any substances other than opioids, caffeine or nicotine;
- Same as Part A #3;
- Smoking of >10 cigarettes/day or equivalent and not able to abstain from smoking cigarettes during each dose administration day;
- Consume, on average, >27 units/week of alcohol in men and >20 units/week of alcohol in women;
- Use of buprenorphine within 10 days of the first study drug administration;
- Require ongoing prescription or OTC medications that are clinically relevant 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;
- Opioid-tolerant patients who have demonstrated allergic reactions which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial;
- Same as Part A #15
- Same as Part A #16
- Same as Part A #17
- Same as Part A #18
- Same as Part A #19
- Same as Part A #20
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Study Examining the Pharmacodynamics Interaction Between Buprenorphine and Fentanyl
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.
Read the detailed description
The study will be performed in 2 parts. Part A is a 3-period study; the first 2 periods have a single-blind, placebo-controlled, cross-over design, where subjects will be randomized in a 1:1 ratio to 2 treatment sequences determined by the order in which they receive buprenorphine or matching placebo. Period 3 is an open-label design where the same subjects will receive buprenorphine only. This period is optional, and will include approximately 6 subjects.
Part B is an open-label study in opioid tolerant patients. All will receive placebo plus fentanyl in Period 1 to permit dose escalation to full respiratory effects of fentanyl before assessing the interaction with buprenorphine. Subjects will receive buprenorphine plus fentanyl during Period 2 to assess the interaction with buprenorphine.
To study ventilation, the dynamic end-tidal forcing technique will be used. This technique enables the Investigator to force end-tidal partial pressure of carbon dioxide and end-tidal partial pressure of oxygen to follow a specific pattern in time. Subjects with a procedure-related adverse event (AE) will be treated according to established ventilatory support and opioid reversal protocols.
- Conditions
- Healthy, Opioid Use
- Being tested
- Buprenorphine Injectable Solution - Part A, Placebo - Parts A + B, Fentanyl - Part A, Ondansetron - Parts A + B, Buprenorphine Injectable Solution - Part B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Buprenorphine Injectable Solution - Part ADrug
Also called TEMGESIC®
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.
Placebo - Parts A + BDrug
0.9% normal saline for IV administration was used as placebo matching the buprenorphine formulation and administration.
Fentanyl - Part ADrug
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.
Ondansetron - Parts A + BDrug
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.
Buprenorphine Injectable Solution - Part BDrug
Also called TEMGESIC®
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.
Fentanyl - Part BDrug
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.
Oxycodone - Part BDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Placebo - Parts A + B; Drug: Ondansetron - Parts A + B; Drug: Buprenorphine Injectable Solution - Part B; Drug: Fentanyl - Part B; Drug: Oxycodone - Part B |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Apnoea is defined as a 20-second pause in respiration. If apnoea is observed at any fentanyl dose, the subject will be classified as "experienced apnoea" for that dose and any higher dose planned will be withheld
Measured: 6 hours
Number (percentage) of subjects who require stimulation for breathing for each fentanyl dose during the placebo treatment vs. the buprenorphine treatment.
If a subject required stimulation for breathing at a fentanyl dose and the next higher dose was withheld, the subject will be classified as requiring breath stimulation for all withheld doses
Measured: 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2018
- Study start22 Mar 2018
- Primary completion4 Jan 2019
- Study completion4 Jan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indivior Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Geert J Groeneveld, Principal investigator, Center for Human Drug Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03747341
- Sponsor's protocol ID
- INDV-6000-101
- Other IDs
- 2017-004858-42, CHDR1754, 2017
- Status last verified
- Mar 2025
- First submitted
- 16 Nov 2018
- Last updated
- 13 Mar 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 35316224Moss 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.
PubMed 35085249
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study Examining the Pharmacodynamics Interaction Between Buprenorphine and Fentanyl
- ClinicalTrials.gov ID
- NCT03747341
- Acronym / sponsor ID
- INDV-6000-101
- Conditions
- Healthy, Opioid Use
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Indivior Inc.Industry (pharma, biotech, devices)
- Study start
- 22 Mar 2018 (actual)
- Primary completion
- 4 Jan 2019 (actual)
- Study completion
- 4 Jan 2019 (actual)
- First posted
- 20 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The study will be performed in 2 parts. Part A is a 3-period study; the first 2 periods have a single-blind, placebo-controlled, cross-over design, where subjects will be randomized in a 1:1 ratio to 2 treatment sequences determined by the order in which they receive buprenorphine or matching placebo. Period 3 is an open-label design where the same subjects will receive buprenorphine only. This period is optional, and will include approximately 6 subjects.
Part B is an open-label study in opioid tolerant patients. All will receive placebo plus fentanyl in Period 1 to permit dose escalation to full respiratory effects of fentanyl before assessing the interaction with buprenorphine. Subjects will receive buprenorphine plus fentanyl during Period 2 to assess the interaction with buprenorphine.
To study ventilation, the dynamic end-tidal forcing technique will be used. This technique enables the Investigator to force end-tidal partial pressure of carbon dioxide and end-tidal partial pressure of oxygen to follow a specific pattern in time. Subjects with a procedure-related adverse event (AE) will be treated according to established ventilatory support and opioid reversal protocols.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 7
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Part A (Healthy Participants): Placebo-Buprenorphine Low | Experimental | Drug: Buprenorphine Injectable Solution - Part A, Drug: Placebo - Parts A + B, Drug: Fentanyl - Part A, Drug: Ondansetron - Parts A + BThree 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. |
| Part A (Healthy Participants): Placebo-Buprenorphine High | Experimental | Drug: Buprenorphine Injectable Solution - Part A, Drug: Placebo - Parts A + B, Drug: Fentanyl - Part A, Drug: Ondansetron - Parts A + BThree 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. |
| Part A (Healthy Participants): Buprenorphine Low-Placebo | Experimental | Drug: Buprenorphine Injectable Solution - Part A, Drug: Placebo - Parts A + B, Drug: Fentanyl - Part A, Drug: Ondansetron - Parts A + BThree 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. |
| Part A (Healthy Participants): Buprenorphine High-Placebo | Experimental | Drug: Buprenorphine Injectable Solution - Part A, Drug: Placebo - Parts A + B, Drug: Fentanyl - Part A, Drug: Ondansetron - Parts A + BThree 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. |
| Part B (Opioid-Tolerant): Placebo-Buprenorphine Low | Experimental | Drug: Placebo - Parts A + B, Drug: Ondansetron - Parts A + B, Drug: Buprenorphine Injectable Solution - Part B, Drug: Fentanyl - Part B, Drug: Oxycodone - Part BOpioid-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. |
| Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid | Experimental | Drug: Placebo - Parts A + B, Drug: Ondansetron - Parts A + B, Drug: Buprenorphine Injectable Solution - Part B, Drug: Fentanyl - Part B, Drug: Oxycodone - Part BOpioid-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. |
| Part B (Opioid-Tolerant): Placebo-Buprenorphine High | Experimental | Drug: Placebo - Parts A + B, Drug: Ondansetron - Parts A + B, Drug: Buprenorphine Injectable Solution - Part B, Drug: Fentanyl - Part B, Drug: Oxycodone - Part BOpioid-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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (16 listed)
- Part A-Healthy Subjects:
- Part B-Opioid-tolerant patients
Key exclusion criteria (40 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Buprenorphine Injectable Solution - Part AAlso: TEMGESIC®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. | Drug | 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 + B0.9% normal saline for IV administration was used as placebo matching the buprenorphine formulation and administration. | Drug | 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 AParticipant 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. | Drug | 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 + BA 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. | Drug | 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 BAlso: TEMGESIC®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. | Drug | Part B (Opioid-Tolerant): Placebo-Buprenorphine High, Part B (Opioid-Tolerant): Placebo-Buprenorphine Low, Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid |
| Fentanyl - Part BParticipant 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. | Drug | Part B (Opioid-Tolerant): Placebo-Buprenorphine High, Part B (Opioid-Tolerant): Placebo-Buprenorphine Low, Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid |
| Oxycodone - Part BAll 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. | Drug | Part B (Opioid-Tolerant): Placebo-Buprenorphine High, Part B (Opioid-Tolerant): Placebo-Buprenorphine Low, Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid |
Primary outcome
Changes in peak ventilatory depression will be measured.
Time frame: 6 hours (during study drug infusion)
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
2 secondary outcomes
Number (percentage) of subjects who experience apnoea for each fentanyl dose during the placebo treatment vs. the buprenorphine treatment
Time frame: 6 hours
Number (percentage) of subjects who require stimulation for breathing for each fentanyl dose during the placebo treatment vs. the buprenorphine treatment.
Time frame: 6 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2025.
- Background: PubMed 35316224Olofsen 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.
- Results publication: PubMed 35085249Moss 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Geert J Groeneveld principal investigator
Center for Human Drug Research
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Buprenorphine Injectable Solution - Part A, Fentanyl - Part A and Ondansetron - Parts A + B in people with Healthy and Opioid Use, run by Indivior Inc. at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes in peak ventilatory depression will be measured. (time frame: 6 hours (during study drug infusion)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03747341, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2025.