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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-004858-42 | EudraCT Number | ||
| CHDR1754 | Other Identifier | Centre for Human Drug Research |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A (Healthy Participants): Placebo-Buprenorphine Low | Experimental | Three treatment periods consisting of 3 days each of investigational treatment
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. |
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| Part A (Healthy Participants): Placebo-Buprenorphine High | Experimental | Three treatment periods consisting of 3 days each of investigational treatment
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. |
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| Part A (Healthy Participants): Buprenorphine Low-Placebo | Experimental | Three treatment periods consisting of 3 days each of investigational treatment
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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 6 hours |
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Inclusion Criteria:
Part A-Healthy Subjects:
Part B-Opioid-tolerant patients
Exclusion Criteria:
Part A
Part B
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
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| Name | Affiliation | Role |
|---|---|---|
| Geert J Groeneveld | Center for Human Drug Research | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Human Drug Research | Leiden | The Netherlands | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35316224 | Background | 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. | |
| 35085249 | Result | 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. |
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| ID | Term |
|---|---|
| D002047 | Buprenorphine |
| ID | Term |
|---|---|
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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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.
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Participants will be blinded to treatment with buprenorphine or placebo during Periods 1 and 2 in Part A only.
| Part A (Healthy Participants): Buprenorphine High-Placebo | Experimental | Three treatment periods consisting of 3 days each of investigational treatment
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. |
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| 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:
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. |
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| 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:
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. |
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| 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:
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. |
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| Placebo - Parts A + B | Drug | 0.9% normal saline for IV administration was used as placebo matching the buprenorphine formulation and administration. |
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| 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. |
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| 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. |
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| 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. |
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| 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. |
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| 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. |
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| 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 | 6 hours |
| D006572 |
| Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |