Buprenorphine-Fentanyl Interaction Study
Condition: Healthy; Opioid Use
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): Buprenorphine Injectable Solution - Part A; Placebo - Parts A + B; Fentanyl - Part A; Ondansetron - Parts A + B; Buprenorphine Injectable Solution - Part B; Fentanyl - Part B; Oxycodone - Part B
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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.; 0.9% normal saline for IV administration was used as placebo matching the buprenorphine formulation and administration.; 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.; 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 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.; 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.; 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.
Other intervention name(s): TEMGESIC®; TEMGESIC®
Intervention MeSH terms: Fentanyl; Oxycodone; Buprenorphine; Ondansetron; Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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 (Participant)
Primary purpose: Prevention