Buprenorphine-Fentanyl Interaction Study

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.

Inclusion criteria

• 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
• No current use of any CNS depressants, besides opioids, for 5 half-lives of the product before first study drug administration

Exclusion criteria

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;
• 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