A Study Examining the Pharmacodynamics Interaction Between Buprenorphine and Fentanyl
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Changes in peak ventilatory depression will be measured.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Single (Participant)
盲法说明
Participants will be blinded to treatment with buprenorphine or placebo during Periods 1 and 2 in Part A only.
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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.
- •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
研究组 & 干预措施
Part A (Healthy Participants): Placebo-Buprenorphine Low
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.
干预措施: Buprenorphine Injectable Solution - Part A (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine Low
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.
干预措施: Placebo - Parts A + B (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine Low
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.
干预措施: Fentanyl - Part A (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine Low
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine High
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.
干预措施: Buprenorphine Injectable Solution - Part A (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine High
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.
干预措施: Placebo - Parts A + B (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine High
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.
干预措施: Fentanyl - Part A (Drug)
Part A (Healthy Participants): Placebo-Buprenorphine High
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part A (Healthy Participants): Buprenorphine Low-Placebo
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.
干预措施: Buprenorphine Injectable Solution - Part A (Drug)
Part A (Healthy Participants): Buprenorphine Low-Placebo
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.
干预措施: Placebo - Parts A + B (Drug)
Part A (Healthy Participants): Buprenorphine Low-Placebo
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.
干预措施: Fentanyl - Part A (Drug)
Part A (Healthy Participants): Buprenorphine Low-Placebo
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part A (Healthy Participants): Buprenorphine High-Placebo
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.
干预措施: Buprenorphine Injectable Solution - Part A (Drug)
Part A (Healthy Participants): Buprenorphine High-Placebo
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.
干预措施: Placebo - Parts A + B (Drug)
Part A (Healthy Participants): Buprenorphine High-Placebo
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.
干预措施: Fentanyl - Part A (Drug)
Part A (Healthy Participants): Buprenorphine High-Placebo
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Low
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.
干预措施: Placebo - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Low
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Low
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.
干预措施: Buprenorphine Injectable Solution - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Low
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.
干预措施: Fentanyl - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Low
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.
干预措施: Oxycodone - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid
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.
干预措施: Placebo - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid
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.
干预措施: Buprenorphine Injectable Solution - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid
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.
干预措施: Fentanyl - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine Mid
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.
干预措施: Oxycodone - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine High
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.
干预措施: Placebo - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine High
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.
干预措施: Ondansetron - Parts A + B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine High
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.
干预措施: Buprenorphine Injectable Solution - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine High
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.
干预措施: Fentanyl - Part B (Drug)
Part B (Opioid-Tolerant): Placebo-Buprenorphine High
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.
干预措施: Oxycodone - Part B (Drug)
结局指标
主要结局
Changes in peak ventilatory depression will be measured.
时间窗: 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
次要结局
- 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)