Single Dose Crossover Study to Compare the Respiratory Drive After Administration of Belbuca, Oxycodone and Placebo.

Study Overview
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Brief Summary
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The purpose of this study is to explore and compare VRH after administration of Belbuca, Oxycodone HCl and Placebo in recreational opioid users. This is a single-center, double -blind, double-dummy , placebo-controlled randomized crossover study in up to 18 men and women self identifying as recreational users. This study will consist of a screening phase, treatment phase (which includes the Naloxone Challenge test) and follow-up visit.

Official Title
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A Randomized, Double-Blind, Double Dummy, 6-Period, Placebo-Controlled, Crossover Study to Explore and Compare the Ventilatory Response to Hypercapnia (VRH), of Belbuca, Oxycodone Hydrochloride (HCl) and Placebo in Recreational Opioid Users

Conditions
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Respiratory Depression

Intervention / Treatment
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* Drug: Belbuca 300 µg
* Drug: Belbuca 600 µg
* Drug: Belbuca 900 µg
* Drug: Oxycodone 30 mg
* Drug: Oxycodone 60 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 to 55 years of age, inclusive. Subjects are in good health as indicated by medical history, PE, vital signs, oxygen saturation, clinical laboratory tests, and 12-lead ECG. A status of good health will be defined by the absence of evidence of any clinically significant, active or chronic disease based on these assessments, in the opinion of the investigator. Subjects with a body mass index (BMI) of 18.0 to 33.0 kg/m2, inclusive, and body weight greater than 50 kg, inclusive. Subject is able to speak, read, and understand English and voluntarily provide written informed consent to participate in the study. Subjects have healthy oral mucosa as determined by examination at screening and admission to the clinical facility. Subject must be a recreational opioid user who is not currently dependent on opioids (based on self-reported DSM-5 criteria and a Clinical Opiate Withdrawal Scale [COWS] score ≤5 on the Naloxone Challenge) but has experience in the use of opioids for non-therapeutic purposes (ie, for psychoactive effects) on at least 10 occasions within the last year and at least once in the 12 weeks prior to the screening visit. Subject demonstrates adequate VRH at screening during VRH assessment, defined as a minimum increase in ETCO2 of 10 mmHg and an increase in minute ventilation appropriate per investigator's discretion. Ability and willingness to abstain from alcohol-, caffeine-, and xanthine-containing beverages or food (eg, coffee, tea, cola, chocolate, energy drinks) as well as poppy seeds from 48 hours (2 days) prior to each admission to the clinical facility until study discharge (including clinic furloughs). Female subjects who are non-pregnant, non-lactating, and either postmenopausal for at least 1 year or surgically sterile for at least 3 months, or, if of childbearing potential, will agree to use adequate contraception from 28 days and/or their last confirmed menstrual period prior to study enrollment (whichever is longer) until 90 days after the follow-up visit. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from first admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception (for both males and females) is defined as using spermicide with a single barrier method: diaphragm, cervical cap, or condom. For female participants and female partners of male participants, being surgically sterilized or using hormonal contraception or an intrauterine device is also acceptable. Also, total abstinence, in accordance with the lifestyle of the subject, is acceptable. For female subjects: a negative pregnancy test at screening and Day -1 of each treatment period. Postmenopausal females: defined as 12 months with no menses prior to screening and a serum follicle stimulating hormone (FSH) >40 IU/L at screening. All prescribed medications, over-the-counter (OTC) medications, dietary supplements or herbal supplements (eg, St. John's Wort extract) must have been stopped at least 14 days prior to the first admission to the clinical research center. An exception is made for acetaminophen, which is allowed up to admission to the clinical research center. An exception is also made for hormonal contraceptives, which may be used throughout the study. Antiemetics may be allowed after the 4-hour VRH assessments while confined in the clinical research unit. Exclusion Criteria: Employee of PRA or the Sponsor. Women who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 90 days after the follow-up visit. Male subjects with female partners who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 90 days after the follow-up visit. Has received study medication in another clinical trial within 30 days prior to the first dose of study medication. Having any disease that, in the opinion of the investigator, poses an unacceptable risk to the subjects. History of drug allergy diagnosed by a physician. Confirmatory circumstances would include treatment with epinephrine or an Emergency Department. Subjects who have smoked on a daily basis within 30 days prior to the first dose of study medication. Occasional nicotine use in the form of cigarettes, cigars, or vape pen is allowable (defined as less than half a pack of cigarettes [10 cigarettes], equivalent vaping [100 puffs], or no more than 2 cigars per week). Nicotine replacement therapies (ie, patches and/or gum) may be used without restriction. Routine or chronic use of more than 3 grams of acetaminophen daily. Strenuous activity and contact sports within 48 hours (2 days) prior to first admission to the clinical facility and for the duration of the study. History of donation of more than 450 mL of blood within 60 days prior to dosing in the clinical research center or planned donation before 30 days has elapsed since intake of study drug. Plasma or platelet donation within 7 days of first dose administration and throughout the entire study. History of or presence of alcohol dependence. This includes subjects who have never been to a drug rehabilitation program. Alcohol consumption will be prohibited 48 hours prior to admission to the clinical facility and throughout the entire study until discharge. Positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or antihuman immunodeficiency virus (HIV)-1 and -2 antibodies. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease, or any other condition, which, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results. Has any condition in which an opioid is contraindicated (eg, significant respiratory depression, acute or severe bronchial asthma or hypercarbia, or has or is suspected of having paralytic ileus). Have a history of chronic obstructive pulmonary disease or any other lung disease (eg, asthma, bronchitis, obstructive sleep apnea, exercise-induced asthma) that would cause CO2 retention. Has participated in (within the last 5 years), is currently participating in, or is seeking treatment for substance-related disorders (excluding nicotine and caffeine). A positive result for drugs of abuse (amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, and opioids, including oxycodone) at screening is acceptable as long as the urine drug screen is negative for these drugs at admission to the clinical facility. A positive test for THC is not exclusionary at screening or at admission to the clinical facility. If a subject has a positive urine drug screen (except THC) upon admission to the clinic (V3-V7) the subject will be dismissed from the clinic and will be allowed to return at a later date (+14 days) to participate in the missed treatment period. A subject may only test positive once (except THC) and be allowed to return. Has oral sores, mucositis, or inflammation in oral cavity at screening and check-in.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: Belbuca 300 µg and oral placebo<br>Subjects treated with Belbuca 300 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Belbuca 300 µg<br>* Belbuca 300 µg buccal film<br>|
| Experimental: Treatment B: Belbuca 600 µg and oral placebo<br>Subjects treated with Belbuca 600 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Belbuca 600 µg<br>* Belbuca 600 µg buccal film<br>|
| Experimental: Treatment C: Belbuca 900 µg and oral placebo<br>Subjects treated with Belbuca 900 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Belbuca 900 µg<br>* Belbuca 900 µg buccal film<br>|
| Active Comparator: Treatment D: Oxycodone 30 mg and buccal placebo<br>Subjects treated with Oxycodone 30 mg and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Oxycodone 30 mg<br>* Oxycodone 30 mg capsule<br>|
| Active Comparator: Treatment E: Oxycodone 60 mg and buccal placebo<br>Subjects treated with Oxycodone 60 mg and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Oxycodone 60 mg<br>* Oxycodone 60 mg capsule<br>|
| Placebo Comparator: Treatment F: Oral Placebo and buccal placebo<br>Subjects treated with oral placebo and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. | Drug: Placebo<br>* placebo buccal film and oral placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory Drive | Respiratory drive was evaluated by measuring the Ventilatory Response to Hypercapnia (VRH) through assessment of the maximum decrease (Emax) in minute ventilation (mL/min) after administration of Belbuca, Oxycodone hydrochloride, and placebo. | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3 and 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pupil Diameter | Pupil diameter will be assessed by pupillometry predose and at multiple timepoints after completion of Belbuca, oxycodone hydrochloride, and placebo dosing. | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3 and 4 hours | 
| Change in Ratio of Minute Ventilation | Change in ratio of maximum decrease (Emax) in minute ventilation (mL/min) over maximum (Emax) end-tidal carbon dioxide (CO2, mmHg) after administration of Belbuca, oxycodone hydrochloride, and placebo. | pre-dose, 0.5, 1, 2, 2.5, 3 and 4 hours | 
| Adverse Event (AE) Reporting of Belbuca, Oxycodone Hydrochloride and Placebo for 6 Periods. | Number of Participants with indicated Adverse Event (AE) in subjects receiving Belbuca, oxycodone hydrochloride, and placebo for 6 periods. | 44 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Pain, Ventilatory Response to Hypercapnia (VRH)