Phase II Pharmacokinetics Study of CAM2038

Study Overview
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Brief Summary
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Phase II, open label, partially randomized, three treatment group study designed to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine following repeated subcutaneous administrations of CAM2038.

Detailed Description
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This is a phase II, open label, partially randomized, three treatment group study designed to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine following repeated subcutaneous administrations of CAM2038 weekly and monthly at different injection sites and to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine after repeated subcutaneous administration of CAM2038 monthly in opioid dependent subjects with a history of chronic non cancer pain. The study will involve three phases: Screening, Treatment, and Follow up.

Official Title
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A Phase II, Open-label, Partially Randomized, 3 Treatment Groups, Multi-Site Study Assessing Pharmacokinetics After Administration of the Once-Weekly and Once-Monthly, Long-Acting Subcutaneous Injectable Depot of Buprenorphine (CAM2038) at Different Injection Sites in Opioid-Dependent Subjects With Chronic Pain

Conditions
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Opioid Use Disorder, Chronic Pain

Intervention / Treatment
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* Drug: CAM2038


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must provide written informed consent prior to the conduct of any study related procedures. Male or non pregnant, non lactating female subject, aged 19 to 65 years, inclusive. Body mass index between 19 and 35 kg/m2, inclusive. Current diagnosis of moderate to severe opioid use disorder (according to the DSM 5) or past medical history of opioid use disorder currently being treated with SL BPN. Subject must be taking SL BPN (Subutex® equivalent) 24 mg (Group 1 and Group 2) or ≥24 mg (Group 3) daily for at least 30 days prior to Screening. Subject has a history of moderate to severe chronic non cancer pain. Male and female subjects of childbearing potential must be willing to use a reliable method of contraception during the entire study (Screening visit to Follow-up phone call). Subject must be willing and able to comply with all study procedures and requirements. Exclusion Criteria: Individuals meeting DSM-V substance use disorder criteria for alcohol, benzodiazepines, central nervous system (CNS) stimulants, or other drugs of abuse (excluding caffeine, tobacco or THC/marijuana). Any clinically significant abnormality on the basis of medical history, vital signs, physical examination, 12-lead electrocardiogram (ECG; Fridericia's corrected QT interval [QTcF] ≥450 msec. for males or ≥470 msec. for females), and laboratory evaluations (including hematology, clinical chemistry, urinalysis at Screening), in the opinion of the Investigator. Significant symptoms, medical conditions, or other circumstances which, in the opinion of the Investigator, would preclude compliance with the protocol, adequate cooperation in the study or obtaining informed consent, or may prevent the subject from safely participating in study, including subjects who are at a risk for gastrointestinal obstruction or paralytic ileus or who have severe respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal motility disorders, biliary tract disease, severe hepatic insufficiency, planned surgery and prior treatment with monoamine oxidase inhibitors. Use (therapeutic or non-therapeutic) of opioids other than SL BPN. Aspartate aminotransferase (AST) levels > 3 X the upper limit of normal, alanine aminotransferase (ALT), levels > 3 X the upper limit of normal, total bilirubin > 1.5 X the upper limit of normal, or creatinine > 1.5 X upper limit of normal on the Screening laboratory assessments, or other clinically significant laboratory abnormalities, which in the opinion of the Investigator may prevent the subject from safely participating in study. Pregnant or lactating or planning to become pregnant during the study. Diagnosis of, or currently under investigation for, fibromyalgia, complex regional pain syndrome, neurogenic claudication due to spinal stenosis, spinal cord compression, acute nerve root compression, severe or progressive lower extremity weakness or numbness. History of chemotherapy or confirmed malignancy (except basal cell or squamous carcinoma of the skin) within the past 2 years. Clinically significant history of, or current evidence for, suicidal ideation or those who are actively suicidal, as based on the Columbia-Suicide Severity Rating Scale (C-SSRS; grade 4 or 5). Clinically significant history of major depressive disorder that is poorly controlled with medication. Hypersensitivity or allergy to BPN or other opioids, or excipients of CAM2038. Exposure to any investigational drug within the 4 weeks prior to Screening. Participants with a clinically significant history of risk factors of Torsades de Pointes and any existing ventricular tachyarrhythmias such as bigeminy, trigeminy, heart failure, hypokalemia, family history of Long QT Syndrome. On medications that have the potential for prolonging the QT interval or who may require such medications during the course of the study along with clinically significant abnormalities on screening electrocardiogram (ECG) readings as deemed by the investigator. Requires current use of agents that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) such as some azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., clarithromycin), or protease inhibitors (e.g., ritonavir, indinavir, and saquinavir). Intolerance to venipuncture and/or difficulty with venous access, as per the judgment of the Investigator/research staff. Is an employee of the Investigator or the study site, with direct involvement in the proposed study or other studies under the direction of the Investigator or study site, or is a family member of an employee or of the Investigator. Any pending legal action that could prohibit participation or compliance in the study.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 32 mg CAM2038 weekly<br>Group 1, 32 mg of CAM2038 subcutaneous weekly injection at multiple injection sites | Drug: CAM2038<br>* Long-Acting Subcutaneous Injectable Depot of Buprenorphine<br>* Other names: Buprenorphine;|
| Experimental: 128 mg CAM2038 monthly injection<br>Group 2: 128 mg of CAM2038 subcutaneous monthly injection in the buttocks | Drug: CAM2038<br>* Long-Acting Subcutaneous Injectable Depot of Buprenorphine<br>* Other names: Buprenorphine;|
| Experimental: 160 mg CAM2038 monthly injection<br>Group 3: 24mg sublingual BPN for the first 7 days, and then 160 mg of CAM2038 subcutaneous monthly injection in the buttocks starting on Day 8. | Drug: CAM2038<br>* Long-Acting Subcutaneous Injectable Depot of Buprenorphine<br>* Other names: Buprenorphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCss(Area Under the Plasma Concentration-time Curve During a 7-day Dosing Interval at Steady State) for Each Injection Site, i.e., Buttock (Reference), Abdomen, Thigh and Back of Upper Arm for the Evaluable Pharmacokinetic (PKEVAL) Population | AUCss (area under the plasma concentration-time curve during a 7-day dosing interval at steady state) for each injection site, i.e., buttock (reference), abdomen, thigh and back of upper arm-Buprenorphine for the Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Css,av(Average Plasma Concentration During a Dosing Interval at Steady State) for Each Injection Site for the Evaluable Pharmacokinetic (PKEVAL) Population | Css,av (average plasma concentration during a dosing interval at steady state) for each injection site-Buprenorphine for the Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Css,Max (Maximum Observed Plasma Concentration During a Dosing Interval at Steady State) for Each Injection Site. | Css,max (maximum observed plasma concentration during a dosing interval at steady state) for each injection site-Buprenorphine | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Tss,Max (Time to Maximum Concentration at Steady State) for Each Injection Site | Tss,max (time to maximum concentration at steady state) for each injection site-buprenorphine | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Area Under the Curve at Steady State (AUC During a 28-day Dosing Interval at Steady State)-Buprenorphine | Area Under the Curve at steady state (AUC during a 28-day dosing interval at steady state)-Buprenorphine for Pharmacokinetic Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Average Steady State Concentration-Buprenorphine | Average steady state concentration-Buprenorphine-Pharmacokinetic Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Maximum Steady State Concentration-Buprenorphine | Maximum steady state concentration-BuprenorphinePharmacokinetic (PK) Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Time to Maximum Concentration at Steady State-Buprenorphine | Time to maximum concentration at steady state-Buprenorphine Pharmacokinetic (PK) Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Norbuprenorphine/Buprenorphine Ratios at Maximum Concentration at Steady State | Norbuprenorphine/buprenorphine ratios at maximum concentration at steady state Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| AUCss(Area Under the Plasma Concentration-time Curve During a 7-day Dosing Interval at Steady State) for Each Injection Site, i.e., Buttock (Reference), Abdomen, Thigh and Back of Upper Arm. | AUCss (area under the plasma concentration-time curve during a 7-day dosing interval at steady state) for each injection site, i.e., buttock (reference), abdomen, thigh and back of upper arm-Norbuprenorphine Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Css,av(Average Plasma Concentration During a Dosing Interval at Steady State) for Each Injection Site | Css,av (average plasma concentration during a dosing interval at steady state) for each injection site-Norbuprenorphine-Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Css,Max (Maximum Observed Plasma Concentration During a Dosing Interval at Steady State) for Each Injection Site. | Css,max (maximum observed plasma concentration during a dosing interval at steady state) for each injection site-Norbuprenorphine-Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Tss,Max (Time to Maximum Concentration at Steady State) for Each Injection Site | Tss,max (time to maximum concentration at steady state) for each injection site-Norbuprenorphine-Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Norbuprenorphine/Buprenorphine Ratios for Area Under the Curve at Steady State | Norbuprenorphine/buprenorphine ratios for Area Under the Curve at steady state Evaluable Pharmacokinetic (PKEVAL) Population | PK samples were collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post-CAM2038 q1w for Doses/Weeks 4, 5, 6, and 7. | 
| Area Under the Curve at Steady State (AUC During a 28-day Dosing Interval at Steady State)-Norepinephrine | Area Under the Curve at steady state (AUC during a 28-day dosing interval at steady state)-Norepinephrine-Pharmacokinetic (PK) Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Average Steady State Concentration-Norbuprenorphine | Average steady state concentration-Norbuprenorphine-Pharmacokinetic (PK) Population | PK samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours and at approximately 24, 48, 72,96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w Dose 4 | 
| Maximum Steady State Concentration-Norbuprenorphine | Maximum steady state concentration-Norbuprenorphine-Pharmacokinetic (PK) Population | PK samples at pre-dose, 0.5, 1, 2, 4, 6,10 hrs and approx. 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hrs after CAM2038 q4w Dose 4 and pre-dose (within 45 mins), 10, 20, 30 and 40 mins, and 1, 1.5, 2, 3, 4, 6, 10, and 24 hrs after SL BPN dose 7 | 
| Time to Maximum Concentration at Steady State-Norbuprenorphine | Time to maximum concentration at steady state-Norbuprenorphine-Pharmacokinetic (PK) Population | PK samples at pre-dose, 0.5, 1, 2, 4, 6,10 hrs and approx. 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hrs after CAM2038 q4w Dose 4 and pre-dose (within 45 mins), 10, 20, 30 and 40 mins, and 1, 1.5, 2, 3, 4, 6, 10, and 24 hrs after SL BPN dose 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events for Both Weekly and Monthly CAM2038 | Number of Participants with Adverse Events for Both weekly and monthly CAM2038-Safety Population | 99 days for Group 1, 162 days for Group 2, 127 days for Group 3 |