Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone

Study Overview
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Brief Summary
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The purpose of this study is to compare the presence, degree, time course and profile of opioid withdrawal symptoms associated with induction onto new formulations of buprenorphine or buprenorphine/naloxone in persons with active opioid dependence. The primary outcome measure is the severity of withdrawal symptoms measured using the Clinical Opiate Withdrawal Scale (COWS). The primary study hypothesis is that neither drug formulation will precipitate an opioid withdrawal syndrome.

Detailed Description
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Buprenorphine sublingual and buccal soluble films are being developed to be used for the same indication and over the same buprenorphine dose range as Subutex and Suboxone sublingual tablets in the treatment of opioid dependence. However, only films administered by the sublingual route were evaluated in this study. The soluble film dosage is expected to provide the following enhancements and potential advantages over the current Subutex and Suboxone product: Mitigation against unintentional pediatric exposure by providing child-resistant packaging in unit dose format. Improvement in subject convenience and compliance by ensuring rapid disintegration. Protection against diversion by providing a dosage form that is very difficult for the subject to remove from the sublingual or buccal mucosa after administration. This provides assurance to the caregiver that the dose has actually been taken appropriately in a supervised setting. Provision of a unit dose product format for hospital and institutional use. Decreased product damage during shipping as compared to Subutex and Suboxone tablets.

Official Title
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Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone

Conditions
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Opioid-related Disorders

Intervention / Treatment
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* Drug: Buprenorphine soluble film
* Drug: Buprenorphine/naloxone film strip
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must: Provide written informed consent. Have a Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of opioid dependence. Be male or female, 18 to 65 years of age, inclusive. If female, have a negative pregnancy test during screening and agree to use an acceptable method of birth control. Exclusion Criteria: Subjects must not: Have participated in an experimental drug or device study within the last 30 days. Be currently (past 30 days from start of screening) engaged in opioid agonist, opioid partial agonist, or opioid antagonist treatment. If female, be breast feeding or lactating. Have any medical condition that in the opinion of the physician investigator would preclude the subject from completing the study. Have any clinically significant non-substance use psychiatric disorder (e.g., schizophrenia). Have current suicidal ideation. Have a Mini Mental Status Exam score less than 24. Have physical dependence on alcohol. Have physical dependence on sedative-hypnotics. Have active aphthous stomatitis. Have active oral herpes. Need on-going prescription medications that interact with the P450 3A4 (a member of the cytochrome P450 superfamily of enzymes) system.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buprenorphine soluble film<br>Day 1: Buprenorphine soluble film administered at a dose of 4 mg 3 times per day, plus placebo. Dosing occurred at 0900, 1100, and 2000 hours. Days 2-5: Buprenorphine soluble film administered at a dose of 16 mg to 24 mg once per day, plus placebo. Dosing occurred at 0900 hours. | Drug: Buprenorphine soluble film<br>* Buprenorphine soluble film strips administered sublingually with doses escalated from 12 mg per day up to 24 mg daily for 5 days of total treatment.<br>* Other names: Subutex;Drug: Placebo<br>* Placebo soluble film administered on the same schedule as active treatment to maintain the study blind.<br>|
| Experimental: Buprenorphine/naloxone soluble film<br>Day 1: Buprenorphine/naloxone soluble film administered at a dose of 4mg/1mg 3 times per day, plus placebo. Dosing occurred at 0900, 1100, and 2000 hours. Days 2 to 5: Buprenorphine/naloxone soluble film administered at a dose of 16mg/4 mg to 24 mg/6 mg once per day, plus placebo. Dosing occurred at 0900 hours. | Drug: Buprenorphine/naloxone film strip<br>* Buprenorphine/naloxone soluble film strips administered sublingually with doses escalated from 12 mg buprenorphine/3 mg naloxone to 24 mg buprenorphine /6 mg naloxone daily for 5 days of total treatment.<br>* Other names: Suboxone;Drug: Placebo<br>* Placebo soluble film administered on the same schedule as active treatment to maintain the study blind.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Withdrawal Symptoms Measured Using the Clinical Opiate Withdrawal Scale (COWS) at Baseline and the Peak COWS up to 23.5 Hours After the First Administration | The COWS is an 11-item instrument used to assess symptoms of opioid withdrawal (Wesson et al., 1999). The score is the sum of the response to each of the 11 items and cover a range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderate/severe withdrawal, and 37-48 severe withdrawal. The baseline COWS was the score obtained 30 minutes prior to administration of soluble films on Day 1. Peak COWS was the highest COWS score obtained between 1-23.5 hours post administration on Day 1. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Withdrawal Symptoms Measured Using the Clinical Opiate Withdrawal Scale (COWS) at the End of Induction and the Peak COWS Post Induction | The COWS is an 11-item instrument used to assess symptoms of opioid withdrawal (Wesson et al., 1999). The score is the sum of the response to each of the 11 items and cover a range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderate/severe withdrawal, and 37-48 severe withdrawal. The end of induction COWS was the score obtained 47.5 hours after first administration of soluble films on Day 1. Peak post induction COWS was the highest COWS score obtained on Days 2-5. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Pupil Diameter Measurements at Baseline and the Maximum Pupil Diameter up to 23.5 Hours After the First Administration | Pupil diameter was measured at baseline and at intervals post drug administration on Day 1. Peak measurement is the maximum pupil diameter recorded from 15 minutes to 23.5 hours post administration of study intervention. | Baseline: 15 minutes prior to first administration on Day 1. Peak: 15 minutes - 23.5 hours post administration on Day 1 | 
| Pupil Diameter Measurements at Baseline and the Minimum Pupil Diameter up to 23.5 Hours After the First Administration | Pupil diameter was measured at baseline and at intervals post drug administration on Day 1. Peak measurement is the minimum pupil diameter recorded from 15 minutes to 23.5 hours post administration of study intervention. | Baseline: 15 minutes prior to first administration on Day 1. Peak: 15 minutes - 23.5 hours post administration on Day 1 | 
| Pupil Diameter Measurements At End of Induction (End of Day 2) and the Minimum Pupil Diameter During the Post Induction Period (Days 3-5) | Pupil diameter was measured at the end of induction (47.5 hours after the first administration of study intervention) and at intervals during the post-induction period (Days 3-5). Peak post induction measurement is the minimum pupil diameter recorded during days 3-5. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: How High Are You? | A visual analog scale (VAS) was used by participants to answer the subjective question, How high are you?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=not high and 100=extremely high. The baseline VAS was the score obtained 30 minutes prior to administration of soluble films on Day 1. Peak VAS was the highest VAS score obtained between 1-23.5 hours post administration on Day 1. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| Visual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: Do You Feel Any Drug Effect? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you feel any drug effect?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no effect and 100=maximum effect. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| Visual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: Does the Drug Have Any Good Effects? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you feel any good effects?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no good effects and 100=maximum good effects. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| Visual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: Does the Drug Have Any Bad Effects? | A visual analog scale (VAS) was used by participants to answer the subjective question, Does the drug have any bad effects?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no bad effects and 100=maximum bad effects. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| CVisual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: Do You Like the Drug? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you like the drug?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no liking and 100=maximum liking. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| Visual Analog Scale (VAS) Score at Baseline and the Peak (Maximum Increase) VAS up to 23.5 Hours After First Administration for the Question: Does the Drug Make You Sick? | A visual analog scale (VAS) was used by participants to answer the subjective question, Does the drug make you sick?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no effect and 100=maximum effect. | Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: How High Are You? | A visual analog scale (VAS) was used by participants to answer the subjective question, How high are you?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=not high and 100=extremely high. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: Do You Feel Any Drug Effect? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you feel any drug effect?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no effect and 100=maximum effect. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: Do You Feel Any Good Effects? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you feel any good effects?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no good effects and 100=maximum good effects. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: Does the Drug Have Any Bad Effects? | A visual analog scale (VAS) was used by participants to answer the subjective question, Does the drug have any bad effects?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no bad effects and 100=maximum bad effects. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: Do You Like the Drug? | A visual analog scale (VAS) was used by participants to answer the subjective question, Do you like the drug?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no liking and 100=maximum liking. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Visual Analog Scale (VAS) Scores at End of Induction Period and the Post-induction Period (Maximum Increase) for the Question: Does the Drug Make You Sick? | A visual analog scale (VAS) was used by participants to answer the subjective question, Does the drug make you sick?. The question was one of six used to measure the extent of opioid blockade following study intervention. VAS questions were selected based on previous demonstration of their sensitivity to opioid agonist and antagonist effects (Preston et al., 1988). Participants indicated how high they feel by marking a score on a horizontal line with 0=no effect and 100=maximum effect. | End of Induction: 47.5 hours after first administration Peak Post Induction: Days 3-5 | 
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-emergent AEs were defined as those starting on the day of the first treatment with buprenorphine soluble films or buprenorphine/ naloxone soluble films until residential research facility release, which typically happened on Day 6. Severity was graded by the investigator as mild (grade 1), moderate (grade 2) and severe (grade 3). | Day 1-6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid dependence, Opioid withdrawal symptoms