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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
38
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.
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.
Placebo soluble film administered on the same schedule as active treatment to maintain the study blind.
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States
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.
Time frame: Baseline: 30 minutes prior to first administration on Day 1. Peak: up to 23.5 hours post administration on Day 1
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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: Day 1-6