A Randomized Acceptability and Safety Study of Suboxone Induction in Heroin Users (P05042)(COMPLETED)

Study Overview
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Brief Summary
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The purpose of this study is to assess the acceptability and safety of Suboxone in heroin users as a replacement therapy for opioid dependency by comparing the clinical response of participants who are inducted directly onto Suboxone with that of participants who are inducted first to Subutex and then transferred to Suboxone.

Detailed Description
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Rationale: Once Suboxone becomes available for widespread clinical use, it is anticipated that opioid-dependent patients seeking treatment with buprenorphine will be placed directly onto Suboxone. Two strategies that have had good success for inducting patients onto Suboxone have been developed: 1) a bridging procedure in which patients initiate therapy with Subutex and then transfer to Suboxone, and 2) a direct Suboxone induction procedure. However, there have been no controlled studies of direct Suboxone induction, and it is not clear whether using a Subutex-to-Suboxone induction procedure would produce any added clinical benefit for the patient relative to direct Suboxone induction. This study addresses a post-marketing commitment to the European Medicines Agency to conduct a prospective, controlled study of induction with Suboxone. Using a prospective, randomized, active-drug-controlled, double-blind and double-dummy design, this study will assess the acceptability and safety of Suboxone in heroin users by comparing the clinical response of participants who are inducted directly onto Suboxone with that of participants who are inducted first to Subutex and then transferred to Suboxone. The dose regimen used during the induction phase of this study is identical to that used in the pivotal efficacy study comparing Suboxone and Subutex (Fudala et al, 2003), which is included in the Suboxone Summary of Product Characteristics. The data collected in this study will include information on the extent of opioid use before treatment initiation. Two strategies for inducting opioid-dependent patients using short-acting opioids (eg, heroin) onto Suboxone have emerged from published US studies. One involves using Subutex to bridge the transition to Suboxone by using Subutex over the first 2 days before transferring directly to Suboxone on the third day. The other involves direct Suboxone induction, in which patients receive Suboxone as the initial dose followed by continued rapid Suboxone dose titration. In the pivotal efficacy study, opiate-dependent heroin users assigned to either Subutex or Suboxone groups received an induction dose of 8 mg of Subutex (administered as a single 8-mg tablet) on Day 1 and 16 mg of Subutex (administered as two 8-mg tablets) on Day 2. The 109 participants assigned to Suboxone received 16 mg of Suboxone (administered as two 8-mg tablets) on Day 3, and the 105 participants assigned to Subutex received 16 mg of Subutex (administered as two 8-mg tablets) on Day 3. The induction schedule used in the pivotal trial, in which a Subutex-to-Suboxone bridging procedure was used, was successful for inducting heroin-dependent patients onto Suboxone, achieving good compliance and resulting in relatively few AEs accounting for treatment discontinuation. Overall, several large-scale studies using Suboxone as an initial medication have been conducted with good results, and it appears clear that, as was the case in the pivotal study, most patients safely tolerate a total dose of at least 8 mg on the first day of treatment. However, as these studies were not controlled, it remains unclear whether using a Subutex-to-Suboxone induction procedure would produce any added clinical benefit to the patient relative to a direct Suboxone induction procedure. Furthermore, there have been no studies of direct Suboxone induction outside of the United States.

Official Title
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A Randomized Acceptability and Safety Study of Suboxone Induction in Heroin Users

Conditions
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Opiate Dependence, Drug Dependence, Substance Dependence

Intervention / Treatment
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* Drug: Suboxone (SCH 000484)
* Drug: Subutex (SCH 028444)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be males or non-pregnant, non-lactating females. Participants must be at least 15 years of age, of either sex, and any race. Participants (and/or the parent or guardian for participants under the age of legal consent or who otherwise are unable to provide independent consent) must demonstrate willingness to participate in the study and to adhere to dose and visit schedules. Participants must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for opioid dependence. Participants must have a methadone- and buprenorphine-negative UDS result prior to randomization. Each participant must confirm that he or she is practicing adequate contraception. Female volunteers of childbearing potential (including women who are less than 1 year postmenopausal and women who will be sexually active during the study) must agree to use a medically accepted method of contraception or must be surgically sterilized prior to screening, while receiving protocol-specified medication, and for 30 days after stopping the medication. Women who have been postmenopausal for >=1 year (ie, women who have experienced 12 or more consecutive months of amenorrhea) will be exempted from the requirement to use contraception during the study. Acceptable methods of contraception include condoms (male and female) with or without a spermicidal agent, diaphragm or cervical cap with a spermicidal agent, medically prescribed intrauterine device, oral or injectable hormonal contraceptives, and surgical sterilization (eg, hysterectomy or tubal ligation). Female participants of childbearing potential must have a negative urine beta-human chorionic gonadotropin (beta-hCG) test prior to enrollment in the study Exclusion Criteria: Participants for whom treatment with either Subutex or Suboxone as required in the protocol would be inconsistent with national labeling. Participants who are unwilling or unable to comply with the requirements of the protocol (eg, pending incarceration) or are in a situation or condition that, in the opinion of the investigator, may interfere with participation in the study. Participants who are participating in any other clinical study in which medication(s) are being delivered. Participants with known allergy or sensitivity to buprenorphine or naloxone. Participants who are on the staff, affiliated with, or a family member of the staff personnel directly involved with this study. Participants with serious untreated Axis I DSM-IV-TR psychiatric co-morbidity (eg, those who are actively suicidal or homicidal, have untreated schizophrenia, etc). Polysubstance abuse or dependence will not exclude participants except in the case of unauthorized and significant benzodiazepine use requiring medical detoxification or alcohol dependence requiring medical detoxification. HIV-positive participants with clinical acquired immunodeficiency syndrome (AIDS). Methadone or buprenorphine maintenance or detoxification within 30 days of enrollment.

Ages Eligible for Study
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Minimum Age: 15 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct Suboxone Induction<br>Participants received 8 mg of Suboxone and placebo Subutex on Day 1, 16 mg of Suboxone and placebo Subutex on Day 2, and all participants received open label Suboxone from Day 3 to Day 28. Suboxone dosage may be titrated from Day 4 to Day 28 up to 24 mg per day. | Drug: Suboxone (SCH 000484)<br>* 2 mg and 8 mg sublingual tablets, Contains Buprenorphine Hydrochloride and Naloxone. Daily dosage of 8 mg - 24 mg. Duration: 28 Days<br>* Other names: SCH 000484;|
| Active Comparator: Subutex-to-Suboxone Induction<br>Participants received 8 mg Subutex and placebo Suboxone on Day 1, 16 mg Subutex and placebo Suboxone on Day 2, and all participants received open label Suboxone from Day 3 to Day 28. Suboxone dosage may be titrated from Day 4 to Day 28 up to 24 mg per day. | Drug: Suboxone (SCH 000484)<br>* 2 mg and 8 mg sublingual tablets, Contains Buprenorphine Hydrochloride and Naloxone. Daily dosage of 8 mg - 24 mg. Duration: 28 Days<br>* Other names: SCH 000484;Drug: Subutex (SCH 028444)<br>* 2 mg and 8 mg sublingual tablets, Contains Buprenorphine Hydrochloride. Daily dosage of 8 mg - 24 mg. Duration: 28 Days<br>* Other names: SCH 028444;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders at Day 3 | Responders included the number of participants who received the scheduled dose of Suboxone at the Day 3 study visit. Participants who discontinued the study at Day 3 were considered non-responders. All participants that continued the study received Suboxone tablets on Day 3. | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Illicit Opioid and Non-opioid Drug Use: Urine Drug Screen (UDS) | Number of participants who tested negative on UDS during open-label phase on Day 28. The drugs screened on Day 28 included amphetamines, methamphetamines, cocaine, morphine, methadone, benzodiazepines, and tetrahydrocannabinol. Buprenorphine was only tested at screening and randomization according to protocol, therefore no values for buprenorphine are available for Day 28. | 28 days | 
| Illicit Opioid and Non-opioid Drug Use: Substance Use Inventory (SUI) | Number of participants with intravenous use of drug as measured by self-reported SUI from Days 3-28. The SUI form consisted of questions addressing the number of days and times a drug was used, and the route of drug use. For suboxone the use of scheduled study medication was not considered illicit use. | Days 3 to 28 | 
| Self-reported Opioid Withdrawal Symptoms (SOWS) | SOWS were 16 items whose intensity was scored on a scale from 0 (not at all) to 4 (extremely) for a maximum possible score of 64. A total score of 0 represented the best outcome and a score of 64 represented the worst outcome. Participants were scored for SOWS at baseline (prior to randomization) and on Day 28. Reported are the scores for Day 28, and the change in scores from baseline to Day 28. | Baseline and 28 days | 
| Observer-rated Opioid Withdrawal Symptoms (OOWS) | The OOWS were 13 physically observable signs that were present (scored 1) or absent (scored 0). A total score of 0 represented the best outcome and a total score of 13 represented the worst outcome. Participants were scored for OOWS at baseline (prior to randomization) and on Day 28. Reported are the total score for Day 28, and the change in scores from baseline to Day 28. | Baseline and 28 days | 
| Addiction-related Severity Index (ASI-Lite): A Composite Score to Evaluate Seven Potential Problem Areas: Medical, Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychiatric | The ASI-Lite is a standardized, multidimensional, semi-structured, comprehensive interview that estimates addiction-related problem severity profiles in seven domains commonly affected in substance abusers. ASI-lite composite score ranges from 0 (worst outcome) to 1 (best outcome) for each category. Reported here is the change in ASI-Lite from baseline to Day 28. The original drug use accounts for heroin, methadone, other opiates, analgesics, medicine/pills, cocaine, amphetamines, cannabis, hallucinogens, and inhalants. Modified drug use accounts for heroin, methadone, cocaine, and cannabis. | Baseline and 28 days | 
| Compliance Rate | Compliance rate was calculated as the number of days study medication was taken divided by the number of days study medication should have been taken X 100. The number of days study medication should have been taken was equal to the duration of treatment. | 28 days | 
| Responders at Day 28 | Responders were the number of participants in each group who received the scheduled 8- to 24-mg dose of Suboxone at study visit day. A participant who discontinued from the study was treated as a non-responder at the timepoint after the participant discontinued. | 28 days |