Starting Treatment With Agonist Replacement Therapies (START)

Study Overview
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Brief Summary
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The Food and Drug Administration (FDA) has requested a study comparing buprenorphine/naloxone (BUP/NX) and methadone (MET) on indices of hepatic safety.

Detailed Description
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This is a randomized, open-label, multi-center, Phase 4 study to assess the changes in liver enzymes related to treatment with buprenorphine/naloxone (BUP/NX) and methadone (MET) in participants entering opioid agonist treatment. Randomization will be stratified, within site, according to normal versus abnormal screening liver function tests. Participants meeting entry criteria will be dosed for 24 weeks during the active phase of the study with assessment of liver function at weeks 1, 2, 4, 8, 12, 16, 20, 24 and with follow-up assessments at week 32. Clinicians will be encouraged to treat with adequate doses of BUP/NX and MET.

Official Title
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Starting Treatment With Agonist Replacement Therapies (START)

Conditions
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Opiate-related Disorders

Intervention / Treatment
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* Drug: Buprenorphine/naloxone
* Drug: Methadone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Were age 18 years or older, Met DSM-IV-TR criteria for opioid dependence, Were in good general health, or, in case of a medical/psychiatric condition requiring ongoing treatment, were under the care of a physician willing to continue participant's medical management and cooperate with study physicians, For female participants, use of one of the following acceptable methods of birth control: oral contraceptives barrier (diaphragm or condom) with spermicide IUD intrauterine progesterone contraceptive system levonorgestrel implant medroxyprogesterone acetate contraceptive injection contraceptive transdermal patch hormonal vaginal contraceptive ring surgical sterilization complete abstinence from sexual intercourse Able to read and verbalize understanding of the study and voluntarily sign study informed consent form. Exclusion Criteria: ALT or AST values > 5 times the upper limit of normal as per testing laboratory range criteria, ALP values >3 times the upper limit of normal per testing laboratory criteria, Any documented past or present history of ascites, presence of esophageal or gastric varices, hepatic encephalopathy or other signs of significant liver disease as indicated by a Model for Endstage Liver Disease score (Kamath et al., 2001) of ≥11, Total bilirubin > 2.0 mg/dl (participants with documented Gilbert's syndrome were not excluded based on this criterion), Prothrombin time more than 3 seconds prolonged, Albumin level less than 2.5 g/dl, Any cardiopathy or risk factor listed below without evidence of a normal ECG* with report performed within 6 months prior to first study medication dose, Congestive heart failure Left ventricular hypertrophy Bradycardia Hereditary QT prolongation Uncorrected electrolyte imbalance Concomitant medications that are known to have a risk of QT interval prolongation; refer to Appendix D for a list of medications. Note: The list was not all-inclusive. *An ECG was abnormal if one or more of the following occurred: Significant ST segment abnormalities: ST segment elevations in two or more continuous leads of > 0.1 mV ST segment depression of greater than 1 mm that are flat or down-sloping at 80 msec after the J point ST segment abnormalities identified as non-specific are acceptable. If a potential participant's ECG indicated ST segment elevations or depression consistent with ischemia, the physician obtained a medical history of cardiac symptoms and referred the participant for evaluation. Conduction abnormalities: Mobitz II 2nd degree or 3rd degree heart block Atrial fibrillation, atrial flutter, or any non-sinus tachyarrhythmia Three or more consecutive ectopic ventricular complexes at a rate of > 100 per minute. QTc greater than 450 msec in men and 480 msec in women Repolarization abnormalities: • Acute medical condition that would make participation, in the opinion of the study physician, medically hazardous (e.g., unstable pancreatic, cardiovascular or renal disease, significant anemia) Known allergy or sensitivity to BUP, naloxone or MET or to any of the inactive ingredients in the study medications (including lactose, mannitol, cornstarch, povidone K30, citric acid, sodium citrate, FD&C Yellow No.6 color, magnesium stearate, Acesulfame K sweetener) Known diagnosis of acute psychosis, severe depression or imminent suicide risk as determined via clinical interview by study physician or surrogates DSM-IV diagnosis of dependence on alcohol requiring immediate medical attention. DSM-IV diagnosis of dependence on benzodiazepines requiring immediate medical attention DSM-IV diagnosis of dependence on other depressants, or stimulants requiring immediate medical attention Participation in an investigational drug study within the past 30 days Treatment with MET, BUP/NX, or BUP for more than 15 of the past 30 days (illicit use of these medications is allowed) Pending legal action that could prohibit study participation Unable or unwilling to comply with study requirements Unable or unwilling to remain in the local area for duration of treatment Poor venous access such that venipuncture could not be accomplished from a vein in an extremity during eligibility Pregnant or lactating (females only)

Ages Eligible for Study
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Minimum Age: 18 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: Buprenorphine/Nx<br>For the BUP/NX group, all participants will receive up to 16 mg BUP/4 mg NX on day 1 and up to 32 mg BUP/8 mg NX on day 2. It is recommended that dose changes be made in 2 to 8 mg buprenorphine increments, with the range of allowable daily doses between 2 mg and 32 mg starting on day 3 and thereafter according to clinical impression and depending upon the participant's clinical need. Investigators are encouraged to dose adequately to decrease craving and to obtain negative urine toxicology specimens. | Drug: Buprenorphine/naloxone<br>* Participants receive up to 16 mg BUP/4 mg NX on day 1 and up to 32 mg BUP/8 mg NX on day 2. It is recommended that dose changes be made in 2 to 8 mg increments, with the range of allowable daily doses between 2 mg and 32 mg starting on day 3 and thereafter according to clinical impression and depending upon the participant's clinical need.<br>|
| Active Comparator: Methadone<br>For the MET group, all participants will receive a maximum of 30 mg for the first dose and a maximum of 40 mg on Day 1. It is recommended that participants receive a dose on day 2 that is 10 mg higher than their total day 1 dose, and a dose on day 3 that is 10 mg higher than their total day 2 dose, unless, in the clinical judgment of the physician, a slower induction is needed. Doses will be adjusted on Day 4 and thereafter according to clinical impression and depending upon the participant's clinical need with no specific upper limit. Investigators are encouraged to dose adequately to decrease craving and to obtain negative urine toxicology specimens. | Drug: Methadone<br>* Participants will receive a maximum of 30 mg for the first dose and a maximum of 40 mg on Day 1. It is recommended that participants receive a dose on day 2 that is 10 mg higher than their total day 1 dose, and a dose on day 3 that is 10 mg higher than their total day 2 dose, unless, in the clinical judgment of the physician, a slower induction is needed. Doses will be adjusted on Day 4 and thereafter according to clinical impression and depending upon the participant's clinical need with no specific upper limit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic Safety | Participants were categorized according liver transaminase (ALT, AST) levels in blood comparing the baseline sample to any and all subsequent samples in the following manner: A: both ALT and AST started at less than or equal to two times the ULN and remained at two times or less ULN throughout the study B: either ALT or AST started at less than or equal to 2 x ULN and at any point in study exceeded 2 x ULN C: Either ALT or AST started > 2 x ULN, decreased (both ALT and AST) to < 2 x ULN, and remained < 2 x ULN D: Either ALT or AST started > 2 x ULN and remained above 2 x ULN throughout the study | 24 Weeks |