Starting Treatment With Agonist Replacement Therapies (START)
Condition: Opiate-related Disorders
Intervention: Buprenorphine/naloxone; Methadone
Intervention description: 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.; 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.
Intervention MeSH terms: Buprenorphine; Methadone; Buprenorphine, Naloxone Drug Combination; Naloxone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1269.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

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

Eligibility criteria:

        Inclusion Criteria:

          1. Were age 18 years or older,

          2. Met DSM-IV-TR criteria for opioid dependence,

          3. 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,

          4. For female participants, use of one of the following acceptable methods of birth
             control:

               1. oral contraceptives

               2. barrier (diaphragm or condom) with spermicide

               3. IUD

               4. intrauterine progesterone contraceptive system

               5. levonorgestrel implant

               6. medroxyprogesterone acetate contraceptive injection

               7. contraceptive transdermal patch

               8. hormonal vaginal contraceptive ring

               9. surgical sterilization

              10. complete abstinence from sexual intercourse

          5. Able to read and verbalize understanding of the study and voluntarily sign study
             informed consent form.

        Exclusion Criteria:

          1. ALT or AST values > 5 times the upper limit of normal as per testing laboratory range
             criteria,

          2. ALP values >3 times the upper limit of normal per testing laboratory criteria,

          3. 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,

          4. Total bilirubin > 2.0 mg/dl (participants with documented Gilbert's syndrome were not
             excluded based on this criterion),

          5. Prothrombin time more than 3 seconds prolonged,

          6. Albumin level less than 2.5 g/dl,

          7. 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,

               1. Congestive heart failure

               2. Left ventricular hypertrophy

               3. Bradycardia

               4. Hereditary QT prolongation

               5. Uncorrected electrolyte imbalance

               6. 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)

          8. 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)

          9. Known diagnosis of acute psychosis, severe depression or imminent suicide risk as
             determined via clinical interview by study physician or surrogates

         10. DSM-IV diagnosis of dependence on alcohol requiring immediate medical attention.

         11. DSM-IV diagnosis of dependence on benzodiazepines requiring immediate medical
             attention

         12. DSM-IV diagnosis of dependence on other depressants, or stimulants requiring immediate
             medical attention

         13. Participation in an investigational drug study within the past 30 days

         14. Treatment with MET, BUP/NX, or BUP for more than 15 of the past 30 days (illicit use
             of these medications is allowed)

         15. Pending legal action that could prohibit study participation

         16. Unable or unwilling to comply with study requirements

         17. Unable or unwilling to remain in the local area for duration of treatment

         18. Poor venous access such that venipuncture could not be accomplished from a vein in an
             extremity during eligibility

         19. Pregnant or lactating (females only)