Opiate-related Disorders
Conditions
Brief summary
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
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.
Interventions
DRUGBuprenorphine/naloxone
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.
DRUGMethadone
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.
Sponsors
National Institute on Drug Abuse (NIDA)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Safety | 24 Weeks | 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 |
Countries
United States
Participant flow
Recruitment details
Methadone clinics in California, Oregon, Washington, Pennsylvania, New York, and Connecticut
Participants by arm
| Arm | Count |
|---|---|
| Buprenorphine/Nx | 740 |
| Methadone | 529 |
| Total | 1,269 |
Baseline characteristics
| Characteristic | Buprenorphine/Nx | Methadone | Total |
|---|---|---|---|
| Age, Continuous | 37.5 years STANDARD_DEVIATION 11.2 | 37.3 years STANDARD_DEVIATION 10.9 | 37.4 years STANDARD_DEVIATION 11.1 |
| Gender Female | 238 Participants | 170 Participants | 408 Participants |
| Gender Male | 502 Participants | 359 Participants | 861 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 530 / 727 | 442 / 520 |
| serious Total, serious adverse events | 38 / 727 | 45 / 520 |
Outcome results
Primary
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
Time frame: 24 Weeks
Population: evaluable subjects stayed in treatment for 24 weeks and gave at least 4 blood samples for liver function tests during the treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Buprenorphine/Nx | Hepatic Safety | ALT - A (low, stays low) | 278 participants |
| Buprenorphine/Nx | Hepatic Safety | ALT - B (low, goes high) | 41 participants |
| Buprenorphine/Nx | Hepatic Safety | ALT - C (high, goes low, stays low) | 4 participants |
| Buprenorphine/Nx | Hepatic Safety | ALT - D (high, stays high) | 17 participants |
| Buprenorphine/Nx | Hepatic Safety | AST - A (low, stay low) | 291 participants |
| Buprenorphine/Nx | Hepatic Safety | AST - B (low, goes high) | 37 participants |
| Buprenorphine/Nx | Hepatic Safety | AST - C (high, goes low, stays low) | 3 participants |
| Buprenorphine/Nx | Hepatic Safety | AST - D (high, stays high) | 9 participants |
| Methadone | Hepatic Safety | AST - D (high, stays high) | 8 participants |
| Methadone | Hepatic Safety | ALT - A (low, stays low) | 318 participants |
| Methadone | Hepatic Safety | AST - A (low, stay low) | 328 participants |
| Methadone | Hepatic Safety | ALT - B (low, goes high) | 62 participants |
| Methadone | Hepatic Safety | AST - C (high, goes low, stays low) | 1 participants |
| Methadone | Hepatic Safety | ALT - C (high, goes low, stays low) | 1 participants |
| Methadone | Hepatic Safety | AST - B (low, goes high) | 54 participants |
| Methadone | Hepatic Safety | ALT - D (high, stays high) | 10 participants |
Comparison: categorized changes in ALT/AST from BL:(1)BL transaminases(both ALT/AST)≤2X upper limit of normal(ULN)\& remained at this level;(2)BL transaminases ≤2X ULN(either ALT/AST)but increased(either ALT/AST)above this level at any time;(3)BL transaminases \>2X ULN(either ALT/AST)\& decreased and remained at ≤2X ULN(both ALT/AST);(4)BL transaminases(both ALT/AST)\>2X ULN \&remained at this level(both ALT/AST);(5)BL transaminases \>2X ULN(either ALT/AST)\& increased 2X above this level ever(either ALT/AST).p-value: <0.05shift table analyses