Clinical trial NCT00315341: Starting Treatment With Agonist Replacement Therapies (START)
Official title: Starting Treatment With Agonist Replacement Therapies (START)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Opiate-related Disorders
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2006-04-18
Enrollment: 1269
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Hepatic Safety
timeFrame: 24 Weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Matrix Institute
state: California
city: Sacramento
country: United States
facility: Bi-Valley Medical Clinic INC.
state: California
city: San Francisco
country: United States
facility: BAART; Turk Street Clinic
state: California
city: Hartford
country: United States
facility: Hartford Dispensary
state: Connecticut
city: Waterbury
country: United States
facility: CT Counseling Centers
state: Connecticut
city: Brooklyn
country: United States
facility: Addiction Research & Treatment Corp
state: New York
city: Portland
country: United States
facility: CODA-Research
state: Oregon
city: Philadelphia
country: United States
facility: NET Steps
state: Pennsylvania
city: Seattle
country: United States
facility: Evergreen Treatment Services
state: Washington
Study officials:
affiliation: University of California, Los Angeles
name: Walter Ling, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Andrew Saxon, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Saxon AJ, Ling W, Hillhouse M, Thomas C, Hasson A, Ang A, Doraimani G, Tasissa G, Lokhnygina Y, Leimberger J, Bruce RD, McCarthy J, Wiest K, McLaughlin P, Bilangi R, Cohen A, Woody G, Jacobs P. Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend. 2013 Feb 1;128(1-2):71-6. doi: 10.1016/j.drugalcdep.2012.08.002. Epub 2012 Aug 22.
citation: Nielsen S, Tse WC, Larance B. Opioid agonist treatment for people who are dependent on pharmaceutical opioids. Cochrane Database Syst Rev. 2022 Sep 5;9(9):CD011117. doi: 10.1002/14651858.CD011117.pub3.
citation: Nwabueze C, Elom H, Liu S, Walter SM, Sha Z, Acevedo P, Liu Y, Su BB, Xu C, Piamjariyakul U, Wang K. Gender differences in the associations of multiple psychiatric and chronic conditions with major depressive disorder among patients with opioid use disorder. J Addict Dis. 2022 Apr-Jun;40(2):168-178. doi: 10.1080/10550887.2021.1957639. Epub 2021 Jul 30.
citation: Crist RC, Li J, Doyle GA, Gilbert A, Dechairo BM, Berrettini WH. Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate. Am J Drug Alcohol Abuse. 2018;44(4):431-440. doi: 10.1080/00952990.2017.1420795. Epub 2018 Jan 15.
citation: Woody GE, Bruce D, Korthuis PT, Chhatre S, Poole S, Hillhouse M, Jacobs P, Sorensen J, Saxon AJ, Metzger D, Ling W. HIV risk reduction with buprenorphine-naloxone or methadone: findings from a randomized trial. J Acquir Immune Defic Syndr. 2014 Jul 1;66(3):288-93. doi: 10.1097/QAI.0000000000000165.
citation: Hser YI, Saxon AJ, Huang D, Hasson A, Thomas C, Hillhouse M, Jacobs P, Teruya C, McLaughlin P, Wiest K, Cohen A, Ling W. Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial. Addiction. 2014 Jan;109(1):79-87. doi: 10.1111/add.12333. Epub 2013 Oct 9.