Starting Treatment With Agonist Replacement Therapies (START)

NCT ID: NCT00315341

Last Updated: 2017-01-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1269 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-04-30
• Study Completion Date: 2010-08-31

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.

Conditions

Opiate-related Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Buprenorphine/Nx

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.

Group Type: EXPERIMENTAL

Buprenorphine/naloxone

Intervention Type: DRUG

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.

Methadone

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.

Group Type: ACTIVE_COMPARATOR

Methadone

Intervention Type: DRUG

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.

Interventions

Buprenorphine/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.

Intervention Type: DRUG

Methadone

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 Type: DRUG

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

University of California, Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Walter Ling

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Walter Ling, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Andrew Saxon, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Matrix Institute

Los Angeles, California, United States

Bi-Valley Medical Clinic INC.

Sacramento, California, United States

BAART; Turk Street Clinic

San Francisco, California, United States

Hartford Dispensary

Hartford, Connecticut, United States

CT Counseling Centers

Waterbury, Connecticut, United States

Addiction Research & Treatment Corp

Brooklyn, New York, United States

CODA-Research

Portland, Oregon, United States

NET Steps

Philadelphia, Pennsylvania, United States

Evergreen Treatment Services

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: RESULT

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Reference Type: DERIVED

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Reference Type: DERIVED

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Reference Type: DERIVED

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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.

Reference Type: DERIVED

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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.

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Other Identifiers

U10DA013045

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NIDA-CTN-0027

Identifier Type: -

Identifier Source: org_study_id