Starting Treatment With Agonist Replacement Therapies (START)

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT00315341
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 1,269
• Locations: 9
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 141
• Patients Per Site Per Month: 2.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Opiate-related Disorders	Drug: Buprenorphine/naloxone; Drug: Methadone	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1269 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Starting Treatment With Agonist Replacement Therapies (START)
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.
Active Comparator: 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.	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.

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

5. oral contraceptives

6. barrier (diaphragm or condom) with spermicide

7. IUD

8. intrauterine progesterone contraceptive system

9. levonorgestrel implant

10. medroxyprogesterone acetate contraceptive injection

11. contraceptive transdermal patch

12. hormonal vaginal contraceptive ring

13. surgical sterilization

14. complete abstinence from sexual intercourse

15. 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,

8. Congestive heart failure

9. Left ventricular hypertrophy

10. Bradycardia

11. Hereditary QT prolongation

12. Uncorrected electrolyte imbalance

13. 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)

1. 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)

2. Known diagnosis of acute psychosis, severe depression or imminent suicide risk as determined via clinical interview by study physician or surrogates

3. DSM-IV diagnosis of dependence on alcohol requiring immediate medical attention.

4. DSM-IV diagnosis of dependence on benzodiazepines requiring immediate medical attention

5. DSM-IV diagnosis of dependence on other depressants, or stimulants requiring immediate medical attention

6. Participation in an investigational drug study within the past 30 days

7. Treatment with MET, BUP/NX, or BUP for more than 15 of the past 30 days (illicit use of these medications is allowed)

8. Pending legal action that could prohibit study participation

9. Unable or unwilling to comply with study requirements

10. Unable or unwilling to remain in the local area for duration of treatment

11. Poor venous access such that venipuncture could not be accomplished from a vein in an extremity during eligibility

12. Pregnant or lactating (females only)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Matrix Institute	Los Angeles	California	United States	90016
2	Bi-Valley Medical Clinic INC.	Sacramento	California	United States	95816
3	BAART; Turk Street Clinic	San Francisco	California	United States	94102
4	Hartford Dispensary	Hartford	Connecticut	United States	06120
5	CT Counseling Centers	Waterbury	Connecticut	United States	06705
6	Addiction Research & Treatment Corp	Brooklyn	New York	United States	11201
7	CODA-Research	Portland	Oregon	United States	97214
8	NET Steps	Philadelphia	Pennsylvania	United States	19137
9	Evergreen Treatment Services	Seattle	Washington	United States	98134

Sponsors and Collaborators

• University of California, Los Angeles
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Walter Ling, M.D., University of California, Los Angeles
• Principal Investigator: Andrew Saxon, M.D., University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Walter Ling, Principal Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00315341
• Other Study ID Numbers: NIDA-CTN-0027; U10DA013045
• First Posted: Apr 18, 2006
• Last Update Posted: Jan 6, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Buprenorphine; Methadone; Buprenorphine, Naloxone Drug Combination; Naloxone

Study Results

Participant Flow

Recruitment Details	Methadone clinics in California, Oregon, Washington, Pennsylvania, New York, and Connecticut

Arm/Group Title	Buprenorphine/Nx	Methadone
Arm/Group Description	Participants received medication for 24 weeks in the active phase of the study. The mean dose of buprenorphine was 22.3 mg. Blood samples for measurement of liver function were taken at baseline and at Weeks 1, 2, 4 8, 12, 16, 20, and 24 with follow-up at Week 32.	The mean dose of methadone was 93.2 mg.
Period Title: Overall Study
STARTED	740	529
COMPLETED	340	391
NOT COMPLETED	400	138

Baseline Characteristics

Arm/Group Title	Buprenorphine/Nx	Methadone	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	740	529	1269
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.5 (11.2)	37.3 (10.9)	37.4 (11.1)
Gender (Count of Participants)
Female	238 32.2%	170 32.1%	408 32.2%
Male	502 67.8%	359 67.9%	861 67.8%

Outcome Measures

1. Primary Outcome

Title	Hepatic Safety
Description	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

Outcome Measure Data

Analysis Population Description

evaluable subjects stayed in treatment for 24 weeks and gave at least 4 blood samples for liver function tests during the treatment period

Arm/Group Title	Buprenorphine/Nx	Methadone
Arm/Group Description
Measure Participants	340	391
ALT - A (low, stays low)	278 37.6%	318 60.1%
ALT - B (low, goes high)	41 5.5%	62 11.7%
ALT - C (high, goes low, stays low)	4 0.5%	1 0.2%
ALT - D (high, stays high)	17 2.3%	10 1.9%
AST - A (low, stay low)	291 39.3%	328 62%
AST - B (low, goes high)	37 5%	54 10.2%
AST - C (high, goes low, stays low)	3 0.4%	1 0.2%
AST - D (high, stays high)	9 1.2%	8 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine/Nx, Methadone
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments
	Method	shift table analyses
	Comments

Adverse Events

Time Frame	Adverse events (medical and/or psychiatric) assessment will initiate with participant randomization and will continue through 30 days post last dose of study medication administered. Study staff should contact each participant 30 days after study completion and/or discontinuation of study medication to follow-up on any adverse events continuing at study end and to determine whether the participant experienced any adverse events within the 30 days after discontinuing study medication.
Adverse Event Reporting Description	All AEs reported during the course of the study requiring medical attention will be reported to a study physician immediately. A study physician may then meet any participants for whom additional follow-up or AE assessment is indicated. The type of AE, severity of the AE and the relationship of the AE to the study treatments will be assessed by appropriately trained medical personnel and recorded on an AE CRF, according to the procedures described in Section 14.2.
Arm/Group Title	Buprenorphine/Nx		Methadone
Arm/Group Description	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.		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.
All Cause Mortality
	Buprenorphine/Nx		Methadone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Buprenorphine/Nx		Methadone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/727 (5.2%)		45/520 (8.7%)
Investigations
death	3/727 (0.4%)	3	1/520 (0.2%)	1
life-threatening	3/727 (0.4%)	3	3/520 (0.6%)	3
hospitalization	38/727 (5.2%)	41	45/520 (8.7%)	50
disability	0/727 (0%)	0	4/520 (0.8%)	4
congenital anomaly	1/727 (0.1%)	1	0/520 (0%)	0
Other (Not Including Serious) Adverse Events
	Buprenorphine/Nx		Methadone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	530/727 (72.9%)		442/520 (85%)
Gastrointestinal disorders
toothache	49/727 (6.7%)	60	55/520 (10.6%)	72
constipation	49/727 (6.7%)	52	47/520 (9%)	51
vomiting	28/727 (3.9%)	28	30/520 (5.8%)	36
gastrointestinal disorders	196/727 (27%)	311	174/520 (33.5%)	291
General disorders
general disorders and administration site conditions	79/727 (10.9%)	99	83/520 (16%)	162
Infections and infestations
nasopharyngitis	119/727 (16.4%)	147	117/520 (22.5%)	165
influenza	35/727 (4.8%)	38	34/520 (6.5%)	37
upper respiratory tract infection	32/727 (4.4%)	38	26/520 (5%)	30
infections and infestations	281/727 (38.7%)	470	249/520 (47.9%)	466
Injury, poisoning and procedural complications
injury, poisoning, and procedural complications	134/727 (18.4%)	238	124/520 (23.8%)	218
Investigations
alanine aminotransferase increased	81/727 (11.1%)	104	70/520 (13.5%)	94
aspartate aminotransferase increased	70/727 (9.6%)	78	63/520 (12.1%)	87
gamma glutamyltransferase increased	47/727 (6.5%)	54	57/520 (11%)	71
weight increased	10/727 (1.4%)	10	26/520 (5%)	26
investigations	215/727 (29.6%)	564	214/520 (41.2%)	619
Musculoskeletal and connective tissue disorders
musculoskeletal and connective tissue disorders	135/727 (18.6%)	208	98/520 (18.8%)	136
back pain	50/727 (6.9%)	56	37/520 (7.1%)	43
Nervous system disorders
nervous system disorders	154/727 (21.2%)	246	106/520 (20.4%)	151
headache	102/727 (14%)	132	54/520 (10.4%)	72
Psychiatric disorders
psychiatric disorders	114/727 (15.7%)	162	89/520 (17.1%)	129
Respiratory, thoracic and mediastinal disorders
respiratory, thoracic, and mediastinal disorders	82/727 (11.3%)	105	64/520 (12.3%)	80
Skin and subcutaneous tissue disorders
skin and subcutaneous tissue disorders	75/727 (10.3%)	92	75/520 (14.4%)	98
hyperhidrosis	12/727 (1.7%)	13	38/520 (7.3%)	44

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.