Trial Outcomes & Findings for Starting Treatment With Agonist Replacement Therapies (START) (NCT NCT00315341)

NCT ID: NCT00315341

Last Updated: 2017-01-06

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 1269 participants
• Primary outcome timeframe: 24 Weeks
• Results posted on: 2017-01-06

Participant Flow

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

Participant milestones

Measure	Buprenorphine/Nx 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.	Methadone The mean dose of methadone was 93.2 mg.
Overall Study STARTED	740	529
Overall Study COMPLETED	340	391
Overall Study NOT COMPLETED	400	138

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Starting Treatment With Agonist Replacement Therapies (START)

Baseline characteristics by cohort

Measure	Buprenorphine/Nx n=740 Participants	Methadone n=529 Participants	Total n=1269 Participants Total of all reporting groups
Age, Continuous	37.5 years STANDARD_DEVIATION 11.2 • n=5 Participants	37.3 years STANDARD_DEVIATION 10.9 • n=7 Participants	37.4 years STANDARD_DEVIATION 11.1 • n=5 Participants
Gender Female	238 Participants n=5 Participants	170 Participants n=7 Participants	408 Participants n=5 Participants
Gender Male	502 Participants n=5 Participants	359 Participants n=7 Participants	861 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

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

Outcome measures

Measure	Buprenorphine/Nx n=340 Participants	Methadone n=391 Participants
Hepatic Safety ALT - A (low, stays low)	278 participants	318 participants
Hepatic Safety ALT - B (low, goes high)	41 participants	62 participants
Hepatic Safety ALT - C (high, goes low, stays low)	4 participants	1 participants
Hepatic Safety ALT - D (high, stays high)	17 participants	10 participants
Hepatic Safety AST - A (low, stay low)	291 participants	328 participants
Hepatic Safety AST - B (low, goes high)	37 participants	54 participants
Hepatic Safety AST - C (high, goes low, stays low)	3 participants	1 participants
Hepatic Safety AST - D (high, stays high)	9 participants	8 participants

Adverse Events

Buprenorphine/Nx

Serious events: 38 serious events

Other events: 530 other events

Deaths: 0 deaths

Methadone

Serious events: 45 serious events

Other events: 442 other events

Deaths: 0 deaths

Serious adverse events

Measure	Buprenorphine/Nx n=727 participants at risk 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.	Methadone n=520 participants at risk 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.
Investigations death	0.41% 3/727 • Number of events 3 • 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. 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.	0.19% 1/520 • Number of events 1 • 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. 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.
Investigations life-threatening	0.41% 3/727 • Number of events 3 • 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. 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.	0.58% 3/520 • Number of events 3 • 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. 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.
Investigations hospitalization	5.2% 38/727 • Number of events 41 • 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. 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.	8.7% 45/520 • Number of events 50 • 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. 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.
Investigations disability	0.00% 0/727 • 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. 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.	0.77% 4/520 • Number of events 4 • 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. 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.
Investigations congenital anomaly	0.14% 1/727 • Number of events 1 • 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. 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.	0.00% 0/520 • 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. 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.

Other adverse events

Measure	Buprenorphine/Nx n=727 participants at risk 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.	Methadone n=520 participants at risk 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.
Investigations alanine aminotransferase increased	11.1% 81/727 • Number of events 104 • 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. 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.	13.5% 70/520 • Number of events 94 • 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. 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.
Investigations aspartate aminotransferase increased	9.6% 70/727 • Number of events 78 • 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. 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.	12.1% 63/520 • Number of events 87 • 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. 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.
Investigations gamma glutamyltransferase increased	6.5% 47/727 • Number of events 54 • 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. 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.	11.0% 57/520 • Number of events 71 • 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. 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.
Investigations weight increased	1.4% 10/727 • Number of events 10 • 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. 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.	5.0% 26/520 • Number of events 26 • 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. 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.
Infections and infestations nasopharyngitis	16.4% 119/727 • Number of events 147 • 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. 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.	22.5% 117/520 • Number of events 165 • 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. 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.
Infections and infestations influenza	4.8% 35/727 • Number of events 38 • 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. 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.	6.5% 34/520 • Number of events 37 • 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. 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.
Infections and infestations upper respiratory tract infection	4.4% 32/727 • Number of events 38 • 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. 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.	5.0% 26/520 • Number of events 30 • 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. 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.
Gastrointestinal disorders toothache	6.7% 49/727 • Number of events 60 • 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. 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.	10.6% 55/520 • Number of events 72 • 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. 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.
Gastrointestinal disorders constipation	6.7% 49/727 • Number of events 52 • 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. 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.	9.0% 47/520 • Number of events 51 • 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. 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.
Gastrointestinal disorders vomiting	3.9% 28/727 • Number of events 28 • 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. 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.	5.8% 30/520 • Number of events 36 • 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. 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.
Injury, poisoning and procedural complications injury, poisoning, and procedural complications	18.4% 134/727 • Number of events 238 • 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. 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.	23.8% 124/520 • Number of events 218 • 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. 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.
Nervous system disorders nervous system disorders	21.2% 154/727 • Number of events 246 • 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. 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.	20.4% 106/520 • Number of events 151 • 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. 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.
Nervous system disorders headache	14.0% 102/727 • Number of events 132 • 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. 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.	10.4% 54/520 • Number of events 72 • 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. 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.
Musculoskeletal and connective tissue disorders musculoskeletal and connective tissue disorders	18.6% 135/727 • Number of events 208 • 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. 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.	18.8% 98/520 • Number of events 136 • 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. 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.
Musculoskeletal and connective tissue disorders back pain	6.9% 50/727 • Number of events 56 • 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. 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.	7.1% 37/520 • Number of events 43 • 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. 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.
Psychiatric disorders psychiatric disorders	15.7% 114/727 • Number of events 162 • 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. 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.	17.1% 89/520 • Number of events 129 • 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. 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.
General disorders general disorders and administration site conditions	10.9% 79/727 • Number of events 99 • 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. 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.	16.0% 83/520 • Number of events 162 • 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. 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.
Skin and subcutaneous tissue disorders skin and subcutaneous tissue disorders	10.3% 75/727 • Number of events 92 • 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. 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.	14.4% 75/520 • Number of events 98 • 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. 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.
Skin and subcutaneous tissue disorders hyperhidrosis	1.7% 12/727 • Number of events 13 • 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. 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.	7.3% 38/520 • Number of events 44 • 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. 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.
Respiratory, thoracic and mediastinal disorders respiratory, thoracic, and mediastinal disorders	11.3% 82/727 • Number of events 105 • 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. 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.	12.3% 64/520 • Number of events 80 • 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. 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.
Investigations investigations	29.6% 215/727 • Number of events 564 • 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. 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.	41.2% 214/520 • Number of events 619 • 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. 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.
Infections and infestations infections and infestations	38.7% 281/727 • Number of events 470 • 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. 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.	47.9% 249/520 • Number of events 466 • 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. 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.
Gastrointestinal disorders gastrointestinal disorders	27.0% 196/727 • Number of events 311 • 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. 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.	33.5% 174/520 • Number of events 291 • 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. 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.

Additional Information

Walter Ling, M.D.

University of California, Los Angeles

Phone: (310) 933-8111

Email: lwalter@ucla.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place