Trial Outcomes & Findings for Combination Pain Therapy in HIV Neuropathy (NCT NCT00863057)

Last Updated: 2021-11-04

Results Overview

Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain" to 10=''Pain as bad as you can imagine". Participants were given pain diaries at weeks 0, 5, 10, and 15. They started the diary 7 days prior to their clinic visits at weeks 0, 4, 9, 14, and 19. During the 7 days, each morning, they recorded their pain level due to neuropathy by circling the number that best described their neuropathy pain on average over the past 24 hours.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

15 participants

Primary outcome timeframe

During the fourth treatment week of each treatment period

Results posted on

2021-11-04

Participant Flow

Participants were recruited across 8 of 15 study sites in the AIDS Clinical Trials Group system between August 2009 and October 2010. The sites were: Harbor-UCLA Medical Center, Harvard MGH, Houston AIDS Research Team, Metrohealth Medical Center in Cleveland, Northwestern University, UC San Diego Medical Center, Washington Univ., Univ. of Colorado.

Participant milestones

Participant milestones
Measure	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine(D) and methadone placebo (MTD-P), (Period 2, Weeks 6 to 9) duloxetine placebo(D-P) and methadone(MTD), (Period 3, Weeks 11 to 14) duloxetine(D) and methadone(MTD), (Period 4, Weeks 16 to 19) duloxetine placebo(D-P) and methadone placebo(MTD-P) Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone, (Period 2,Weeks6 to9)duloxetine placebo and methadone placebo, (Period 3, Weeks 11 to 14)duloxetine and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine and methadone, (Period 2, Weeks 6 to 9) duloxetine and methadone placebo, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine placebo and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone placebo, (Period 2, Weeks 6 to 9) duloxetine and methadone, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone, (Period 4, Weeks 16 to 19) duloxetine and methadone placebo Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.
Milestones Period 1 (Weeks 0-5) STARTED	4	4	3	4
Milestones Period 1 (Weeks 0-5) COMPLETED	3	2	3	3
Milestones Period 1 (Weeks 0-5) NOT COMPLETED	1	2	0	1
Period 2 (Weeks 6-10) STARTED	3	2	3	3
Period 2 (Weeks 6-10) COMPLETED	3	1	2	2
Period 2 (Weeks 6-10) NOT COMPLETED	0	1	1	1
Period 3 (Weeks 11-15) STARTED	3	1	2	2
Period 3 (Weeks 11-15) COMPLETED	3	1	2	2
Period 3 (Weeks 11-15) NOT COMPLETED	0	0	0	0
Period 4 (Weeks 16-20) STARTED	3	1	2	2
Period 4 (Weeks 16-20) COMPLETED	3	1	2	2
Period 4 (Weeks 16-20) NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine(D) and methadone placebo (MTD-P), (Period 2, Weeks 6 to 9) duloxetine placebo(D-P) and methadone(MTD), (Period 3, Weeks 11 to 14) duloxetine(D) and methadone(MTD), (Period 4, Weeks 16 to 19) duloxetine placebo(D-P) and methadone placebo(MTD-P) Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone, (Period 2,Weeks6 to9)duloxetine placebo and methadone placebo, (Period 3, Weeks 11 to 14)duloxetine and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine and methadone, (Period 2, Weeks 6 to 9) duloxetine and methadone placebo, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine placebo and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone placebo, (Period 2, Weeks 6 to 9) duloxetine and methadone, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone, (Period 4, Weeks 16 to 19) duloxetine and methadone placebo Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.
Milestones Period 1 (Weeks 0-5) Adverse Event	1	1	0	1
Milestones Period 1 (Weeks 0-5) Physician Decision	0	1	0	0
Period 2 (Weeks 6-10) Adverse Event	0	1	1	0
Period 2 (Weeks 6-10) Physician Decision	0	0	0	1

Baseline Characteristics

Combination Pain Therapy in HIV Neuropathy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P n=4 Participants Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine(D) and methadone placebo (MTD-P), (Period 2, Weeks 6 to 9) duloxetine placebo(D-P) and methadone(MTD), (Period 3, Weeks 11 to 14) duloxetine(D) and methadone(MTD), (Period 4, Weeks 16 to 19) duloxetine placebo(D-P) and methadone placebo(MTD-P) Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD n=4 Participants Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone, (Period 2,Weeks6 to9)duloxetine placebo and methadone placebo, (Period 3, Weeks 11 to 14)duloxetine and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD n=3 Participants Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine and methadone, (Period 2, Weeks 6 to 9) duloxetine and methadone placebo, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine placebo and methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P n=4 Participants Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone placebo, (Period 2, Weeks 6 to 9) duloxetine and methadone, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone, (Period 4, Weeks 16 to 19) duloxetine and methadone placebo Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	Total n=15 Participants Total of all reporting groups
Age, Customized 20-29	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	1 participants n=21 Participants
Age, Customized 30-39	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Age, Customized 40-49	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	2 participants n=21 Participants
Age, Customized 50-59	3 participants n=5 Participants	2 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants	8 participants n=21 Participants
Age, Customized >= 60	1 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	3 participants n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants	13 Participants n=21 Participants
Race/Ethnicity, Customized White/Caucasian	1 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants	7 participants n=21 Participants
Race/Ethnicity, Customized Black/African American	2 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	5 participants n=21 Participants
Race/Ethnicity, Customized Hispanic/Latino	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	3 participants n=21 Participants
Region of Enrollment United States	4 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	4 participants n=4 Participants	15 participants n=21 Participants
Baseline CD4 Counts	400 cells/µL STANDARD_DEVIATION 278 • n=5 Participants	522 cells/µL STANDARD_DEVIATION 328 • n=7 Participants	867 cells/µL STANDARD_DEVIATION 162 • n=5 Participants	249 cells/µL STANDARD_DEVIATION 173 • n=4 Participants	486 cells/µL STANDARD_DEVIATION 315 • n=21 Participants
Baseline CD8 Counts	970 cells/µL STANDARD_DEVIATION 639 • n=5 Participants	490 cells/µL STANDARD_DEVIATION 205 • n=7 Participants	1042.33 cells/µL STANDARD_DEVIATION 1110 • n=5 Participants	794.75 cells/µL STANDARD_DEVIATION 534 • n=4 Participants	809.73 cells/µL STANDARD_DEVIATION 618 • n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL <= 1.70	2 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants	2 participants n=4 Participants	10 participants n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL =1.71	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	1 participants n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL =2.19	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL =2.34	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL =4.61	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Baseline Log10(HIV RNA Viral Load) in copies/mL =5.90	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	1 participants n=21 Participants
Baseline Daily Mean Pain Intensity (MPI) Scores	7.8 Scores on a scale STANDARD_DEVIATION 0.5 • n=5 Participants	6.5 Scores on a scale STANDARD_DEVIATION 1.3 • n=7 Participants	6 Scores on a scale STANDARD_DEVIATION 1 • n=5 Participants	7.3 Scores on a scale STANDARD_DEVIATION 2.2 • n=4 Participants	6.9 Scores on a scale STANDARD_DEVIATION 1.4 • n=21 Participants
Baseline Night Time Mean Pain Intensity (MPI) Scores	7.3 Scores on a scale STANDARD_DEVIATION 1.0 • n=5 Participants	6.8 Scores on a scale STANDARD_DEVIATION 1.0 • n=7 Participants	7.3 Scores on a scale STANDARD_DEVIATION 1.2 • n=5 Participants	8 Scores on a scale STANDARD_DEVIATION 1.4 • n=4 Participants	7.3 Scores on a scale STANDARD_DEVIATION 1.1 • n=21 Participants
Baseline Brief Pain Inventory (BPI) Interference Scores	5.6 Scores on a scale STANDARD_DEVIATION 1.1 • n=5 Participants	4.1 Scores on a scale STANDARD_DEVIATION 0.5 • n=7 Participants	4.5 Scores on a scale STANDARD_DEVIATION 2.8 • n=5 Participants	6.1 Scores on a scale STANDARD_DEVIATION 3.7 • n=4 Participants	5.1 Scores on a scale STANDARD_DEVIATION 2.3 • n=21 Participants
Baseline Center for Epidemiologic Studies Depression (CES-D) Scores	13 Scores on a scale STANDARD_DEVIATION 10 • n=5 Participants	11 Scores on a scale STANDARD_DEVIATION 8 • n=7 Participants	9 Scores on a scale STANDARD_DEVIATION 9 • n=5 Participants	16 Scores on a scale STANDARD_DEVIATION 22 • n=4 Participants	12 Scores on a scale STANDARD_DEVIATION 13 • n=21 Participants

PRIMARY outcome

Timeframe: During the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale	5.20 Scores on a scale Standard Deviation 2.44 • Interval 4.0 to 7.0	5.91 Scores on a scale Standard Deviation 2.47 • Interval 4.0 to 8.0	6.20 Scores on a scale Standard Deviation 2.35 • Interval 5.0 to 8.0	5.70 Scores on a scale Standard Deviation 2.16 • Interval 4.0 to 8.0

SECONDARY outcome

Timeframe: At Baseline and over the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain" to 10=''Pain as bad as you can imagine" at baseline and over the fourth treatment week of each treatment period. The % of improvement was calculated as (x-y)/x,where x was the MPI score at baseline, and y was the MPI score at the end of each treatment stage.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale	2 participants	2 participants	2 participants	2 participants

SECONDARY outcome

Timeframe: At Baseline and over the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale	2 participants	2 participants	1 participants	2 participants

SECONDARY outcome

Timeframe: Over the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Mean Nighttime Pain Measure on an 11-point Likert Scale	5.20 Scores on a scale Standard Error 2.35 • Interval 4.0 to 6.0	5.82 Scores on a scale Standard Error 2.27 • Interval 4.0 to 8.0	5.90 Scores on a scale Standard Error 2.33 • Interval 5.0 to 7.0	6.10 Scores on a scale Standard Error 2.47 • Interval 4.0 to 8.0

SECONDARY outcome

Timeframe: At the fourth week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

The BPI interference scale measured level of interference with the following seven items: 1. General activity 2. Mood 3. Walking ability 4. Normal work 5. Relations with other people 6. Sleep 7. Enjoyment of life Interference scales range from 0='Does not interfere' to 10='Completely interferes'. The overall BPI score is the mean of seven item with the minimum and maximal scores of 0 and 70, respectively.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items	3.14 Scores on a scale Interval 2.57 to 4.57	4.14 Scores on a scale Interval 2.29 to 7.14	3.64 Scores on a scale Interval 3.29 to 6.71	3.14 Scores on a scale Interval 2.57 to 5.57

SECONDARY outcome

Timeframe: At the fourth treatment week of each treatment period

The data for this outcome are not available for the analysis due to an issue with a company which provides software to calculate SF-36.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

The CES-D is a 20-item self-report rating inventory measuring characteristic attitudes and symptoms of depression. Participants were asked to score each item: (0) Rarely, (1) Occasionally, (2) Sometimes, and (3) Most of time. Some items are multiplied by -1 to change direction. The overall CES-D score is simply the sum of 20 items. The highest possible total CES-D score is 48, and the lowest possible score is -12. The total CES-D score is considered missing if more than 4 items are not answered.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)	13.8 Scores on a scale Standard Deviation 10.9	13.8 Scores on a scale Standard Deviation 14.5	13.3 Scores on a scale Standard Deviation 10.8	13.3 Scores on a scale Standard Deviation 13.2

SECONDARY outcome

Timeframe: At the fourth treatment week of each treatment period

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale: 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse Participants were carefully instructed to consider the impact of study treatments on their level of neuropathic pain intensity during the baseline phase of the study.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale PGIC - Very much improved	1 participants	0 participants	1 participants	1 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale PGIC - Much improved	4 participants	1 participants	2 participants	1 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale PGIC - Minimally improved	2 participants	4 participants	4 participants	4 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale PGIC - No change	3 participants	6 participants	2 participants	4 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale PGIC - Much worse	0 participants	0 participants	1 participants	0 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale CGIC - Very much improved	1 participants	1 participants	1 participants	1 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale CGIC - Much improved	4 participants	1 participants	3 participants	1 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale CGIC - Minimally improved	1 participants	1 participants	3 participants	3 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale CGIC - No change	4 participants	8 participants	3 participants	4 participants
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale CGIC - Much worse	0 participants	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: During each treatment period and the subsequent cross-over (or final study week) period

Population: The analysis was per protocol. Because of a cross-over trial, the # of participants analyzed do not match with the flow chart. Any participant who took the rescue med during the study period (incl. cross-over period) was counted in this analysis. If a participant took the rescue med twice within the same period, the number is counted as one.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Use of Rescue Medication (Acetaminophen) Cross-over period (5, 10, 15, 20 weeks)	1 participants	0 participants	1 participants	1 participants
Use of Rescue Medication (Acetaminophen) Treatment period (1-4, 6-9, 11-14, 16-19 weeks)	0 participants	0 participants	0 participants	2 participants

SECONDARY outcome

Timeframe: During each treatment period

Population: The number below is the highest tolerated daily dose in mg based on n=12 for Methadone and n=10 for Duloxetine.

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=12 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Maximum Tolerated Dose of Duloxetine and Methadone	30 mg	60 mg	—	—

SECONDARY outcome

Timeframe: From study entry to end of study at week 20 or premature study discontinuation

Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.

The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 was used (see the link to the grading table in Protocol Section)

Outcome measures

Outcome measures
Measure	Duloxetine and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine and Methadone Placebo n=11 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.	Duloxetine Placebo and Methadone Placebo n=10 Participants Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6.
Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events	5 Participants	4 Participants	6 Participants	5 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At the fourth treatment week of each treatment period

Population: This was one of the exploratory objectives and was not analyzed as the study was terminated.

This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint in the future.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: During the fourth week of each treatment period

Population: This was one of the exploratory objectives and was not analyzed as the study was terminated.

This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint.

Outcome measures

Outcome data not reported

Adverse Events

Duloxetine and Methadone

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Duloxetine and Methadone Placebo

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Duloxetine Placebo and Methadone

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Duloxetine Placebo and Methadone Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

ACTG ClinicalTrials.gov Coordinator

ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

Phone: (301) 628-3313

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Duloxetine and Methadone n=10 participants at risk Duloxetine was initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Methadone was initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	Duloxetine and Methadone Placebo n=11 participants at risk Duloxetine was initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Methadone placebo was initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	Duloxetine Placebo and Methadone n=10 participants at risk Duloxetine placebo was initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Methadone was initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.	Duloxetine Placebo and Methadone Placebo n=10 participants at risk Duloxetine placebo was initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Methadone placebo was initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments.
Eye disorders Diplopia	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Constipation	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	20.0% 2/10 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Diarrhoea	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Dry mouth	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Nausea	20.0% 2/10 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	9.1% 1/11 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	20.0% 2/10 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Vomiting	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	9.1% 1/11 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
General disorders Fatigue	30.0% 3/10 • Number of events 3 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
General disorders Malaise	20.0% 2/10 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
General disorders Pain	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	9.1% 1/11 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Metabolism and nutrition disorders Decreased appetite	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Nervous system disorders Dizziness	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Nervous system disorders Headache	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Anxiety	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Depression	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Agitation	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Insomnia	25.0% 2/8 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Dreams, Abnormal	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Renal and urinary disorders Urinary retention	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Blood and lymphatic system disorders Total Bilirubin	20.0% 2/10 • Number of events 2 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Renal and urinary disorders Creatinine	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	9.1% 1/11 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Hepatobiliary disorders Sgot	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
General disorders Ache	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Nervous system disorders Cognition, Abnormal	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Psychiatric disorders Mental Status Change, Psychiatric	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Cramp	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Hepatobiliary disorders Alkaline Phosphatase	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Gastrointestinal disorders Congestion	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Ear and labyrinth disorders Ear Abnormality	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/11 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	0.00% 0/10 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.	10.0% 1/10 • Number of events 1 • Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.