Combination Pain Therapy in HIV Neuropathy

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ClinicalTrials.gov Identifier: NCT00863057

Recruitment Status : Terminated (Due to slow rate of enrollment, which compromised the ability to meet study objectives in a timely manner.)

First Posted : March 17, 2009

Results First Posted : April 25, 2012

Last Update Posted : February 18, 2019

Sponsor:

Information provided by (Responsible Party):

National Institute of Allergy and Infectious Diseases (NIAID)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Treatment
Conditions	HIV Infections Peripheral Neuropathy
Interventions	Drug: Duloxetine Drug: Duloxetine placebo Drug: Methadone Drug: Methadone placebo
Enrollment	15

Participant Flow

Recruitment Details	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.
Pre-assignment Details


Arm/Group Title	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P
Arm/Group Description	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...
Arm/Group Description	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.	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.	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.	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.
Period Title: Milestones Period 1 (Weeks 0-5)
Started	4	4	3	4
Completed	3	2	3	3
Not Completed	1	2	0	1
Reason Not Completed
Adverse Event	1	1	0	1
Physician Decision	0	1	0	0
Period Title: Period 2 (Weeks 6-10)
Started	3	2	3	3
Completed	3	1	2	2
Not Completed	0	1	1	1
Reason Not Completed
Adverse Event	0	1	1	0
Physician Decision	0	0	0	1
Period Title: Period 3 (Weeks 11-15)
Started	3	1	2	2
Completed	3	1	2	2
Not Completed	0	0	0	0
Period Title: Period 4 (Weeks 16-20)
Started	3	1	2	2
Completed	3	1	2	2
Not Completed	0	0	0	0

Baseline Characteristics

Arm/Group Title		D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P	Total
Arm/Group Description		Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...	Total of all reporting groups
Arm/Group Description		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.	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.	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.	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 of all reporting groups
Overall Number of Baseline Participants		4	4	3	4	15
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
20-29		0	0	0	1	1
30-39		0	1	0	0	1
40-49		0	0	1	1	2
50-59		3	2	1	2	8
>= 60		1	1	1	0	3
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
	Female	0 0.0%	0 0.0%	2 66.7%	0 0.0%	2 13.3%
	Male	4 100.0%	4 100.0%	1 33.3%	4 100.0%	13 86.7%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
White/Caucasian		1	3	1	2	7
Black/African American		2	1	1	1	5
Hispanic/Latino		1	0	1	1	3
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
United States		4	4	3	4	15
Baseline CD4 Counts Mean (Standard Deviation) Unit of measure: cells/µL
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		400 (278)	522 (328)	867 (162)	249 (173)	486 (315)
Baseline CD8 Counts Mean (Standard Deviation) Unit of measure: cells/µL
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		970 (639)	490 (205)	1042.33 (1110)	794.75 (534)	809.73 (618)
Baseline Log10(HIV RNA Viral Load) in copies/mL Measure Type: Number Unit of measure: Participants	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
<= 1.70		2	3	3	2	10
=1.71		0	0	0	1	1
=2.19		1	0	0	0	1
=2.34		1	0	0	0	1
=4.61		0	1	0	0	1
=5.90		0	0	0	1	1
Baseline Daily Mean Pain Intensity (MPI) Scores ^[1] Mean (Standard Deviation) Unit of measure: Scores on a scale
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		7.8 (0.5)	6.5 (1.3)	6 (1)	7.3 (2.2)	6.9 (1.4)
		[1] Measure Description: 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 diary at weeks 0, 5, 10, and 15. They started diary 7 days prior to their clinic visits at 0,4,9,14,19. Each day, recorded a number from 0 to 10. These numbers were averaged by the number of days so the total range of scores is still from 0 to 10.
Baseline Night Time Mean Pain Intensity (MPI) Scores ^[1] Mean (Standard Deviation) Unit of measure: Scores on a scale
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		7.3 (1.0)	6.8 (1.0)	7.3 (1.2)	8 (1.4)	7.3 (1.1)
		[1] Measure Description: 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 diary at weeks 0, 5, 10, and 15. They started diary 7 days prior to their clinic visits at 0,4,9,14,19. Each day, recorded a number from 0 to 10. These numbers were averaged by the number of days so the total range of scores is still from 0 to 10.
Baseline Brief Pain Inventory (BPI) Interference Scores ^[1] Mean (Standard Deviation) Unit of measure: Scores on a scale
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		5.6 (1.1)	4.1 (0.5)	4.5 (2.8)	6.1 (3.7)	5.1 (2.3)
		[1] Measure Description: The BPI interference scale measured level of interference with the following seven items: General activity Mood Walking ability Normal work Relations with other people Sleep Enjoyment of life Interference scales range from 0=’Does not interfere’ to 10=’Completely interferes’. The overall BPI score is the mean of seven items.
Baseline Center for Epidemiologic Studies Depression (CES-D) Scores ^[1] Mean (Standard Deviation) Unit of measure: Scores on a scale
	Number Analyzed	4 participants	4 participants	3 participants	4 participants	15 participants
		13 (10)	11 (8)	9 (9)	16 (22)	12 (13)
		[1] Measure Description: 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,(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

1.Primary Outcome


Title	Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
Description	Pain was measured on an ...
Description	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.
Time Frame	During the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Mean (Standard Deviation) Unit of Measure: Scores on a scale
	5.20 (2.44)	5.91 (2.47)	6.20 (2.35)	5.70 (2.16)

2.Secondary Outcome


Title	Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale
Description	Pain was measured on an ...
Description	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.
Time Frame	At Baseline and over the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Measure Type: Number Unit of Measure: participants
	2	2	2	2

3.Secondary Outcome


Title	Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale
Description	Pain was measured on an ...
Description	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.
Time Frame	At Baseline and over the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Measure Type: Number Unit of Measure: participants
	2	2	1	2

4.Secondary Outcome


Title	Mean Nighttime Pain Measure on an 11-point Likert Scale
Description	Pain was measured on an ...
Description	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 during the night time.
Time Frame	Over the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Mean (Standard Error) Unit of Measure: Scores on a scale
	5.20 (2.35)	5.82 (2.27)	5.90 (2.33)	6.10 (2.47)

5.Secondary Outcome


Title	Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items
Description	The BPI interference sca...
Description	The BPI interference scale measured level of interference with the following seven items: General activity Mood Walking ability Normal work Relations with other people Sleep 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.
Time Frame	At the fourth week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Median (Inter-Quartile Range) Unit of Measure: Scores on a scale
	3.14 (2.57 to 4.57)	4.14 (2.29 to 7.14)	3.64 (3.29 to 6.71)	3.14 (2.57 to 5.57)

6.Secondary Outcome


Title	Quality of Life Measured by SF-36 Healthy Survey (SF-36)
Description	The data for this outcome are not available for the analysis due to an...
Description	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.
Time Frame	At the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

7.Secondary Outcome


Title	Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)
Description	The CES-D is a 20-item self-report rating inventory measuring characte...
Description	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.
Time Frame	At the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Mean (Standard Deviation) Unit of Measure: Scores on a scale
	13.8 (10.9)	13.8 (14.5)	13.3 (10.8)	13.3 (13.2)

8.Secondary Outcome


Title	Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale
Description	The GIC scale is a valid...
Description	The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale: Very much improved Much improved Minimally improved No change Minimally worse Much worse 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.
Time Frame	At the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Measure Type: Number Unit of Measure: participants
PGIC - Very much improved	1	0	1	1
PGIC - Much improved	4	1	2	1
PGIC - Minimally improved	2	4	4	4
PGIC - No change	3	6	2	4
PGIC - Much worse	0	0	1	0
CGIC - Very much improved	1	1	1	1
CGIC - Much improved	4	1	3	1
CGIC - Minimally improved	1	1	3	3
CGIC - No change	4	8	3	4
CGIC - Much worse	0	0	0	1

9.Secondary Outcome


Title	Use of Rescue Medication (Acetaminophen)
Description	[Not Specified]
Description	[Not Specified]
Time Frame	During each treatment period and the subsequent cross-over (or final study week) period

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Measure Type: Number Unit of Measure: participants
Treatment period (1-4, 6-9, 11-14, 16-19 weeks)	0	0	0	2
Cross-over period (5, 10, 15, 20 weeks)	1	0	1	1

10.Secondary Outcome


Title	Maximum Tolerated Dose of Duloxetine and Methadone
Description	[Not Specified]
Description	[Not Specified]
Time Frame	During each treatment period

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Methadone	Duloxetine
Arm/Group Description:	Maximum tolerated daily dose of Met...	Maximum tolerated daily dose of Dul...
Arm/Group Description:	Maximum tolerated daily dose of Methadone was reported.	Maximum tolerated daily dose of Duloxetine was reported.
Overall Number of Participants Analyzed	12	10
Measure Type: Number Unit of Measure: mg
	30	60

11.Secondary Outcome


Title	Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events
Description	The DAIDS Table for Grading the Severity of Adult and Pediatric Advers...
Description	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)
Time Frame	From study entry to end of study at week 20 or premature study discontinuation

Outcome Measure Data

Analysis Population Description

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.


Arm/Group Title	Duloxetine and Methadone	Duloxetine and Methadone Placebo	Duloxetine Placebo and Methadone	Duloxetine Placebo and Methadone Placebo
Arm/Group Description:	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...	Methadone and matching placebo were...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	10	11	10	10
Measure Type: Count of Participants Unit of Measure: Participants
	5 50.0%	4 36.4%	6 60.0%	5 50.0%

12.Other Pre-specified Outcome


Title	Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF)
Description	This was one of the exploratory objectives and was not analyzed as the...
Description	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.
Time Frame	At the fourth treatment week of each treatment period

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P
Arm/Group Description:	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

13.Other Pre-specified Outcome


Title	Methadone Trough Level and Weekly Mean Pain Scores
Description	This was one of the exploratory objectives and was not analyzed as the...
Description	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.
Time Frame	During the fourth week of each treatment period

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P	D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD	D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD	D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P
Arm/Group Description:	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...	Participants will receive treatment...
Arm/Group Description:	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.	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.	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.	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.
Overall Number of Participants Analyzed	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Duloxetine and Methadone		Duloxetine and Methadone Placebo		Duloxetine Placebo and Methadone		Duloxetine Placebo and Methadone Placebo
Arm/Group Description	Duloxetine was initiated at 30mg da...		Duloxetine was initiated at 30mg da...		Duloxetine placebo was initiated at...		Duloxetine placebo was initiated at...
Arm/Group Description	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 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 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 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.
All-Cause Mortality
	Duloxetine and Methadone		Duloxetine and Methadone Placebo		Duloxetine Placebo and Methadone		Duloxetine Placebo and Methadone Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/10 (0.00%)		0/11 (0.00%)		0/10 (0.00%)		0/10 (0.00%)
Serious Adverse Events Serious Adverse Events
	Duloxetine and Methadone		Duloxetine and Methadone Placebo		Duloxetine Placebo and Methadone		Duloxetine Placebo and Methadone Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0.00%)		0/11 (0.00%)		0/10 (0.00%)		0/10 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Duloxetine and Methadone		Duloxetine and Methadone Placebo		Duloxetine Placebo and Methadone		Duloxetine Placebo and Methadone Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/10 (50.00%)		4/11 (36.36%)		6/10 (60.00%)		5/10 (50.00%)
Blood and lymphatic system disorders
Total Bilirubin ^† 1	2/10 (20.00%)	2	0/11 (0.00%)	0	0/10 (0.00%)	0	1/10 (10.00%)	1
Ear and labyrinth disorders
Ear Abnormality ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	0/10 (0.00%)	0	1/10 (10.00%)	1
Eye disorders
Diplopia ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	0/10 (0.00%)	0	1/10 (10.00%)	1
Gastrointestinal disorders
Constipation ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	2/10 (20.00%)	2	0/10 (0.00%)	0
Diarrhoea ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Dry mouth ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Nausea ^† 1	2/10 (20.00%)	2	1/11 (9.09%)	1	2/10 (20.00%)	2	0/10 (0.00%)	0
Vomiting ^† 1	0/10 (0.00%)	0	1/11 (9.09%)	1	0/10 (0.00%)	0	0/10 (0.00%)	0
Cramp ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Congestion ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	0/10 (0.00%)	0	1/10 (10.00%)	1
General disorders
Fatigue ^† 1	3/10 (30.00%)	3	0/11 (0.00%)	0	0/10 (0.00%)	0	1/10 (10.00%)	1
Malaise ^† 1	2/10 (20.00%)	2	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Pain ^† 1	0/10 (0.00%)	0	1/11 (9.09%)	1	1/10 (10.00%)	1	1/10 (10.00%)	1
Ache ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Hepatobiliary disorders
Sgot ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Alkaline Phosphatase ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Headache ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Cognition, Abnormal ^† 1	0/10 (0.00%)	0	0/1 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Depression ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Agitation ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Insomnia ^† 1	2/8 (25.00%)	2	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Dreams, Abnormal ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Mental Status Change, Psychiatric ^† 1	0/10 (0.00%)	0	0/11 (0.00%)	0	1/10 (10.00%)	1	0/10 (0.00%)	0
Renal and urinary disorders
Urinary retention ^† 1	1/10 (10.00%)	1	0/11 (0.00%)	0	0/10 (0.00%)	0	0/10 (0.00%)	0
Creatinine ^† 1	0/10 (0.00%)	0	1/11 (9.09%)	1	0/10 (0.00%)	0	0/10 (0.00%)	0
1 Term from vocabulary, MedDRA 13.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

The results should be interpreted with caution since the total sample size was much lower than planned.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Name/Title: ACTG ClinicalTrials.gov Coordinator

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

Phone: (301) 628-3313

EMail: ACTGCT.Gov@s-3.com

Publications:

Evans SR, Clifford DB, Kitch DW, Goodkin K, Schifitto G, McArthur JC, Simpson DM. Simplification of the research diagnosis of HIV-associated sensory neuropathy. HIV Clin Trials. 2008 Nov-Dec;9(6):434-9. doi: 10.1310/hct0906-434.

Valcour V, Yeh TM, Bartt R, Clifford D, Gerschenson M, Evans SR, Cohen BA, Ebenezer GJ, Hauer P, Millar L, Gould M, Tran P, Shikuma C, Souza S, McArthur JC; AIDS Clinical Trials Group (ACTG) 5157 protocol team. Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection. HIV Med. 2009 Feb;10(2):103-10. doi: 10.1111/j.1468-1293.2008.00658.x.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Harrison T, Miyahara S, Lee A, Evans S, Bastow B, Simpson D, Gilron I, Dworkin R, Daar ES, Wieclaw L, Clifford DB; ACTG A5252 Team. Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies. Pain Med. 2013 Jul;14(7):1039-47. doi: 10.1111/pme.12084. Epub 2013 Apr 8.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00863057 History of Changes
Other Study ID Numbers:	A5252 10636 ( Registry Identifier: DAIDS ES ) ACTG A5252
First Submitted:	March 16, 2009
First Posted:	March 17, 2009
Results First Submitted:	December 14, 2011
Results First Posted:	April 25, 2012
Last Update Posted:	February 18, 2019

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