Combination Pain Therapy in HIV Neuropathy

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

National Institute of Allergy and Infectious Diseases (NIAID)

ClinicalTrials.gov Identifier:

NCT00863057

First received: March 16, 2009

Last updated: September 3, 2014

Last verified: September 2014

History of Changes

Results First Received: December 14, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Crossover Assignment; Masking: Double Blind (Subject, Caregiver); Primary Purpose: Treatment
Conditions:	HIV Infections Peripheral Neuropathy
Interventions:	Drug: Duloxetine Drug: Duloxetine placebo Drug: Methadone Drug: Methadone placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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.

Participant Flow for 4 periods

Period 1: Milestones Period 1 (Weeks 0-5)

	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
STARTED	4	4	3	4
COMPLETED	3	2	3	3
NOT COMPLETED	1	2	0	1
Adverse Event	1	1	0	1
Physician Decision	0	1	0	0

Period 2: Period 2 (Weeks 6-10)

	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
STARTED	3	2	3	3
COMPLETED	3	1	2	2
NOT COMPLETED	0	1	1	1
Adverse Event	0	1	1	0
Physician Decision	0	0	0	1

Period 3: Period 3 (Weeks 11-15)

	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
STARTED	3	1	2	2
COMPLETED	3	1	2	2
NOT COMPLETED	0	0	0	0

Period 4: Period 4 (Weeks 16-20)

	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
STARTED	3	1	2	2
COMPLETED	3	1	2	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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.
Total	Total of all reporting groups

Baseline Measures

	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
Number of Participants [units: participants]	4	4	3	4	15
Age, Customized [units: 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
Gender [units: participants]
Female	0	0	2	0	2
Male	4	4	1	4	13
Race/Ethnicity, Customized [units: 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 [units: participants]
United States	4	4	3	4	15
Baseline CD4 Counts [units: cells/µL] Mean ± Standard Deviation	400 ± 278	522 ± 328	867 ± 162	249 ± 173	486 ± 315
Baseline CD8 Counts [units: cells/µL] Mean ± Standard Deviation	970 ± 639	490 ± 205	1042.33 ± 1110	794.75 ± 534	809.73 ± 618
Baseline Log10(HIV RNA Viral Load) in copies/mL [units: 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] [units: Scores on a scale] Mean ± Standard Deviation	7.8 ± 0.5	6.5 ± 1.3	6 ± 1	7.3 ± 2.2	6.9 ± 1.4
Baseline Night Time Mean Pain Intensity (MPI) Scores ^[1] [units: Scores on a scale] Mean ± Standard Deviation	7.3 ± 1.0	6.8 ± 1.0	7.3 ± 1.2	8 ± 1.4	7.3 ± 1.1
Baseline Brief Pain Inventory (BPI) Interference Scores ^[2] [units: Scores on a scale] Mean ± Standard Deviation	5.6 ± 1.1	4.1 ± 0.5	4.5 ± 2.8	6.1 ± 3.7	5.1 ± 2.3
Baseline Center for Epidemiologic Studies Depression (CES-D) Scores ^[3] [units: Scores on a scale] Mean ± Standard Deviation	13 ± 10	11 ± 8	9 ± 9	16 ± 22	12 ± 13

[1]	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.
[2]	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.
[3]	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.

[1]

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.

[2]

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.

[3]

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

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1. Primary:

Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale [ Time Frame: During the fourth treatment week of each treatment period ]

Show Outcome Measure 1

2. Secondary:

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

Show Outcome Measure 2

3. Secondary:

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

Show Outcome Measure 3

4. Secondary:

Mean Nighttime Pain Measure on an 11-point Likert Scale [ Time Frame: Over the fourth treatment week of each treatment period ]

Show Outcome Measure 4

5. Secondary:

Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items [ Time Frame: At the fourth week of each treatment period ]

Show Outcome Measure 5

6. Secondary:

Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: At the fourth treatment week of each treatment period ]

Show Outcome Measure 6

7. Secondary:

Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale [ Time Frame: At the fourth treatment week of each treatment period ]

Show Outcome Measure 7

8. Secondary:

Use of Rescue Medication (Acetaminophen) [ Time Frame: During each treatment period and the subsequent cross-over (or final study week) period ]

Show Outcome Measure 8

9. Secondary:

Maximum Tolerated Dose of Duloxetine and Methadone [ Time Frame: During each treatment period ]

Show Outcome Measure 9

10. Secondary:

Quality of Life Measured by SF-36 Healthy Survey (SF-36) [ Time Frame: At the fourth treatment week of each treatment period ]

Results not yet reported. Anticipated Reporting Date: No text entered. Safety Issue: No

11. Secondary:

Incidence of Treatment-emergent Grade 3 to 4 (Safety) and Grade 2 (Tolerability) Toxicities [ Time Frame: Throughout study ]

Results not yet reported. Anticipated Reporting Date: No text entered. Safety Issue: Yes

12. Other Pre-specified:

Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF) [ Time Frame: At the fourth treatment week of each treatment period ]

Results not yet reported. Anticipated Reporting Date: No text entered. Safety Issue: No

13. Other Pre-specified:

Methadone Trough Level and Weekly Mean Pain Scores [ Time Frame: During the fourth week of each treatment period ]

Results not yet reported. Anticipated Reporting Date: No text entered. Safety Issue: No

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The results should be interpreted with caution since the total sample size was much lower than planned.

More Information

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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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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: Clinicaltrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617) 432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu

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:

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, ACTG A5252
Study First Received:	March 16, 2009
Results First Received:	December 14, 2011
Last Updated:	September 3, 2014
Health Authority:	United States: Food and Drug Administration

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