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| ID | Type | Description | Link |
|---|---|---|---|
| 10636 | Registry Identifier | DAIDS ES | |
| ACTG A5252 |
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Due to slow rate of enrollment, which compromised the ability to meet study objectives in a timely manner.
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Neuropathy results from damage to the nerves in the feet and legs. It is usually experienced as pain, tingling or numbness. In HIV-infected people, neuropathy can result from the infection itself or be a side effect of antiretroviral treatment. The purpose of this study is to determine whether two different drugs, methadone and duloxetine, reduce neuropathy-associated pain in HIV-infected people. This study will also examine whether utilization of both of these drugs is more effective than treatment with only one.
Peripheral neuropathy is now recognized as the most common neurological complication of HIV disease and its treatment. Before highly active antiretroviral therapy (HAART) was introduced, the prevalence of HIV-associated distal sensory polyneuropathy (DSP) was already estimated to be 35%, mostly contained to populations with moderate to advanced immunosuppression. Now, since the advent of HAART, the prevalence of HIV-associated neuropathy has increased to 52%, possibly due to a combination of antiretroviral toxic neuropathy (ATN), decreased mortality, and accumulated medical comorbidities.
Successful treatment of neuropathic pain is inherently difficult, and treatment of HIV-associated neuropathic pain is particularly complicated. To date, evidence supporting effective therapies for neuropathic HIV-associated pain is lacking, despite several types and classes of drugs having been evaluated in clinical trials. This study will evaluate the safety and efficacy of duloxetine, methadone, and the combination of duloxetine and methadone in painful HIV-associated neuropathy. Both of these drugs are approved by the Food and Drug Administration (FDA) but for purposes unrelated to HIV-associated neuropathy, and no previous studies have utilized these two treatments for this purpose.
For this study, 120 participants with painful HIV-associated neuropathy will be recruited. The trial will last for approximately 23 weeks. Each participant will receive a total of 4 study treatments. The following treatment pairings will be given in a sequence determined by randomization:
Each treatment period will last 4 weeks and will be followed by a 1-week combined taper and washout.
People wishing to enroll in this study will have a screening visit that will last about 3 hours. During this visit, participants will have an HIV test, physical exam, neurologic exam, blood drawn, electrocardiogram (EKG), and a pregnancy test, if applicable. Participants will also be asked about their current health and any medications they may be taking. They will also be asked about their mood and be given the results of tests performed at the screening visit.
If screening qualifies participants for the study, they will return for a pre-entry visit lasting 2 hours. During this visit, participants will have a limited physical exam and be asked about changes in their health or medicines since screening. Participants will also be given a pain diary with instructions to record neuropathy pain every day for each of the 7 days before beginning the study and throughout the study.
After beginning the study, participants will return to the clinic for another 8 visits. These visits are at the end of each 4-week treatment period and at the end of each 1-week crossover period. At each visit, there will be a limited physical exam and participants will answer questions about their health and medications. Participants will also be told the results of routine lab tests and pregnancy tests performed during the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine and methadone placebo, (Period 2, Weeks 6 to 9) duloxetine placebo and methadone, (Period 3, Weeks 11 to 14) duloxetine and methadone, (Period 4, Weeks 16 to 19) duloxetine placebo and methadone placebo |
|
| 2 | Experimental | Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone, (Period 2, Weeks 6 to 9) duloxetine placebo and methadone placebo, (Period 3, Weeks 11 to 14) duloxetine and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine and methadone |
|
| 3 | Experimental | 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 |
|
| 4 | Experimental | 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Duloxetine | Drug | During each treatment period, participants will take duloxetine in the following doses. On Days 1 to 5, participants will take one 30-mg capsule orally, once daily. On Days 6 to 28, participants will take two 30-mg capsules orally, once daily. During days 29 to 31 dosage will be reduced to one capsule daily and then discontinued on Day 32. |
| Measure | Description | Time Frame |
|---|---|---|
| Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 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. | During the fourth treatment week of each treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF) | 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. | At the fourth treatment week of each treatment period |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David B. Clifford, MD | Washington University School of Medicine | Study Chair |
| Taylor B. Harrison, MD | Emory University, Department of Neurology, Neuromuscular Division | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ucsd, Avrc Crs | San Diego | California | 92103 | United States | ||
| Harbor-UCLA Med. Ctr. CRS |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19203909 | Background | 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. | |
| 19200173 | Background | 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. |
| Label | URL |
|---|---|
| The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009) | View source |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Milestones Period 1 (Weeks 0-5) |
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| Period 2 (Weeks 6-10) |
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| Period 3 (Weeks 11-15) |
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| Period 4 (Weeks 16-20) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 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. | 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. | Posted | Mean | Standard Deviation | Scores on a scale | During the fourth treatment week of each treatment period |
|
Through out the study period. Participants were followed for the duration of study period, which is 20 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Duloxetine and Methadone | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diplopia | Eye disorders | MedDRA 13.1 | Systematic Assessment |
The results should be interpreted with caution since the total sample size was much lower than planned.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| ACTG ClinicalTrials.gov Coordinator | ACTG Network Coordinating Center, Social and Scientific Systems, Inc. | (301) 628-3313 | ACTGCT.Gov@s-3.com |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D010523 | Peripheral Nervous System Diseases |
| D010146 | Pain |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| D000068736 | Duloxetine Hydrochloride |
| D008691 | Methadone |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| Duloxetine placebo | Drug | During each treatment period, participants will take duloxetine placebo in the following doses. On Days 1 to 5, participants will take one 30-mg capsule orally, once daily. On Days 6 to 28, participants will take two 30-mg capsules orally, once daily. During days 29 to 31 dosage will be reduced to one capsule daily and then discontinued on Day 32. |
|
| Methadone | Drug | During each treatment period, participants will take methadone in the following doses. On Days 1 to 5, participants will take one 5-mg capsule orally, twice daily. On Days 6 to 10, participants will take one 5-mg capsule orally, three times daily. On Days 11 to 28, participants will take two 5-mg capsules orally, three times daily. On Days 29 to 31, dosage will be one 5-mg capsule orally, three times daily. On Days 32 to 34, dosage will be decreased to one 5-mg capsule, twice daily and ultimately discontinued on Day 35. |
|
| Methadone placebo | Drug | During each treatment period, participants will take methadone placebo in the following doses. On Days 1 to 5, participants will take one 5-mg capsule orally, twice daily. On Days 6 to 10, participants will take one 5-mg capsule orally, three times daily. On Days 11 to 28, participants will take two 5-mg capsules orally, three times daily. On Days 29 to 31, dosage will be one 5-mg capsule orally, three times daily. On Days 32 to 34, dosage will be decreased to one 5-mg capsule, twice daily and ultimately discontinued on Day 35. |
|
| At Baseline and over the fourth treatment week of each treatment period |
| Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 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. | At Baseline and over the fourth treatment week of each treatment period |
| Mean Nighttime Pain Measure on an 11-point Likert Scale | 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. | Over the fourth treatment week of each treatment period |
| Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | The BPI interference scale measured level of interference with the following seven items:
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. | At the fourth week of each treatment period |
| Quality of Life Measured by SF-36 Healthy Survey (SF-36) | 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. | At the fourth treatment week of each treatment period |
| Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 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. | At the fourth treatment week of each treatment period |
| Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale:
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. | At the fourth treatment week of each treatment period |
| Use of Rescue Medication (Acetaminophen) | During each treatment period and the subsequent cross-over (or final study week) period |
| Maximum Tolerated Dose of Duloxetine and Methadone | During each treatment period |
| Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 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) | From study entry to end of study at week 20 or premature study discontinuation |
| Methadone Trough Level and Weekly Mean Pain Scores |
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. |
| During the fourth week of each treatment period |
| Torrance |
| California |
| 90502 |
| United States |
| University of Colorado Hospital CRS | Aurora | Colorado | 80045 | United States |
| Northwestern University CRS | Chicago | Illinois | 60611 | United States |
| Massachusetts General Hospital ACTG CRS | Boston | Massachusetts | 02114 | United States |
| Washington U CRS | St Louis | Missouri | 63110 | United States |
| MetroHealth CRS | Cleveland | Ohio | 44109 | United States |
| Houston AIDS Research Team CRS | Houston | Texas | 77030 | United States |
| 23565581 | Derived | 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. |
| Physician Decision |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Baseline CD4 Counts | Mean | Standard Deviation | cells/µL |
|
| Baseline CD8 Counts | Mean | Standard Deviation | cells/µL |
|
| Baseline Log10(HIV RNA Viral Load) in copies/mL | Number | participants |
|
| Baseline Daily Mean Pain Intensity (MPI) Scores | 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. | Mean | Standard Deviation | Scores on a scale |
|
| Baseline Night Time Mean Pain Intensity (MPI) Scores | 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. | Mean | Standard Deviation | Scores on a scale |
|
| Baseline Brief Pain Inventory (BPI) Interference Scores | The BPI interference scale measured level of interference with the following seven items:
Interference scales range from 0='Does not interfere' to 10='Completely interferes'. The overall BPI score is the mean of seven items. | Mean | Standard Deviation | Scores on a scale |
|
| Baseline Center for Epidemiologic Studies Depression (CES-D) Scores | 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. | Mean | Standard Deviation | Scores on a scale |
|
| OG001 | 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. |
| OG002 | 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. |
| OG003 | 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. |
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| Secondary | Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 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. | 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. | Posted | Number | participants | At Baseline and over the fourth treatment week of each treatment period |
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| Secondary | Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 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. | 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. | Posted | Number | participants | At Baseline and over the fourth treatment week of each treatment period |
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| Secondary | Mean Nighttime Pain Measure on an 11-point Likert Scale | 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. | 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. | Posted | Mean | Standard Error | Scores on a scale | Over the fourth treatment week of each treatment period |
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| Secondary | Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | The BPI interference scale measured level of interference with the following seven items:
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. | 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. | Posted | Median | Inter-Quartile Range | Scores on a scale | At the fourth week of each treatment period |
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| Secondary | Quality of Life Measured by SF-36 Healthy Survey (SF-36) | 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. | Posted | At the fourth treatment week of each treatment period |
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| Secondary | Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 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. | 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. | Posted | Mean | Standard Deviation | Scores on a scale | At the fourth treatment week of each treatment period |
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| Secondary | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale:
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. | 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. | Posted | Number | participants | At the fourth treatment week of each treatment period |
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| Secondary | Use of Rescue Medication (Acetaminophen) | 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. | Posted | Number | participants | During each treatment period and the subsequent cross-over (or final study week) period |
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| Secondary | Maximum Tolerated Dose of Duloxetine and Methadone | The number below is the highest tolerated daily dose in mg based on n=12 for Methadone and n=10 for Duloxetine. | Posted | Number | mg | During each treatment period |
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| Secondary | Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 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) | 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. | Posted | Count of Participants | Participants | From study entry to end of study at week 20 or premature study discontinuation |
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| Other Pre-specified | Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF) | 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. | This was one of the exploratory objectives and was not analyzed as the study was terminated. | Posted | At the fourth treatment week of each treatment period |
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| Other Pre-specified | Methadone Trough Level and Weekly Mean Pain Scores | 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. | This was one of the exploratory objectives and was not analyzed as the study was terminated. | Posted | During the fourth week of each treatment period |
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| 0 |
| 10 |
| 0 |
| 10 |
| 5 |
| 10 |
| EG001 | Duloxetine and Methadone Placebo | 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. | 0 | 11 | 0 | 11 | 4 | 11 |
| EG002 | Duloxetine Placebo and Methadone | 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. | 0 | 10 | 0 | 10 | 6 | 10 |
| EG003 | Duloxetine Placebo and Methadone Placebo | 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. | 0 | 10 | 0 | 10 | 5 | 10 |
| Constipation | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 13.1 | Systematic Assessment |
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| Malaise | General disorders | MedDRA 13.1 | Systematic Assessment |
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| Pain | General disorders | MedDRA 13.1 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 13.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 13.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 13.1 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Agitation | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Dreams, Abnormal | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Urinary retention | Renal and urinary disorders | MedDRA 13.1 | Systematic Assessment |
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| Total Bilirubin | Blood and lymphatic system disorders | MedDRA 13.1 | Systematic Assessment |
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| Creatinine | Renal and urinary disorders | MedDRA 13.1 | Systematic Assessment |
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| Sgot | Hepatobiliary disorders | MedDRA 13.1 | Systematic Assessment |
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| Ache | General disorders | MedDRA 13.1 | Systematic Assessment |
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| Cognition, Abnormal | Nervous system disorders | MedDRA 13.1 | Systematic Assessment |
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| Mental Status Change, Psychiatric | Psychiatric disorders | MedDRA 13.1 | Systematic Assessment |
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| Cramp | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Alkaline Phosphatase | Hepatobiliary disorders | MedDRA 13.1 | Systematic Assessment |
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| Congestion | Gastrointestinal disorders | MedDRA 13.1 | Systematic Assessment |
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| Ear Abnormality | Ear and labyrinth disorders | MedDRA 13.1 | Systematic Assessment |
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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.
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
| D007659 | Ketones |
| PGIC - Much improved |
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| PGIC - Minimally improved |
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| PGIC - No change |
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| PGIC - Much worse |
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| CGIC - Very much improved |
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| CGIC - Much improved |
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| CGIC - Minimally improved |
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| CGIC - No change |
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| CGIC - Much worse |
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| Cross-over period (5, 10, 15, 20 weeks) |
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