Combination Pain Therapy in HIV Neuropathy
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Duloxetine and Methadone for the Treatment of HIV-Associated Painful Peripheral Neuropathy
研究概览
详细说明
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:
- duloxetine and methadone placebo
- methadone and duloxetine placebo
- duloxetine and methadone
- duloxetine placebo and methadone placebo
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.
研究类型
注册 (实际的)
阶段
- 阶段2
联系人和位置
学习地点
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California
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San Diego、California、美国、92103
- Ucsd, Avrc Crs
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Torrance、California、美国、90502
- Harbor-UCLA Med. Ctr. CRS
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Colorado
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Aurora、Colorado、美国、80045
- University of Colorado Hospital CRS
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Illinois
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Chicago、Illinois、美国、60611
- Northwestern University CRS
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Massachusetts
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Boston、Massachusetts、美国、02114
- Massachusetts General Hospital ACTG CRS
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Missouri
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Saint Louis、Missouri、美国、63110
- Washington U CRS
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Ohio
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Cleveland、Ohio、美国、44109
- MetroHealth CRS
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Texas
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Houston、Texas、美国、77030
- Houston AIDS Research Team CRS
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- HIV infected
- HIV-associated neuropathy
- Able and willing to provide informed consent
- Successful completion of a daily baseline pain diary over 1 week immediately prior to entry with a mean pain intensity of 4 or more on an 11-point Likert scale
- Karnofsky performance score of 60 or more within 45 days prior to entry
- Required laboratory values. More information on this criterion can be found in the study protocol.
- Willing to comply with protocol requirements for the duration of the study, to include daily completion of the pain diary as instructed, attendance at all study visits, and avoidance of prohibited medications
- On stable or no antiretroviral therapy for 30 days prior to entry. Participants on ARV therapy should plan to remain on the same regimen and drug dose for the duration of the study. Participants not on ARV therapy should have no plans to initiate therapy during study enrollment.
- Not pregnant
Exclusion Criteria:
- Conditions that confound a diagnosis of HIV-associated neuropathy or preclude accurate assessment of neuropathy symptoms, at the discretion of the site investigator. More information on this criterion can be found in the study protocol.
- Potential for unstable neuropathy symptoms during study participation due tthe following: (1) discontinuation of dideoxynucleoside nucleoside reverse transcriptase inhibitor (NRTI) within 16 weeks prior to entry, (2)treatment within 120 days prior to entry with any drug that the site investigator considers may contribute to sensory neuropathy
- Current history of significant depression on antidepressant therapy precluding withdrawal from antidepressants, upon impression of site investigator with input from the participant's mental health provider where available
- History of active substance abuse or dependence identified through medical chart review or self-report such that, in the opinion of the site investigator, participation poses undue risk for the participant
- History of alcohol-related complications within 6 months prior to entry that include but are not restricted to alcohol withdrawal seizures, alcoholic hallucinosis, delirium tremens, or being in an alcohol detoxification program - Treatment with tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors (SNRIs), bupropion, or tramadol that, upon judgment of the site investigator, cannot be tapered and discontinued prior to the pre-entry visit
- Treatment with an analgesic opioid regimen of more than 60 mg oral morphine equivalent per day within 45 days prior to entry
- Cognitive impairment that, in the opinion of the site investigator and based on clinical impression, might impact the ability to comply with the study protocol
- Use of an investigational agent within 45 days prior to entry except for expanded-access drugs or drugs used in an ACTG protocol for HIV treatment or for HIV-associated complications, if the drug is not prohibited by this protocol
- Acute active AIDS-defining opportunistic infection (OI) within 30 days prior to entry. Participants with no evidence of active disease and receiving maintenance therapy of AIDS-related OIs will be eligible
- Serious illness requiring systemic treatment and/or hospitalization within 45 days prior to entry
- End-stage renal dialysis requiring hemodialysis
- History of known or suspected hepatic cirrhosis diagnosed by signs and symptoms, radiography, or prior liver biopsy with Metavir score of more than 2
- Prolonged QTc interval (more than 0.45 seconds) within 90 days prior to entry
- Felt to be at high risk of opioid-induced respiratory compromise. More information on this criterion can be found in the study protocol.
- Diagnosis of a new seizure disorder or seizure within 90 days prior to entry
- History of acute angle-closure glaucoma, at the discretion of the site investigator
- Known allergy/sensitivity or any hypersensitivity to duloxetine, methadone, acetaminophen, or their ingredients
- Breastfeeding
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：随机化
- 介入模型：交叉作业
- 屏蔽：双倍的
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的：1
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
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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.
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.
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.
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.
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实验性的：2
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
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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.
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.
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.
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.
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实验性的：3
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
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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.
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.
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.
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.
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实验性的：4
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
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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.
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.
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.
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.
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
大体时间：During the fourth treatment week of each treatment period
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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
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale
大体时间：At Baseline and over the fourth treatment week of each treatment period
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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
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Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale
大体时间：At Baseline and over the fourth treatment week of each treatment period
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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
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Mean Nighttime Pain Measure on an 11-point Likert Scale
大体时间：Over the fourth treatment week of each treatment period
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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
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Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items
大体时间：At the fourth week of each treatment period
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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
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Quality of Life Measured by SF-36 Healthy Survey (SF-36)
大体时间：At the fourth treatment week of each treatment period
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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.
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At the fourth treatment week of each treatment period
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Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)
大体时间：At the fourth treatment week of each treatment period
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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.
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At the fourth treatment week of each treatment period
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Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale
大体时间：At the fourth treatment week of each treatment period
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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
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Use of Rescue Medication (Acetaminophen)
大体时间：During each treatment period and the subsequent cross-over (or final study week) period
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During each treatment period and the subsequent cross-over (or final study week) period
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Maximum Tolerated Dose of Duloxetine and Methadone
大体时间：During each treatment period
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During each treatment period
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Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events
大体时间：From study entry to end of study at week 20 or premature study discontinuation
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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)
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From study entry to end of study at week 20 or premature study discontinuation
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其他结果措施
结果测量 |
措施说明 |
大体时间 |
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Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF)
大体时间：At the fourth treatment week of each treatment period
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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.
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At the fourth treatment week of each treatment period
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Methadone Trough Level and Weekly Mean Pain Scores
大体时间：During the fourth week of each treatment period
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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.
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During the fourth week of each treatment period
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合作者和调查者
调查人员
- 学习椅：David B. Clifford, MD、Washington University School of Medicine
- 学习椅：Taylor B. Harrison, MD、Emory University, Department of Neurology, Neuromuscular Division
出版物和有用的链接
一般刊物
- 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.
- 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.
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (实际的)
研究完成 (实际的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- A5252
- 10636 (注册表标识符：DAIDS ES)
- ACTG A5252
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.
艾滋病毒感染的临床试验
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Hospital Clinic of Barcelona完全的
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National Institute of Allergy and Infectious Diseases...完全的HIV-1 感染 | HIV抗体 | 中和抗体 | 病毒载量 | 单克隆抗体美国
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AIDS Healthcare FoundationUniversity of California, Los Angeles完全的
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ANRS, Emerging Infectious DiseasesInstitut National de la Santé Et de la Recherche Médicale, France; University of Bergen; Centre... 和其他合作者完全的
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Hospital Universitari Vall d'Hebron Research InstituteGilead Sciences完全的
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Hospital Universitari Vall d'Hebron Research InstituteUniversity Hospital, Ghent; IrsiCaixa完全的