A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Duloxetine and Methadone for the Treatment of HIV-Associated Painful Peripheral Neuropathy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 15
- 试验地点
- 8
- 主要终点
- Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: Duloxetine (Drug)
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
干预措施: Duloxetine placebo (Drug)
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
干预措施: Methadone (Drug)
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
干预措施: Methadone placebo (Drug)
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
干预措施: Duloxetine (Drug)
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
干预措施: Duloxetine placebo (Drug)
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
干预措施: Methadone (Drug)
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
干预措施: Methadone placebo (Drug)
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
干预措施: Duloxetine (Drug)
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
干预措施: Duloxetine placebo (Drug)
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
干预措施: Methadone (Drug)
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
干预措施: Methadone placebo (Drug)
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
干预措施: Duloxetine (Drug)
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
干预措施: Duloxetine placebo (Drug)
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
干预措施: Methadone (Drug)
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
干预措施: Methadone placebo (Drug)
结局指标
主要结局
Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
时间窗: During the fourth treatment week of each treatment period
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.
次要结局
- Use of Rescue Medication (Acetaminophen)(During each treatment period and the subsequent cross-over (or final study week) period)
- Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events(From study entry to end of study at week 20 or premature study discontinuation)
- Maximum Tolerated Dose of Duloxetine and Methadone(During each treatment period)
- Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale(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(At Baseline and over the fourth treatment week of each treatment period)
- Mean Nighttime Pain Measure on an 11-point Likert Scale(Over the fourth treatment week of each treatment period)
- Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items(At the fourth week of each treatment period)
- Quality of Life Measured by SF-36 Healthy Survey (SF-36)(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(At the fourth treatment week of each treatment period)
- Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)(At the fourth treatment week of each treatment period)