Clinical trial NCT00863057: Combination Pain Therapy in HIV Neuropathy
Official title: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Duloxetine and Methadone for the Treatment of HIV-Associated Painful Peripheral Neuropathy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infections
Peripheral Neuropathy
Keywords: HIV Infections
Neuropathy
Pain
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2009-03-17
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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:

1. duloxetine and methadone placebo
2. methadone and duloxetine placebo
3. duloxetine and methadone
4. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
timeFrame: During the fourth treatment week of each treatment period
Secondary outcomes:
measure: Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale
timeFrame: At Baseline and over the fourth treatment week of each treatment period
measure: Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale
timeFrame: At Baseline and over the fourth treatment week of each treatment period
measure: Mean Nighttime Pain Measure on an 11-point Likert Scale
timeFrame: Over the fourth treatment week of each treatment period
measure: Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items
timeFrame: At the fourth week of each treatment period
measure: Quality of Life Measured by SF-36 Healthy Survey (SF-36)
timeFrame: At the fourth treatment week of each treatment period
measure: Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)
timeFrame: At the fourth treatment week of each treatment period
measure: Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale
timeFrame: At the fourth treatment week of each treatment period
measure: Use of Rescue Medication (Acetaminophen)
timeFrame: During each treatment period and the subsequent cross-over (or final study week) period
measure: Maximum Tolerated Dose of Duloxetine and Methadone
timeFrame: During each treatment period
measure: Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events
timeFrame: From study entry to end of study at week 20 or premature study discontinuation
Other outcomes:
measure: Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF)
timeFrame: At the fourth treatment week of each treatment period
measure: Methadone Trough Level and Weekly Mean Pain Scores
timeFrame: During the fourth week of each treatment period
Locations:
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
Study officials:
affiliation: Washington University School of Medicine
name: David B. Clifford, MD
role: STUDY_CHAIR
affiliation: Emory University, Department of Neurology, Neuromuscular Division
name: Taylor B. Harrison, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.