Combination Pain Therapy in HIV Neuropathy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00863057
First received: March 16, 2009
Last updated: February 3, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
HIV Infections
Peripheral Neuropathy
Drug: Duloxetine
Drug: Duloxetine placebo
Drug: Methadone
Drug: Methadone placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Duloxetine and Methadone for the Treatment of HIV-Associated Painful Peripheral Neuropathy

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale [ Time Frame: During the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale [ Time Frame: At Baseline and over the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]

    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.


  • Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale [ Time Frame: At Baseline and over the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]

    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.


  • Mean Nighttime Pain Measure on an 11-point Likert Scale [ Time Frame: Over the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]

    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.


  • Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items [ Time Frame: At the fourth week of each treatment period ] [ Designated as safety issue: No ]

    The BPI interference scale measured level of interference with the following seven items:

    1. General activity
    2. Mood
    3. Walking ability
    4. Normal work
    5. Relations with other people
    6. Sleep
    7. Enjoyment of life

    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.


  • Quality of Life Measured by SF-36 Healthy Survey (SF-36) [ Time Frame: At the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]
    This endpoint was not analyzed as there was an issue with a company which provides a software to calculate SF-36. We do not have any plan to analyze this endpoint in the future.

  • Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: At the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]
    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.

  • Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale [ Time Frame: At the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]

    The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale:

    1. Very much improved
    2. Much improved
    3. Minimally improved
    4. No change
    5. Minimally worse
    6. Much worse
    7. Very much worse

    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.


  • Use of Rescue Medication (Acetaminophen) [ Time Frame: During each treatment period and the subsequent cross-over (or final study week) period ] [ Designated as safety issue: Yes ]
  • Maximum Tolerated Dose of Duloxetine and Methadone [ Time Frame: During each treatment period ] [ Designated as safety issue: Yes ]
  • Incidence of Treatment-emergent Grade 3 to 4 (Safety) and Grade 2 (Tolerability) Toxicities [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
    Grade 2, 3, and 4 events are listed in the AE section.


Other Outcome Measures:
  • Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF) [ Time Frame: At the fourth treatment week of each treatment period ] [ Designated as safety issue: No ]
    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.

  • Methadone Trough Level and Weekly Mean Pain Scores [ Time Frame: During the fourth week of each treatment period ] [ Designated as safety issue: No ]
    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.


Enrollment: 15
Study Start Date: May 2009
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: Duloxetine
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.
Drug: Duloxetine placebo
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.
Drug: Methadone
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.
Drug: Methadone placebo
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.
Experimental: 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
Drug: Duloxetine
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.
Drug: Duloxetine placebo
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.
Drug: Methadone
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.
Drug: Methadone placebo
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.
Experimental: 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
Drug: Duloxetine
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.
Drug: Duloxetine placebo
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.
Drug: Methadone
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.
Drug: Methadone placebo
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.
Experimental: 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
Drug: Duloxetine
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.
Drug: Duloxetine placebo
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.
Drug: Methadone
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.
Drug: Methadone placebo
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.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00863057

Locations
United States, California
Ucsd, Avrc Crs
San Diego, California, United States, 92103
Harbor-UCLA Med. Ctr. CRS
Torrance, California, United States, 90502
United States, Colorado
University of Colorado Hospital CRS
Aurora, Colorado, United States, 80045
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Massachusetts
Massachusetts General Hospital ACTG CRS
Boston, Massachusetts, United States, 02114
United States, Missouri
Washington U CRS
St. Louis, Missouri, United States, 63110
United States, Ohio
MetroHealth CRS
Cleveland, Ohio, United States, 44109
United States, Texas
Houston AIDS Research Team CRS
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Study Chair: David B. Clifford, MD Washington University School of Medicine
Study Chair: Taylor B. Harrison, MD Emory University, Department of Neurology, Neuromuscular Division
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00863057     History of Changes
Other Study ID Numbers: A5252, 10636, ACTG A5252
Study First Received: March 16, 2009
Results First Received: December 14, 2011
Last Updated: February 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
HIV Infections
Neuropathy
Pain

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Peripheral Nervous System Diseases
Demyelinating Diseases
Polyneuropathies
Nerve Compression Syndromes
Neurologic Manifestations
Neurotoxicity Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Neuromuscular Diseases
Nervous System Diseases
Signs and Symptoms
Poisoning
Substance-Related Disorders
Methadone
Duloxetine
Analgesics, Opioid
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014