Combination Pain Therapy in HIV Neuropathy

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.

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