A Phase II/III Double-Blind Study of Amitriptyline and Mexiletine for Painful Neuropathy in HIV Infection

To assess the efficacy, safety, and tolerability of amitriptyline hydrochloride versus mexiletine hydrochloride in reducing pain intensity in patients with HIV-related painful peripheral neuropathy.

No large-scale controlled clinical trials of symptomatic therapy for painful HIV-related neuropathy have been attempted. Both amitriptyline and mexiletine have been useful in the management of painful neuropathies; however, both are associated with certain toxicities. In this comparative study of amitriptyline and mexiletine, benztropine mesylate also will be included as an active placebo to mimic the side effects of the study drugs.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Peripheral Nervous System Disease
• Intervention / Treatment: Drug: Mexiletine hydrochloride; Drug: Benztropine mesylate; Drug: Amitriptyline hydrochloride

Detailed Description

No large-scale controlled clinical trials of symptomatic therapy for painful HIV-related neuropathy have been attempted. Both amitriptyline and mexiletine have been useful in the management of painful neuropathies; however, both are associated with certain toxicities. In this comparative study of amitriptyline and mexiletine, benztropine mesylate also will be included as an active placebo to mimic the side effects of the study drugs.

Patients are randomized to receive amitriptyline, mexiletine, or benztropine mesylate as an active placebo to mimic the mild side effects associated with both amitriptyline and mexiletine. Doses are gradually increased over 4 weeks until a minimum effective dose or MTD is reached, then patients are treated for at least 4 additional weeks at the final dose before gradually tapering off. Neurologic exams are performed at screening and at the end of treatment. Intensity of pain is rated twice daily by the patient. Patients are followed at Weeks 2, 4, and 8, and at 10 days after completely tapering off of drug.

PER 3/16/95 AMENDMENT: Patients with no pain relief 14 days after initiation of study therapy may have dose doubled or increased to maximum allowable dose, whichever is lower. Then if no improvement occurs within 14 days after dose increase, patients have the option of discontinuing study medication.

• Study Type: Interventional
• Enrollment: 240
• Phase: Phase 2

Contacts and Locations

Study Locations

• Tanzania
  • Mbeya, Tanzania
    • Mbeya Med. Research Program, Mbeya Referral Hosp. CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama Therapeutics CRS
  • California
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS
    • San Diego, California, United States, 921036325
      • Ucsd, Avrc Crs
    • San Francisco, California, United States
      • Ucsf Aids Crs
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States, 80262
      • University of Colorado Hospital CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20059
      • Howard University Hosp., Div. of Infectious Diseases, ACTU
  • Florida
    • Miami, Florida, United States, 331361013
      • Univ. of Miami AIDS CRS
  • Georgia
    • Atlanta, Georgia, United States
      • The Ponce de Leon Ctr. CRS
  • Hawaii
    • Honolulu, Hawaii, United States, 96816
      • Univ. of Hawaii at Manoa, Leahi Hosp.
    • Honolulu, Hawaii, United States, 96816
      • Queens Med. Ctr.
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp. CORE Ctr.
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS
    • Chicago, Illinois, United States, 60640
      • Weiss Memorial Hosp.
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp. of Indiana
    • Indianapolis, Indiana, United States, 462025250
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Univ. of Iowa Healthcare, Div. of Infectious Diseases
  • Louisiana
    • New Orleans, Louisiana, United States
      • Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Adult AIDS CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
    • Boston, Massachusetts, United States, 02118
      • Bmc Actg Crs
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS
    • Boston, Massachusetts, United States
      • Beth Israel Deaconess - East Campus A0102 CRS
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, ACTU
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Med. Ctr., Div. of Infectious Diseases
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington U CRS
    • Saint Louis, Missouri, United States, 63112
      • St. Louis ConnectCare, Infectious Diseases Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 681985130
      • Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
  • New York
    • Buffalo, New York, United States, 13210
      • SUNY - Buffalo, Erie County Medical Ctr.
    • Rochester, New York, United States, 14642
      • Univ. of Rochester ACTG CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Unc Aids Crs
  • Ohio
    • Cincinnati, Ohio, United States, 452670405
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44106
      • Case CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

• Aspirin and acetaminophen.
• Nonsteroidal anti-inflammatory agents.
• Opiates.
• Pyridoxine (only if accompanied by isoniazid).
• ddI, ddC, d4T, and 3TC if on a stable dose.
• AZT.
• Cimetidine if on a stable dose.

NOTE:

• Per 3/16/95 amendment, Lactaid may be taken by lactose-intolerant patients for effects of lactose in placebo capsules.

Concurrent Treatment:

Allowed:

• Acupuncture.

Patients must have:

• Documented HIV infection.
• Painful peripheral neuropathy.

NOTE:

• Patients in ACTG blinded studies of dideoxynucleosides such as ddI, ddC, and d4T are encouraged to enroll in this study.

Prior Medication:

Allowed:

• Prior ddI, ddC, d4T, or 3TC, if on a stable dose for at least 8 weeks prior to study entry.
• Prior cimetidine if on a stable dose for at least 2 weeks prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Diabetes mellitus.
• Neurological disease of sufficient severity to confound the evaluation of peripheral neuropathy, such as myelopathy without neuropathy. (NOTE: Patients with both myelopathy AND painful peripheral neuropathy are eligible.)
• Electrocardiogram (EKG) indicating malignant arrhythmia or cardiac conduction disturbances (such as second or third degree AV block, anterior hemi-block, or prolonged QT interval).
• Suicidal thoughts of sufficient severity to require treatment with antidepressant medication.

Concurrent Medication:

Excluded:

• Phenytoin or carbamazepine (unless on stable dose for 8 weeks prior to study entry).
• Capsaicin.
• Any MAO inhibitor antidepressants, any tricyclic or tetracyclic antidepressants, certain serotonin re-uptake inhibitors (fluoxetine, paroxetine, and venlafaxine), or mexiletine (except as dispensed for this study).
• Disopyramide.
• Procainamide.
• Quinidine.
• Tocainide.
• Flecainide acetate.
• Encainide.
• Lidocaine.
• Cisplatin.
• Vincristine.
• Chloramphenicol, disulfiram, ethionamide glutethimide, gold, hydralazine, iodoquinol, metronidazole, nitrofurantoin, or ribavirin (only in patients in whom the onset or clear worsening of painful peripheral neuropathy was attributed to previously taking these drugs).
• Any investigational drugs other than 3TC (except with permission of the protocol team).
• Terfenadine (if concurrent with ketoconazole).

Patients with the following prior conditions are excluded:

• Documented history of cardiac disease.
• History of allergy to, or intolerance of, tricyclic antidepressants, mexiletine, or benztropine.

Prior Medication:

Excluded:

• Prior disopyramide.
• Prior procainamide.
• Prior quinidine.
• Prior tocainide.
• Prior flecainide acetate.
• Prior encainide.
• Prior lidocaine.
• Cisplatin or vincristine within 8 weeks prior to study entry.
• Chloramphenicol, disulfiram, ethionamide glutethimide, gold, hydralazine, iodoquinol, metronidazole, nitrofurantoin, or ribavirin within 8 weeks prior to study entry (only in patients in whom the onset or clear worsening of painful peripheral neuropathy was attributed to taking these drugs).
• Any MAO inhibitor antidepressants, any tricyclic or tetracyclic antidepressants, certain serotonin re-uptake inhibitors (fluoxetine, paroxetine, and venlafaxine), or mexiletine, within 4 weeks prior to study entry.
• More than 50 percent change in the weekly dosage of any pain control medications within 2 weeks prior to study entry.

Per 3/16/95 amendment:

• ddI, ddC, d4T, or 3TC within 8 weeks prior to study entry ONLY IF dideoxynucleoside dosing was suspended or permanently discontinued.

Risk Behavior:

Excluded:

• Active drug or alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: Double

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Boehringer Ingelheim
• Investigators: Study Chair: K Kieburtz; Study Chair: D Simpson

Publications and helpful links

General Publications

• Lein B. Potential therapy for painful neuropathy. PI Perspect. 1995 May;(no 16):11.
• Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, Marra CM, McKendall R, Singer E, Dal Pan GJ, Clifford DB, Tucker T, Cohen B. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology. 1998 Dec;51(6):1682-8. doi: 10.1212/wnl.51.6.1682.

Study record dates

Study Major Dates

• Study Completion (Actual): October 1, 1997

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Pain; Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Parasympatholytics; Amitriptyline; Peripheral Nervous System Diseases; Mexiletine; benzatropine methanesulfonate
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Neuromuscular Diseases; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Peripheral Nervous System Diseases; Nervous System Diseases; Acquired Immunodeficiency Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Antidepressive Agents, Tricyclic; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Dopamine Uptake Inhibitors; Adrenergic Uptake Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Amitriptyline; Mexiletine; Benztropine
• Other Study ID Numbers: ACTG 242; 11219 (Registry Identifier: DAIDS-ES)