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.

Condition	Treatment or Intervention	Phase
HIV Infections Peripheral Nervous System Disease	Drug: Mexiletine hydrochloride  Drug: Benztropine mesylate  Drug: Amitriptyline hydrochloride	Phase II

Further Study Details: 

Expected Total Enrollment:  240

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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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.

Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  35294,  United States
California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States
      VA Hosp at San Diego / Pediatrics, San Diego,  California,  92161,  United States
      San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
      San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
      Summitt Med Ctr / San Francisco Gen Hosp, Oakland,  California,  94609,  United States
      UCLA CARE Ctr, Los Angeles,  California,  90095,  United States
      Harbor UCLA Med Ctr, Torrance,  California,  90502,  United States
Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States
      Kaiser Permanente Franklin Med Ctr, Denver,  Colorado,  80262,  United States
      Rose Med Ctr, Denver,  Colorado,  80262,  United States
Connecticut
      Yale Univ / New Haven, New Haven,  Connecticut,  065102483,  United States
District of Columbia
      Howard Univ, Washington,  District of Columbia,  20059,  United States
      Georgetown Univ Med Ctr, Washington,  District of Columbia,  20007,  United States
Florida
      Univ of Miami School of Medicine, Miami,  Florida,  331361013,  United States
Georgia
      Emory Univ, Atlanta,  Georgia,  30308,  United States
Hawaii
      Queens Med Ctr, Honolulu,  Hawaii,  96816,  United States
      Univ of Hawaii, Honolulu,  Hawaii,  96816,  United States
Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States
      Rush Presbyterian - Saint Luke's Med Ctr, Chicago,  Illinois,  60612,  United States
      Cook County Hosp, Chicago,  Illinois,  60612,  United States
      Illinois Masonic Med Ctr, Chicago,  Illinois,  606575147,  United States
      Louis A Weiss Memorial Hosp, Chicago,  Illinois,  60640,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
      Methodist Hosp of Indiana / Life Care Clinic, Indianapolis,  Indiana,  46202,  United States
Iowa
      Univ of Iowa Hosp and Clinic, Iowa City,  Iowa,  52242,  United States
Louisiana
      Charity Hosp / Tulane Univ Med School, New Orleans,  Louisiana,  70112,  United States
Maryland
      Johns Hopkins Hosp, Baltimore,  Maryland,  21287,  United States
Massachusetts
      Harvard (Massachusetts Gen Hosp), Boston,  Massachusetts,  02114,  United States
      Beth Israel Deaconess - West Campus, Boston,  Massachusetts,  02215,  United States
      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States
Minnesota
      Univ of Minnesota, Minneapolis,  Minnesota,  55455,  United States
      St Paul Ramsey Med Ctr, St. Paul,  Minnesota,  55101,  United States
      Hennepin County Med Clinic, Minneapolis,  Minnesota,  55415,  United States
Missouri
      St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis,  Missouri,  63112,  United States
Nebraska
      Univ of Nebraska Med Ctr, Omaha,  Nebraska,  681985130,  United States
New York
      Montefiore Drug Treatment Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      SUNY / State Univ of New York, Syracuse,  New York,  13210,  United States
      Univ of Rochester Medical Center, Rochester,  New York,  14642,  United States
      Mount Sinai Med Ctr, New York,  New York,  10029,  United States
      Jack Weiler Hosp / Bronx Municipal Hosp, Bronx,  New York,  10465,  United States
      Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx,  New York,  10461,  United States
      Montefiore Med Ctr / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States
      SUNY / Erie County Med Ctr at Buffalo, Buffalo,  New York,  14215,  United States
      North Central Bronx Hosp / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States
      Comprehensive Health Care Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Columbia Presbyterian Med Ctr, New York,  New York,  100323784,  United States
North Carolina
      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States
Ohio
      Case Western Reserve Univ, Cleveland,  Ohio,  44106,  United States
      Univ of Cincinnati, Cincinnati,  Ohio,  452670405,  United States
Pennsylvania
      Univ of Pennsylvania at Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Thomas Jefferson Univ Hosp, Philadelphia,  Pennsylvania,  191075098,  United States
South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States
Tennessee
      Meharry Med College, Nashville,  Tennessee,  37203,  United States
Texas
      Univ of Texas Galveston, Galveston,  Texas,  775550435,  United States
Washington
      Univ of Washington, Seattle,  Washington,  981224304,  United States

Study chairs or principal investigators

K Kieburtz,  Study Chair
D Simpson,  Study Chair

Study ID Numbers:  ACTG 242
Record last reviewed:  December 1996
Last Updated:  October 13, 2004
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000793
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08