Clinical trial NCT00000793: A Phase II/III Double-Blind Study of Amitriptyline and Mexiletine for Painful Neuropathy in HIV Infection
Official title: A Phase II/III Double-Blind Study of Amitriptyline and Mexiletine for Painful Neuropathy in HIV Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Peripheral Nervous System Disease
Keywords: Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Peripheral Nervous System Diseases
Amitriptyline
Pain
Mexiletine
benzatropine methanesulfonate
Parasympatholytics
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Boehringer Ingelheim
First posted: 2001-08-31
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids 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: Washington
country: United States
facility: Howard University Hosp., Div. of Infectious Diseases, ACTU
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS
state: Georgia
city: Honolulu
country: United States
facility: Queens Med. Ctr.
state: Hawaii
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp. CORE Ctr.
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Chicago
country: United States
facility: Weiss Memorial Hosp.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: Iowa City
country: United States
facility: Univ. of Iowa Healthcare, Div. of Infectious Diseases
state: Iowa
city: New Orleans
country: United States
facility: Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - East Campus A0102 CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med. Ctr., Div. of Infectious Diseases
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Mbeya
country: Tanzania
facility: Mbeya Med. Research Program, Mbeya Referral Hosp. CRS
Study officials:
name: K Kieburtz
role: STUDY_CHAIR
name: D Simpson
role: STUDY_CHAIR
References:
citation: Lein B. Potential therapy for painful neuropathy. PI Perspect. 1995 May;(no 16):11.
citation: 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.