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An Efficacy Study of 2',3'-Di...

An Efficacy Study of 2',3'-Dideoxyinosine (ddI) (BMY-40900) Administered Orally Twice Daily to Zidovudine Intolerant Patients With AIDS or AIDS-Related Complex

Last Updated: 2011-03-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

660 participants

Study Classification

INTERVENTIONAL

Brief Summary

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AMENDED: 8/29/90 Inclusion of asymptomatic patients with CD4 counts less than 200 cells/mm3. Standardization of baseline evaluation schedule to allow 14 days prior to study dosing. Reduction in frequency and intensity of follow-up evaluations. Standardization of study endpoints. Inclusion of toxicity scoring and management for amylase and triglyceride elevations. Clarification of concomitant medication use. Original design: To determine the effectiveness of didanosine (ddI) in patients with AIDS or advanced AIDS related complex (ARC) who have documented hematologic intolerance to zidovudine (AZT) therapy. To determine if the efficacy of ddI increases with increasing doses.

AZT is effective in reducing mortality in patients with AIDS who receive the drug after the first episode of Pneumocystis carinii pneumonia (PCP) and in patients with advanced ARC. However, AZT therapy has been associated with significant toxicities. In addition, the effectiveness of AZT appears to decrease during the second and third years of therapy. For these reasons, the development of alternative therapy that would be at least as effective but less toxic is of great importance. The drug ddI is an antiviral agent that inhibits replication (reproduction) of HIV with less apparent toxicity than AZT. The major dose-limiting toxicities found in the Phase I studies have been pains in the feet and legs of 2 patients initially receiving 12 mg/kg/day and 12 patients receiving daily doses of 25.8 to 51.2 mg/kg; symptoms began 8 to 27 weeks after initiating ddI treatment. These neuropathy-like symptoms have generally not been associated with significant abnormalities in nerve conduction studies and patients have reported marked improvement in symptoms within 1 to 2 weeks of discontinuing ddI. Some patients have resumed ddI treatment at a reduced dose after resolution of their symptoms. Studies indicate that ddI remains active in the body for at least 12 hours. This indicates that benefits of ddI might be achieved with a low frequency of drug administration.

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Detailed Description

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AZT is effective in reducing mortality in patients with AIDS who receive the drug after the first episode of Pneumocystis carinii pneumonia (PCP) and in patients with advanced ARC. However, AZT therapy has been associated with significant toxicities. In addition, the effectiveness of AZT appears to decrease during the second and third years of therapy. For these reasons, the development of alternative therapy that would be at least as effective but less toxic is of great importance. The drug ddI is an antiviral agent that inhibits replication (reproduction) of HIV with less apparent toxicity than AZT. The major dose-limiting toxicities found in the Phase I studies have been pains in the feet and legs of 2 patients initially receiving 12 mg/kg/day and 12 patients receiving daily doses of 25.8 to 51.2 mg/kg; symptoms began 8 to 27 weeks after initiating ddI treatment. These neuropathy-like symptoms have generally not been associated with significant abnormalities in nerve conduction studies and patients have reported marked improvement in symptoms within 1 to 2 weeks of discontinuing ddI. Some patients have resumed ddI treatment at a reduced dose after resolution of their symptoms. Studies indicate that ddI remains active in the body for at least 12 hours. This indicates that benefits of ddI might be achieved with a low frequency of drug administration.

Patients are randomized to one of three ddI treatment groups; within each group, doses will be adjusted according to patient's weight at study entry. Stratification is by diagnosis of AIDS or AIDS related complex (ARC) and Medical Center. Data will be tabulated for the Data and Safety Monitoring Board at 3 month intervals.

Conditions

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HIV Infections

Study Design

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Primary Study Purpose

TREATMENT

Interventions

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Didanosine

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

Concurrent Medication:

Required:

* Aerosolized pentamidine (300 mg every 4 weeks). In the event of physiological intolerance, alternative PCP prophylaxis may be trimethoprim/sulfamethoxazole 1 DS tab per day or dapsone 50 - 100 mg per day.

Allowed:

* Chronic suppressive treatment for toxoplasmosis, Pneumocystis carinii pneumonia (PCP), cryptococcal meningitis, herpes simplex virus, cytomegalovirus, coccidioidomycosis, and histoplasmosis (absorption of ketoconazole or dapsone may be inhibited if given at the same time as the buffered solution of ddI, and should be taken 2 hours before or 2 hours after taking ddI; oral acidifying agents are not allowed). Isoniazid is permitted only if no acceptable alternative therapy is available. Metronidazole may be used for single courses not to exceed 14 days within consecutive 90 day intervals, the first of which begins at the initiation of the study. Erythropoietin for patients under the relevant treatment IND. Intravenous acyclovir for short courses of therapy.

Patients must:

* Have documented hematologic intolerance to zidovudine (AZT).
* Have the diagnosis of AIDS or advanced AIDS related complex (ARC).
* Have ended treatment for acute Pneumocystis carinii pneumonia (PCP) at least 2 weeks before study entry.

Have previous intolerance on at least two courses of AZT therapy (one of which must have been at daily doses of 500 mg of AZT or less).

* Be able to provide informed consent (and/or guardian as appropriate).
* Be available for follow-up for at least 6 months.
* Have baseline laboratory values as measured within 7 days before initial drug dosing.
* Allowed:
* Development of new opportunistic infections during the study - patients remain in the protocol.

Prior Medication:

Required:

* Prior use and intolerance to zidovudine (AZT).
* Allowed:
* Intralesional agents.

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

* Presence of Kaposi's sarcoma (KS) with known or suspected visceral disease or where KS requires chemotherapy.
* Active AIDS defining opportunistic infections not specifically allowed.
* Intractable diarrhea.
* Stage 2 AIDS-dementia complex.
* History of intolerance to aerosolized pentamidine.
* Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
* Prior history of acute or chronic pancreatitis.
* History of seizures within past 2 years or currently requiring anticonvulsants for control.
* Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.

Concurrent Medication:

Excluded:

* Isoniazid (INH).

Patients with the following are excluded:

* Active AIDS-defining opportunistic infections not specifically allowed.
* Intractable diarrhea.
* AIDS-dementia complex = or \> stage 2.
* History of intolerance to aerosolized pentamidine. Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
* Prior history of acute or chronic pancreatitis.
* History of seizures within past 2 years or currently requiring anticonvulsants for control.
* Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.
* Previous participation in any Phase I ddI study.
* Life expectancy \< 6 months.

Prior Medication:

Excluded:

* Chronic therapy for cytomegalovirus infection with ganciclovir.
* ddI.
* d4T.
* ddC.

Excluded within 2 weeks of study entry:

* Zidovudine (AZT).

Excluded within 1 month of study entry:

* Therapy with any other antiretroviral drug or investigational agent not specifically allowed, including interferon and immunomodulating drugs.
* Ganciclovir.
* Neurotoxic drugs.

Excluded within 3 months of study entry:

* Ribavirin.
* Cytotoxic anticancer therapy.

Prior Treatment:

Excluded within 2 weeks of study randomization:

* Transfusion.

Active alcohol or drug abuse that is sufficient, in investigator's opinion, to prevent adequate compliance with study therapy.

Minimum Eligible Age

12 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Principal Investigators

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JD Allan

Role: STUDY_CHAIR

J Groopman

Role: STUDY_CHAIR

M Seidlin

Role: STUDY_CHAIR

Locations

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Los Angeles County - USC Med Ctr

Los Angeles, California, United States

Site Status

Cedars Sinai / UCLA Med Ctr

Los Angeles, California, United States

Site Status

UCLA Med Ctr / Pediatric

Los Angeles, California, United States

Site Status

Harbor - UCLA Med Ctr / UCLA School of Medicine

Los Angeles, California, United States

Site Status

Palo Alto Veterans Adm Med Ctr / Stanford Univ

Palo Alto, California, United States

Site Status

Univ of California / San Diego Treatment Ctr

San Diego, California, United States

Site Status

Stanford Univ School of Medicine

Stanford, California, United States

Site Status

Olive View Med Ctr

Sylmar, California, United States

Site Status

Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr

Sylmar, California, United States

Site Status

Harbor UCLA Med Ctr

Torrance, California, United States

Site Status

Mountain States Regional Hemophilia Ctr / Univ of Colorado

Denver, Colorado, United States

Site Status

Univ of Colorado Health Sciences Ctr

Denver, Colorado, United States

Site Status

George Washington Univ Med Ctr

Washington D.C., District of Columbia, United States

Site Status

G E Morey Jr

Fort Lauderdale, Florida, United States

Site Status

Univ of Miami School of Medicine

Miami, Florida, United States

Site Status

Univ of South Florida

Tampa, Florida, United States

Site Status

Northwestern Univ Med School

Chicago, Illinois, United States

Site Status

Edward Hines Veterans Administration Hosp

Hines, Illinois, United States

Site Status

Indiana Univ Hosp

Indianapolis, Indiana, United States

Site Status

Univ of Kansas School of Medicine

Wichita, Kansas, United States

Site Status

Louisiana Comprehensive Hemophilia Care Ctr

New Orleans, Louisiana, United States

Site Status

Louisiana State Univ Med Ctr / Tulane Med School

New Orleans, Louisiana, United States

Site Status

Tulane Univ School of Medicine

New Orleans, Louisiana, United States

Site Status

Johns Hopkins Hosp

Baltimore, Maryland, United States

Site Status

Harvard (Massachusetts Gen Hosp)

Boston, Massachusetts, United States

Site Status

Boston Med Ctr

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess - West Campus

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess Med Ctr

Boston, Massachusetts, United States

Site Status

Baystate Med Ctr of Springfield

Springfield, Massachusetts, United States

Site Status

Med Ctr of Central Massachusetts

Worcester, Massachusetts, United States

Site Status

Univ of Massachusetts Med Ctr

Worcester, Massachusetts, United States

Site Status

Univ of Minnesota

Minneapolis, Minnesota, United States

Site Status

Nebraska Regional Hemophilia Ctr

Omaha, Nebraska, United States

Site Status

SUNY / Erie County Med Ctr at Buffalo

Buffalo, New York, United States

Site Status