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

March 11, 2011 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment

660

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 009275800
        • San Juan Veterans Administration Med Ctr
  • United States
    • California
      • Los Angeles, California, United States, 90033
        • Los Angeles County - USC Med Ctr
      • Los Angeles, California, United States, 900481804
        • Cedars Sinai / UCLA Med Ctr
      • Los Angeles, California, United States, 905022004
        • Harbor - UCLA Med Ctr / UCLA School of Medicine
      • Los Angeles, California, United States, 900951752
        • UCLA Med Ctr / Pediatric
      • Palo Alto, California, United States, 94304
        • Palo Alto Veterans Adm Med Ctr / Stanford Univ
      • San Diego, California, United States, 921036325
        • Univ of California / San Diego Treatment Ctr
      • Stanford, California, United States, 94305
        • Stanford Univ School of Medicine
      • Sylmar, California, United States, 91342
        • Olive View Med Ctr
      • Sylmar, California, United States, 91342
        • Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr
      • Torrance, California, United States, 90502
        • Harbor UCLA Med Ctr
    • Colorado
      • Denver, Colorado, United States, 80262
        • Univ of Colorado Health Sciences Ctr
      • Denver, Colorado, United States, 80262
        • Mountain States Regional Hemophilia Ctr / Univ of Colorado
    • District of Columbia
      • Washington, District of Columbia, United States, 20037
        • George Washington Univ Med Ctr
    • Florida
      • Fort Lauderdale, Florida, United States, 33316
        • G E Morey Jr
      • Miami, Florida, United States, 331361013
        • Univ of Miami School of Medicine
      • Tampa, Florida, United States, 33612
        • Univ of South Florida
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Univ Med School
      • Hines, Illinois, United States, 60141
        • Edward Hines Veterans Administration Hosp
    • Indiana
      • Indianapolis, Indiana, United States, 462025250
        • Indiana Univ Hosp
    • Kansas
      • Wichita, Kansas, United States, 67214
        • Univ of Kansas School of Medicine
    • Louisiana
      • New Orleans, Louisiana, United States, 70112
        • Louisiana Comprehensive Hemophilia Care Ctr
      • New Orleans, Louisiana, United States, 70112
        • Louisiana State Univ Med Ctr / Tulane Med School
      • New Orleans, Louisiana, United States, 70112
        • Tulane Univ School of Medicine
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hosp
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Harvard (Massachusetts Gen Hosp)
      • Boston, Massachusetts, United States, 02118
        • Boston Med Ctr
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess - West Campus
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Med Ctr
      • Springfield, Massachusetts, United States, 01199
        • Baystate Med Ctr of Springfield
      • Worcester, Massachusetts, United States, 01605
        • Med Ctr of Central Massachusetts
      • Worcester, Massachusetts, United States, 01655
        • Univ of Massachusetts Med Ctr
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Univ of Minnesota
    • Nebraska
      • Omaha, Nebraska, United States, 68105
        • Nebraska Regional Hemophilia Ctr
    • New York
      • Bronx, New York, United States, 10461
        • Bronx Municipal Hosp Ctr/Jacobi Med Ctr
      • Bronx, New York, United States, 10465
        • Jack Weiler Hosp / Bronx Municipal Hosp
      • Bronx, New York, United States, 10467
        • Montefiore Med Ctr / Bronx Municipal Hosp
      • Bronx, New York, United States, 10468
        • Bronx Veterans Administration / Mount Sinai Hosp
      • Buffalo, New York, United States, 14215
        • SUNY / Erie County Med Ctr at Buffalo
      • Elmhurst, New York, United States, 11373
        • City Hosp Ctr at Elmhurst / Mount Sinai Hosp
      • New York, New York, United States, 10003
        • Beth Israel Med Ctr / Peter Krueger Clinic
      • New York, New York, United States, 10016
        • Bellevue Hosp / New York Univ Med Ctr
      • New York, New York, United States, 10021
        • Mem Sloan - Kettering Cancer Ctr
      • New York, New York, United States, 10025
        • Saint Luke's - Roosevelt Hosp Ctr
      • New York, New York, United States, 10029
        • Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr
      • New York, New York, United States, 10029
        • Mount Sinai Med Ctr
      • Rochester, New York, United States, 14642
        • Univ of Rochester Medical Center
      • Stony Brook, New York, United States, 117948153
        • SUNY - Stony Brook
      • Syracuse, New York, United States, 13210
        • SUNY / State Univ of New York
    • North Carolina
      • Chapel Hill, North Carolina, United States, 275997215
        • Univ of North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke Univ Med Ctr
      • Winston-Salem, North Carolina, United States, 27103
        • Bowman Gray School of Medicine / Wake Forest Univ
    • Ohio
      • Cincinnati, Ohio, United States, 452670405
        • Holmes Hosp / Univ of Cincinnati Med Ctr
      • Cleveland, Ohio, United States, 44106
        • Univ Hosp of Cleveland / Case Western Reserve Univ
      • Columbus, Ohio, United States, 432101228
        • Ohio State Univ Hosp Clinic
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 170330850
        • Milton S Hershey Med Ctr
      • Philadelphia, Pennsylvania, United States, 19104
        • Univ of Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15219
        • Hemophilia Ctr of Western PA / Univ of Pittsburgh
      • Pittsburgh, Pennsylvania, United States
        • Univ of Pittsburgh Med School
    • South Carolina
      • West Columbia, South Carolina, United States, 29169
        • Julio Arroyo
    • Tennessee
      • Knoxville, Tennessee, United States, 37920
        • Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
    • Texas
      • Galveston, Texas, United States, 77550
        • Univ TX Galveston Med Branch
      • Houston, Texas, United States, 77030
        • Hermann Hosp / Univ Texas Health Science Ctr
      • Houston, Texas, United States, 77030
        • Texas Children's Hosp / Baylor Univ
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • Univ of Utah School of Medicine
    • Washington
      • Seattle, Washington, United States, 98105
        • Univ of Washington
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53233
        • Great Lakes Hemophilia Foundation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Bristol-Myers Squibb

Investigators

  • Study Chair: JD Allan
  • Study Chair: J Groopman
  • Study Chair: M Seidlin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Primary Completion (Actual)

February 1, 1993

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 (Estimate)

March 14, 2011

Last Update Submitted That Met QC Criteria

March 11, 2011

Last Verified

October 1, 1994

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACTG 118
  • 070V1
  • AI454-007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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