Comparison of ddI Versus Zidovudine in HIV-Infected Patients

Comparison of 2',3'-Dideoxyinosine (ddI) (BMY-40900) and Zidovudine in Therapy of Patients With HIV Infection

To compare the effectiveness and toxicity of didanosine (ddI) and zidovudine (AZT) in patients with AIDS, advanced AIDS-related complex (ARC), or asymptomatic infection with CD4 counts < 200 cells/mm3.

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Zidovudine; Drug: Didanosine

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.

AMENDED: 9/28/90 Patients are assigned to one of 2 treatments under a double-blind, randomly allocated, experimental design if their duration of prior AZT therapy is 0 to 16 weeks. (Patients who entered with no more than 16 weeks prior AZT and who were randomized to ddI will continue to be dosed at that level, adjusted for weight, and followed as originally planned.) Patients are assigned to one of 3 treatments as explained prior to this amendment if their duration of prior to AZT therapy is greater than 16 weeks. Original design: Patients are assigned to one of three treatments under a double-blind randomly allocated experimental design. ddI will be administered at two dose levels.

It is anticipated that patients will be seen as outpatients every 2 weeks for the first 4 weeks of the study and monthly thereafter. This study continues for at least 18 months after the entry of the first subject.

• Study Type: Interventional
• Enrollment: 1500
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 009275800
    • San Juan Veterans Administration Med Ctr
• United States
  • California
    • Los Angeles, California, United States, 900276016
      • Children's Hosp of Los Angeles/UCLA Med Ctr
    • Los Angeles, California, United States, 90033
      • Los Angeles County - USC Med Ctr
    • 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
    • Washington, District of Columbia, United States, 20009
      • Whitman - Walker Clinic
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • G E Morey Jr
    • Miami, Florida, United States, 331361013
      • Univ of Miami School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Univ Med School
    • Chicago, Illinois, United States, 60612
      • Rush Presbyterian - Saint Luke's Med Ctr
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp
    • 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
    • New Orleans, Louisiana, United States, 70112
      • Charity Hosp / Tulane Univ Med School
  • 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, 10021
      • Cornell Univ Med Ctr
    • 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 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
    • Columbus, Ohio, United States, 432101228
      • Ohio State Univ Hosp Clinic
    • Toledo, Ohio, United States, 43699
      • Med College of Ohio
  • 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
  • Virginia
    • Hampton, Virginia, United States, 23666
      • Dr Stephen L Green
  • Washington
    • Seattle, Washington, United States, 98105
      • Univ of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Dr Brian Buggy
    • Milwaukee, Wisconsin, United States, 53226
      • Milwaukee County Med Complex
    • Milwaukee, Wisconsin, United States, 53233
      • Great Lakes Hemophilia Foundation

Participation Criteria

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 using a Respirgard II nebulizer). In the event of physiological intolerance, alternative prophylaxis may be: Trimethoprim / sulfamethoxazole 1 DS tab per day or dapsone 50 - 100 mg/day.

Allowed:

Maintenance therapy for active AIDS defining opportunistic infections for patients with 9 to 47 weeks' experience with zidovudine (AZT).

Treatment of opportunistic infections with other than sulfonamide containing drugs:

• Pyrimethamine and sulfadiazine or clindamycin for suppression of toxoplasmosis acquired after study entry; fluconazole or amphotericin B for suppression of cryptococcosis or ketoconazole for candidiasis.

Intravenous acyclovir for up to 10 days. Erythropoietin for patients under the relevant treatment IND. Analgesics, antihistamines, antiemetics, antidiarrheal agents for symptomatic therapy for toxicities.

Isoniazid (INH) if no other acceptable therapy is available.

Metronidazole may be used for single courses of therapy not to exceed 14 days within consecutive 90 day intervals. Note:

• Ketoconazole and dapsone should be taken 2 hours before or 2 hours after taking ddI (amendment 5/20/91).

Concurrent Treatment:

Allowed:

• Blood transfusions for hemoglobin toxicity.

Patients must:

• Have a diagnosis of AIDS or advanced AIDS related complex (ARC), or per 8/09/90 amendment, asymptomatic HIV infection with CD4 count = or < 200 cells/mm3.
• Be either naive to zidovudine (AZT) or have taken AZT for = or < 48 weeks.
• Have ended treatment for acute Pneumocystis carinii pneumonia (PCP) at least 2 weeks before study entry. For patients with 2 months or less experience with AZT, PCP infection will be the single and only AIDS-defining infection and must have been within 120 days of study entry. Per amendment, other AIDS-defining conditions are allowed in the 8 weeks prior to study entry (for patients in the AZT stratum).Only one episode of PCP is permitted unless patient has > 2 months AZT experience in which case > 1 prior episode of PCP infection is allowed.
• Not have experienced a major intolerance to AZT at doses of at least 500 mg if the patient was on AZT therapy for = or < 48 weeks. A major intolerance is defined as recurrent grade 3 or greater toxicity which results in discontinuation of drug.

Allowed:

• Basal cell carcinoma.
• In situ carcinoma of the cervix.
• Occasional premature atrial or ventricular contraction.
• Patients developing new opportunistic infections after study entry will remain on this protocol.
• Patients whose AIDS-defining condition is Kaposi's sarcoma alone must have CD4 cell counts < 300 cells/mm3.

Prior Medication:

Allowed:

• Previous treatment with zidovudine (AZT) up to 48 weeks.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or diseases are excluded:

• Kaposi's sarcoma (KS) with evidence of visceral disease or where KS requires chemotherapy; subjects with localized KS having CD4 counts = or > 200 cells/mm3.
• AIDS-dementia complex = or > stage 2.
• Prior history of acute pancreatitis within past 2 years or chronic pancreatitis.
• Intractable diarrhea.
• History of seizures within past 6 months or currently requiring anticonvulsants for control.
• History of past or current heart disease.
• Presence of a malignancy likely in the investigators opinion to require cytotoxic myelosuppressive chemotherapy during the expected course of this trial.

Concurrent Medication:

Excluded:

• Oral acidifying agents.
• Neurotoxic drugs. NOTE: If patients require therapy for PCP with IV pentamidine, study mediation is stopped.

Patients with the following are excluded:

• Active AIDS defining events. Maintenance therapy for prior AIDS-defining opportunistic infections is permitted.
• Intolerance to AZT at doses of 500 mg because of recurrent grade 3 toxicity or greater which resulted in discontinuation of drug.
• Neoplasms not specifically allowed.
• Previous enrollment in any study of ddI, ddC or d4T.
• > 48 weeks of AZT therapy.
• An opportunistic infection not adequately controlled with suppressive therapies allowed in the protocol.
• Psychological or emotional problems sufficient, in the investigator's opinion, to prevent adequate compliance study therapy.
• Life expectancy = or < 6 months.

Prior Medication:

Excluded:

• Ganciclovir.
• AZT for = or > 48 weeks.

Excluded within 14 days of study entry:

• Erythropoietin (Eprex).

Excluded within 30 days of study entry:

• Anti-HIV therapy other than AZT.
• Biologic response modifiers.
• Other investigational drugs.
• Corticosteroids.
• Neurotoxic drugs.

Excluded within 90 days of study entry:

• Ribavirin.

Prior Treatment:

Excluded within 14 days of study entry:

• Transfusion.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Chair: R Dolin

Publications and helpful links

General Publications

• Bozzette SA, Hays RD, Berry SH, Kanouse DE. A Perceived Health Index for use in persons with advanced HIV disease: derivation, reliability, and validity. Med Care. 1994 Jul;32(7):716-31. doi: 10.1097/00005650-199407000-00005.
• Fiscus SA, Heggem-Snow A, Troiani L, Wallmark E, Folds JD, Sheff B, van der Horst CM. Transient high titers of HIV-1 in plasma and progression of disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 May 1;9(1):51-7.
• Kozal MJ, Kroodsma K, Winters MA, Shafer RW, Efron B, Katzenstein DA, Merigan TC. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med. 1994 Aug 15;121(4):263-8. doi: 10.7326/0003-4819-121-4-199408150-00005.
• Schooley RT. Correlation between viral load measurements and outcome in clinical trials of antiviral drugs. AIDS. 1995 Dec;9 Suppl 2:S15-S19.
• Dolin R, Amato DA, Fischl MA, Pettinelli C, Beltangady M, Liou SH, Brown MJ, Cross AP, Hirsch MS, Hardy WD, et al. Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group. Arch Intern Med. 1995 May 8;155(9):961-74. Erratum In: Arch Intern Med 1995 Nov 13;155(20):2255.
• Fichtenbaum CJ, Clifford DB, Powderly WG. Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Oct 1;10(2):169-74. doi: 10.1097/00042560-199510020-00009.
• Spino C, Kahn JO, Dolin R, Phair JP. Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Aug 15;15(5):346-55. doi: 10.1097/00042560-199708150-00004.
• Richardson D, Liou SH, Kahn JO. Uric acid and didanosine compliance in AIDS clinical trials: an analysis of AIDS Clinical Trials Group protocols 116A and 116B/117. J Acquir Immune Defic Syndr (1988). 1993 Nov;6(11):1212-23.
• Welles SL, Jackson JB, Yen-Lieberman B, Demeter L, Japour AJ, Smeaton LM, Johnson VA, Kuritzkes DR, D'Aquila RT, Reichelderfer PA, Richman DD, Reichman R, Fischl M, Dolin R, Coombs RW, Kahn JO, McLaren C, Todd J, Kwok S, Crumpacker CS. Prognostic value of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS Clinical Trials Group Protocol 116A/116B/117 Team. J Infect Dis. 1996 Oct;174(4):696-703. doi: 10.1093/infdis/174.4.696.
• Coombs RW, Welles SL, Hooper C, Reichelderfer PS, D'Aquila RT, Japour AJ, Johnson VA, Kuritzkes DR, Richman DD, Kwok S, Todd J, Jackson JB, DeGruttola V, Crumpacker CS, Kahn J. Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection. AIDS Clinical Trials Group (ACTG) 116B/117 Study Team. ACTG Virology Committee Resistance and HIV-1 RNA Working Groups. J Infect Dis. 1996 Oct;174(4):704-12. doi: 10.1093/infdis/174.4.704.
• Mildvan D, Spritzler J, Grossberg SE, Fahey JL, Johnston DM, Schock BR, Kagan J. Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection. Clin Infect Dis. 2005 Mar 15;40(6):853-8. doi: 10.1086/427877. Epub 2005 Feb 18.

Study record dates

Study Major Dates

• Study Start: December 7, 2022
• Primary Completion (Actual): October 1, 1992
• Study Completion: December 7, 2022

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: January 1, 2003

More Information

Terms related to this study

• Keywords: Didanosine; Zidovudine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Zidovudine; Didanosine
• Other Study ID Numbers: ACTG 116; 070V1; ACTG 116-A; ACTG 116-B/117; AI454-008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No