Clinical Trial: A Phase II Efficacy Study Comparing 2',3'-Dideoxyinosine (ddI) (BMY-40900) and Zidovudine Therapy of Patients With HIV Infection Who Have Been on Long Term Zidovudine Treatment

This study has been completed.

Sponsors and Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
Bristol-Myers Squibb
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

To compare the effectiveness and toxicity of didanosine (ddI) and zidovudine (AZT) in patients with AIDS or advanced AIDS-related complex (ARC) who have tolerated AZT therapy for 12 months or longer. Per amendment, asymptomatic patients with CD4 counts less than 200 cells/mm3 are eligible. 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 of HIV with less apparent toxicity than AZT. Studies indicate that ddI remains active in the body for at least 12 hours; thus benefits of ddI might be achieved with a low frequency of drug administration.

Condition Treatment or Intervention Phase
HIV Infections
 Drug: Zidovudine
 Drug: Didanosine
Phase II

MedlinePlus related topics:  AIDS

Study Type: Interventional
Study Design: Treatment, Double-Blind

Further Study Details: 

Expected Total Enrollment:  750

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 of HIV with less apparent toxicity than AZT. Studies indicate that ddI remains active in the body for at least 12 hours; thus benefits of ddI might be achieved with a low frequency of drug administration.

Two dose levels of ddI, each adjusted depending on patient's weight at study entry, are compared with a variable dosage regimen of AZT (the dose which the patient is tolerating at the time of study entry). Randomization is stratified by baseline CD4 cell count (less than 100 or 100-300) and Medical Center. This study continues for at least 12 months after the entry of the first subject. Patients randomized to AZT will receive orally. All patients randomized to AZT also receive a ddI placebo at 12 hour intervals. Patients randomized to ddI receive AZT placebo.

Eligibility

Ages Eligible for Study:  12 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication: Required:

  • Aerosolized pentamidine (300 mg every 4 weeks).

Allowed:

  • Chronic suppressive treatment for toxoplasmosis, Pneumocystis carinii pneumonia (PCP), cryptococcal meningitis, herpes simplex virus infection.
  • Ganciclovir for patients developing cytomegalovirus (CMV) infection while in study.
  • Erythropoietin for patients under the relevant treatment IND.
  • Treatment of opportunistic infections with other than sulfonamide-containing regimens.
  • Aspirin, acetaminophen, or non-steroidal anti-inflammatory agents is discouraged, but is permitted for as short a period of time as possible.
  • Chronic use of trimethoprim - sulfamethoxazole or other sulfonamide preparations is not encouraged while on study.

Patients must:

  • Have had the diagnosis of AIDS or advanced AIDS related complex (ARC).
  • Have received AZT therapy for at least 12 months, with a minimal daily dose of 500 mg/day and with no more than 60 days off AZT therapy within the 12 month period; medical records with documentation of AZT dosing must be provided.
  • Provide informed consent (guardian as appropriate).
  • Be available for follow-up for at least 6 months.
  • Have the inclusion laboratory values within approximately 14 days of initiating therapy (except for CD4 cell counts).
  • Patients whose AIDS-defining condition is Kaposi's sarcoma alone must have CD4 cell counts < 300 cells/mm3.

Allowed:

  • Positive blood culture for Mycobacterium avium or Cytomegalovirus.
  • Prior history of toxoplasmosis, Herpes simplex, Cryptococcus, or Pneumocystis carinii pneumonia (PCP) requiring chronic suppressive therapy.
  • Occasional premature atrial or ventricular contractions.

Prior Medication: Required:

  • Zidovudine (AZT) therapy for at least 12 months, with a minimal daily dose of 500 mg/day, and with no more than 60 days off AZT therapy within the 12-month period (documentation of AZT dosing must be provided).

Allowed:

  • Intralesional agents.

Exclusion Criteria

Co-existing Condition: Patients with the following are excluded:

  • Psychological or emotional problems sufficient, in the investigator's opinion, to prevent adequate compliance with study therapy.
  • AIDS-dementia complex = or > stage 2.
  • Active AIDS defining opportunistic infections not specifically allowed.
  • Intractable diarrhea.
  • 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 hyperreflexia.
  • Prior history of acute pancreatitis within past 2 years or chronic pancreatitis.
  • History of seizures within past 2 years or currently requiring anticonvulsants for control.
  • History of past or current heart disease.
  • Malignancy likely in the investigator's opinion to require cytotoxic chemotherapy during the expected course of this trial.
  • Life expectancy < 3 months.

Concurrent Medication: Excluded:

  • Isoniazid (INH). Neurotoxic drugs. Oral acidifying agents.

Patients with the following are excluded:

  • Psychological or emotional problems sufficient, in the investigator's opinion, to prevent adequate compliance with study therapy.
  • AIDS-dementia complex = or > stage 2.
  • Active AIDS defining opportunistic infections not specifically allowed.
  • Intractable diarrhea.
  • Prior history of acute pancreatitis within past 2 years or chronic pancreatitis.
  • History of seizures within past 2 years or currently requiring anticonvulsants for control.
  • History of past or current heart disease.
  • Malignancy likely in the investigator's opinion to require cytotoxic chemotherapy during the expected course of this trial.
  • Life expectancy = or < 3 months.
  • Previous participation in any study of ddI, ddC or d4T.

Prior Medication: Excluded:

  • Ganciclovir (DHPG).
  • Excluded within 1 month of study entry:
  • ddI and any other antiretroviral drug or investigational anti-HIV agent except for zidovudine (AZT). Interferons.
  • Immunomodulating drugs.
  • Cytotoxic agents not specifically allowed.
  • Neurotoxic drugs.

Excluded within 3 months of study entry:

  • Ribavirin.

Prior Treatment: Excluded within 14 days of study randomization:

  • Blood transfusion.

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


Location Information


California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States

      Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr, Sylmar,  California,  91342,  United States

      Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco,  California,  94115,  United States

      San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States

      Harbor - UCLA Med Ctr / UCLA School of Medicine, Los Angeles,  California,  905022004,  United States

      Palo Alto Veterans Adm Med Ctr / Stanford Univ, Palo Alto,  California,  94304,  United States

      UCLA CARE Ctr, Los Angeles,  California,  90095,  United States

      Children's Hosp of Los Angeles/UCLA Med Ctr, Los Angeles,  California,  900276016,  United States

      Cedars Sinai / UCLA Med Ctr, Los Angeles,  California,  900481804,  United States

      Los Angeles County - USC Med Ctr, Los Angeles,  California,  90033,  United States

      Stanford Univ School of Medicine, Stanford,  California,  94305,  United States

      Harbor UCLA Med Ctr, Torrance,  California,  90502,  United States

      Olive View Med Ctr, Sylmar,  California,  91342,  United States

Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States

      Mountain States Regional Hemophilia Ctr / Univ of Colorado, Denver,  Colorado,  80262,  United States

District of Columbia
      George Washington Univ Med Ctr, Washington,  District of Columbia,  20037,  United States

Florida
      Univ of Miami School of Medicine, Miami,  Florida,  331361013,  United States

      G E Morey Jr, Fort Lauderdale,  Florida,  33316,  United States

Illinois
      Rush Presbyterian - Saint Luke's Med Ctr, Chicago,  Illinois,  60612,  United States

      Edward Hines Veterans Administration Hosp, Hines,  Illinois,  60141,  United States

      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States

Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States

Kansas
      Univ of Kansas School of Medicine, Wichita,  Kansas,  67214,  United States

Louisiana
      Louisiana State Univ Med Ctr / Tulane Med School, New Orleans,  Louisiana,  70112,  United States

      Tulane Univ School of Medicine, New Orleans,  Louisiana,  70112,  United States

      Louisiana Comprehensive Hemophilia Care Ctr, New Orleans,  Louisiana,  70112,  United States

Massachusetts
      Harvard (Massachusetts Gen Hosp), Boston,  Massachusetts,  02114,  United States

      Beth Israel Deaconess Med Ctr, Boston,  Massachusetts,  02215,  United States

      Beth Israel Deaconess - West Campus, Boston,  Massachusetts,  02215,  United States

      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States

      Baystate Med Ctr of Springfield, Springfield,  Massachusetts,  01199,  United States

      Univ of Massachusetts Med Ctr, Worcester,  Massachusetts,  01655,  United States

      Med Ctr of Central Massachusetts, Worcester,  Massachusetts,  01605,  United States

Minnesota
      Univ of Minnesota, Minneapolis,  Minnesota,  55455,  United States

Nebraska
      Nebraska Regional Hemophilia Ctr, Omaha,  Nebraska,  68105,  United States

New York
      SUNY / State Univ of New York, Syracuse,  New York,  13210,  United States

      SUNY - Stony Brook, Stony Brook,  New York,  117948153,  United States

      Univ of Rochester Medical Center, Rochester,  New York,  14642,  United States

      Mem Sloan - Kettering Cancer Ctr, New York,  New York,  10021,  United States

      Bellevue Hosp / New York Univ Med Ctr, New York,  New York,  10016,  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

      Cornell Univ Med Ctr, New York,  New York,  10021,  United States

      Saint Luke's - Roosevelt Hosp Ctr, New York,  New York,  10025,  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

      Bronx Veterans Administration / Mount Sinai Hosp, Bronx,  New York,  10468,  United States

      SUNY / Erie County Med Ctr at Buffalo, Buffalo,  New York,  14215,  United States

      Beth Israel Med Ctr / Peter Krueger Clinic, New York,  New York,  10003,  United States

      Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr, New York,  New York,  10029,  United States

      City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst,  New York,  11373,  United States

North Carolina
      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States

      Duke Univ Med Ctr, Durham,  North Carolina,  27710,  United States

      Bowman Gray School of Medicine / Wake Forest Univ, Winston Salem,  North Carolina,  27103,  United States

Ohio
      Ohio State Univ Hosp Clinic, Columbus,  Ohio,  432101228,  United States

      Med College of Ohio, Toledo,  Ohio,  43699,  United States

      Holmes Hosp / Univ of Cincinnati Med Ctr, Cincinnati,  Ohio,  452670405,  United States

      Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland,  Ohio,  44106,  United States

Pennsylvania
      Milton S Hershey Med Ctr, Hershey,  Pennsylvania,  170330850,  United States

      Hemophilia Ctr of Western PA / Univ of Pittsburgh, Pittsburgh,  Pennsylvania,  15219,  United States

      Univ of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States

      Univ of Pittsburgh Med School, Pittsburgh,  Pennsylvania,  United States

South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States

Tennessee
      Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr, Knoxville,  Tennessee,  37920,  United States

Texas
      Hermann Hosp / Univ Texas Health Science Ctr, Houston,  Texas,  77030,  United States

Virginia
      Dr Stephen L Green, Hampton,  Virginia,  23666,  United States

Washington
      Univ of Washington, Seattle,  Washington,  98105,  United States

Wisconsin
      Great Lakes Hemophilia Foundation, Milwaukee,  Wisconsin,  53233,  United States

      Dr Brian Buggy, Milwaukee,  Wisconsin,  53215,  United States

      Milwaukee County Med Complex, Milwaukee,  Wisconsin,  53226,  United States

Puerto Rico
      San Juan Veterans Administration Med Ctr, San Juan,  009275800,  Puerto Rico

Study chairs or principal investigators

J Kahn,  Study Chair
D Richman,  Study Chair

More Information

Click here for more information about Zidovudine

Click here for more information about Didanosine

Publications

Smith MS, Koerber KL, Pagano JS. Long-term persistence of zidovudine resistance mutations in plasma isolates of human immunodeficiency virus type 1 of dideoxyinosine-treated patients removed from zidovudine therapy. J Infect Dis. 1994 Jan;169(1):184-8.

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.

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.

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.

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. 1993 Nov;6(11):1212-23.

Kozal M, Winters M, Shafer R, Kroodsma K, Katzenstein D, Merigan T. Behavior of codon 74 and 215 pol gene mutations in 62 AZT experienced patients on ddI monotherapy. Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;55

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.

Schooley RT. Correlation between viral load measurements and outcome in clinical trials of antiviral drugs. AIDS. 1995 Dec;9 Suppl 2:S15-S19. Review.

Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Liou SH, Brown M, Volberding PA, Crumpacker CS, Beall G, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. N Engl J Med. 1992 Aug 27;327(9):581-7.

Richman DD. Clinical significance of drug resistance in human immunodeficiency virus. Clin Infect Dis. 1995 Oct;21 Suppl 2:S166-9. Review.

Study ID Numbers:  ACTG 117; 070V1; AI454-009
Record last reviewed:  August 1992
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000671
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08


Source: ClinicalTrials.gov
Cache Date: April 9, 2005

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