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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.
First Received: November 2, 1999   Last Updated: July 31, 2008   History of Changes
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator: Bristol-Myers Squibb
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000671
  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 Intervention Phase
HIV Infections
Drug: Zidovudine
Drug: Didanosine
Phase II

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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 750
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 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 older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00000671

  Hide Study Locations
Locations
United States, California
Univ of California / San Diego Treatment Ctr
San Diego, California, United States, 921036325
Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr
Sylmar, California, United States, 91342
Stanford at Kaiser / Kaiser Permanente Med Ctr
San Francisco, California, United States, 94115
San Francisco AIDS Clinic / San Francisco Gen Hosp
San Francisco, California, United States, 941102859
Children's Hosp of Los Angeles/UCLA Med Ctr
Los Angeles, California, United States, 900276016
Palo Alto Veterans Adm Med Ctr / Stanford Univ
Palo Alto, California, United States, 94304
UCLA CARE Ctr
Los Angeles, California, United States, 90095
Harbor - UCLA Med Ctr / UCLA School of Medicine
Los Angeles, California, United States, 905022004
Cedars Sinai / UCLA Med Ctr
Los Angeles, California, United States, 900481804
Los Angeles County - USC Med Ctr
Los Angeles, California, United States, 90033
Stanford Univ School of Medicine
Stanford, California, United States, 94305
Harbor UCLA Med Ctr
Torrance, California, United States, 90502
Olive View Med Ctr
Sylmar, California, United States, 91342
United States, Colorado
Univ of Colorado Health Sciences Ctr
Denver, Colorado, United States, 80262
Mountain States Regional Hemophilia Ctr / Univ of Colorado
Denver, Colorado, United States, 80262
United States, District of Columbia
George Washington Univ Med Ctr
Washington, District of Columbia, United States, 20037
United States, Florida
Univ of Miami School of Medicine
Miami, Florida, United States, 331361013
G E Morey Jr
Fort Lauderdale, Florida, United States, 33316
United States, Illinois
Rush Presbyterian - Saint Luke's Med Ctr
Chicago, Illinois, United States, 60612
Edward Hines Veterans Administration Hosp
Hines, Illinois, United States, 60141
Northwestern Univ Med School
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana Univ Hosp
Indianapolis, Indiana, United States, 462025250
United States, Kansas
Univ of Kansas School of Medicine
Wichita, Kansas, United States, 67214
United States, Louisiana
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
Louisiana Comprehensive Hemophilia Care Ctr
New Orleans, Louisiana, United States, 70112
United States, Massachusetts
Harvard (Massachusetts Gen Hosp)
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Med Ctr
Boston, Massachusetts, United States, 02215
Beth Israel Deaconess - West Campus
Boston, Massachusetts, United States, 02215
Boston Med Ctr
Boston, Massachusetts, United States, 02118
Baystate Med Ctr of Springfield
Springfield, Massachusetts, United States, 01199
Univ of Massachusetts Med Ctr
Worcester, Massachusetts, United States, 01655
Med Ctr of Central Massachusetts
Worcester, Massachusetts, United States, 01605
United States, Minnesota
Univ of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Nebraska
Nebraska Regional Hemophilia Ctr
Omaha, Nebraska, United States, 68105
United States, New York
SUNY / State Univ of New York
Syracuse, New York, United States, 13210
SUNY - Stony Brook
Stony Brook, New York, United States, 117948153
Univ of Rochester Medical Center
Rochester, New York, United States, 14642
Mem Sloan - Kettering Cancer Ctr
New York, New York, United States, 10021
Bellevue Hosp / New York Univ Med Ctr
New York, New York, United States, 10016
Saint Luke's - Roosevelt Hosp Ctr
New York, New York, United States, 10025
Jack Weiler Hosp / Bronx Municipal Hosp
Bronx, New York, United States, 10465
Cornell Univ Med Ctr
New York, New York, United States, 10021
Mount Sinai Med Ctr
New York, New York, United States, 10029
Bronx Municipal Hosp Ctr/Jacobi Med Ctr
Bronx, New York, United States, 10461
Montefiore Med Ctr / Bronx Municipal Hosp
Bronx, New York, United States, 10467
Bronx Veterans Administration / Mount Sinai Hosp
Bronx, New York, United States, 10468
SUNY / Erie County Med Ctr at Buffalo
Buffalo, New York, United States, 14215
Beth Israel Med Ctr / Peter Krueger Clinic
New York, New York, United States, 10003
Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr
New York, New York, United States, 10029
City Hosp Ctr at Elmhurst / Mount Sinai Hosp
Elmhurst, New York, United States, 11373
United States, North Carolina
Univ of North Carolina
Chapel Hill, North Carolina, United States, 275997215
Duke Univ Med Ctr
Durham, North Carolina, United States, 27710
Bowman Gray School of Medicine / Wake Forest Univ
Winston-Salem, North Carolina, United States, 27103
United States, Ohio
Ohio State Univ Hosp Clinic
Columbus, Ohio, United States, 432101228
Med College of Ohio
Toledo, Ohio, United States, 43699
Holmes Hosp / Univ of Cincinnati Med Ctr
Cincinnati, Ohio, United States, 452670405
Univ Hosp of Cleveland / Case Western Reserve Univ
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Univ of Pittsburgh Med School
Pittsburgh, Pennsylvania, United States
Hemophilia Ctr of Western PA / Univ of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15219
Univ of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Milton S Hershey Med Ctr
Hershey, Pennsylvania, United States, 170330850
United States, South Carolina
Julio Arroyo
West Columbia, South Carolina, United States, 29169
United States, Tennessee
Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
Knoxville, Tennessee, United States, 37920
United States, Texas
Hermann Hosp / Univ Texas Health Science Ctr
Houston, Texas, United States, 77030
United States, Virginia
Dr Stephen L Green
Hampton, Virginia, United States, 23666
United States, Washington
Univ of Washington
Seattle, Washington, United States, 98105
United States, Wisconsin
Great Lakes Hemophilia Foundation
Milwaukee, Wisconsin, United States, 53233
Dr Brian Buggy
Milwaukee, Wisconsin, United States, 53215
Milwaukee County Med Complex
Milwaukee, Wisconsin, United States, 53226
Puerto Rico
San Juan Veterans Administration Med Ctr
San Juan, Puerto Rico, 009275800
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Chair: J Kahn
Study Chair: D Richman
  More Information

Additional Information:
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
Study First Received: November 2, 1999
Last Updated: July 31, 2008
ClinicalTrials.gov Identifier: NCT00000671     History of Changes
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Didanosine
Zidovudine

Additional relevant MeSH terms:
Antimetabolites
Communicable Diseases
Anti-Infective Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Zidovudine
Infection
Reverse Transcriptase Inhibitors
Anti-Retroviral Agents
Therapeutic Uses
Retroviridae Infections
Nucleic Acid Synthesis Inhibitors
RNA Virus Infections
Anti-HIV Agents
Immune System Diseases
Acquired Immunodeficiency Syndrome
Enzyme Inhibitors
Antiviral Agents
Immunologic Deficiency Syndromes
Pharmacologic Actions
Virus Diseases
Didanosine
HIV Infections
Sexually Transmitted Diseases
Lentivirus Infections

ClinicalTrials.gov processed this record on November 27, 2009