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
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections
Intervention: Zidovudine (Drug); Didanosine (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID) Official(s) and/or principal investigator(s):
J Kahn, Study Chair
D Richman, Study Chair
Summary
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.
Clinical Details
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
Study design: Treatment, Double-Blind
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
Minimum age: 12 Years.
Maximum age: N/A.
Gender(s): 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.
Locations and Contacts
San Juan Veterans Administration Med Ctr, San Juan 009275800, Puerto Rico
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
Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States
Mountain States Regional Hemophilia Ctr / Univ of Colorado, Denver, Colorado 80262, United States
George Washington Univ Med Ctr, Washington, District of Columbia 20037, United States
Univ of Miami School of Medicine, Miami, Florida 331361013, United States
G E Morey Jr, Fort Lauderdale, Florida 33316, United States
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 Univ Hosp, Indianapolis, Indiana 462025250, United States
Univ of Kansas School of Medicine, Wichita, Kansas 67214, United States
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
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
Univ of Minnesota, Minneapolis, Minnesota 55455, United States
Nebraska Regional Hemophilia Ctr, Omaha, Nebraska 68105, United States
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
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 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
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
Julio Arroyo, West Columbia, South Carolina 29169, United States
Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr, Knoxville, Tennessee 37920, United States
Hermann Hosp / Univ Texas Health Science Ctr, Houston, Texas 77030, United States
Dr Stephen L Green, Hampton, Virginia 23666, United States
Univ of Washington, Seattle, Washington 98105, United States
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
Additional Information
Click here for more information about Zidovudine Click here for more information about Didanosine
Related 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.
Last updated: June 23, 2005
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