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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000671
• Other study ID #: ACTG 117
• Secondary ID: 070V1AI454-009
• Status: Completed
• Phase: Phase 2
• First received: November 2, 1999
• Last updated: March 11, 2011

Study information

• Verified date: August 1992
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 750
• Est. primary completion date: March 1992
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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.

Study Design

Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Infection

Intervention

Drug:
• Zidovudine

• Didanosine

Locations

Country	Name	City	State
Puerto Rico	San Juan Veterans Administration Med Ctr	San Juan
United States	Beth Israel Deaconess - West Campus	Boston	Massachusetts
United States	Beth Israel Deaconess Med Ctr	Boston	Massachusetts
United States	Boston Med Ctr	Boston	Massachusetts
United States	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts
United States	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York
United States	Bronx Veterans Administration / Mount Sinai Hosp	Bronx	New York
United States	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York
United States	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois
United States	Holmes Hosp / Univ of Cincinnati Med Ctr	Cincinnati	Ohio
United States	Univ Hosp of Cleveland / Case Western Reserve Univ	Cleveland	Ohio
United States	Ohio State Univ Hosp Clinic	Columbus	Ohio
United States	Mountain States Regional Hemophilia Ctr / Univ of Colorado	Denver	Colorado
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	Duke Univ Med Ctr	Durham	North Carolina
United States	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York
United States	G E Morey Jr	Fort Lauderdale	Florida
United States	Dr Stephen L Green	Hampton	Virginia
United States	Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Edward Hines Veterans Administration Hosp	Hines	Illinois
United States	Hermann Hosp / Univ Texas Health Science Ctr	Houston	Texas
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee
United States	Cedars Sinai / UCLA Med Ctr	Los Angeles	California
United States	Children's Hosp of Los Angeles/UCLA Med Ctr	Los Angeles	California
United States	Harbor - UCLA Med Ctr / UCLA School of Medicine	Los Angeles	California
United States	Los Angeles County - USC Med Ctr	Los Angeles	California
United States	UCLA CARE Ctr	Los Angeles	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Dr Brian Buggy	Milwaukee	Wisconsin
United States	Great Lakes Hemophilia Foundation	Milwaukee	Wisconsin
United States	Milwaukee County Med Complex	Milwaukee	Wisconsin
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Louisiana Comprehensive Hemophilia Care Ctr	New Orleans	Louisiana
United States	Louisiana State Univ Med Ctr / Tulane Med School	New Orleans	Louisiana
United States	Tulane Univ School of Medicine	New Orleans	Louisiana
United States	Bellevue Hosp / New York Univ Med Ctr	New York	New York
United States	Beth Israel Med Ctr / Peter Krueger Clinic	New York	New York
United States	Cornell Univ Med Ctr	New York	New York
United States	Mem Sloan - Kettering Cancer Ctr	New York	New York
United States	Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Saint Luke's - Roosevelt Hosp Ctr	New York	New York
United States	Nebraska Regional Hemophilia Ctr	Omaha	Nebraska
United States	Palo Alto Veterans Adm Med Ctr / Stanford Univ	Palo Alto	California
United States	Univ of Pennsylvania	Philadelphia	Pennsylvania
United States	Hemophilia Ctr of Western PA / Univ of Pittsburgh	Pittsburgh	Pennsylvania
United States	Univ of Pittsburgh Med School	Pittsburgh	Pennsylvania
United States	Univ of Rochester Medical Center	Rochester	New York
United States	Univ of California / San Diego Treatment Ctr	San Diego	California
United States	San Francisco AIDS Clinic / San Francisco Gen Hosp	San Francisco	California
United States	Stanford at Kaiser / Kaiser Permanente Med Ctr	San Francisco	California
United States	Univ of Washington	Seattle	Washington
United States	Baystate Med Ctr of Springfield	Springfield	Massachusetts
United States	Stanford Univ School of Medicine	Stanford	California
United States	SUNY - Stony Brook	Stony Brook	New York
United States	Olive View Med Ctr	Sylmar	California
United States	Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr	Sylmar	California
United States	SUNY / State Univ of New York	Syracuse	New York
United States	Med College of Ohio	Toledo	Ohio
United States	Harbor UCLA Med Ctr	Torrance	California
United States	George Washington Univ Med Ctr	Washington	District of Columbia
United States	Julio Arroyo	West Columbia	South Carolina
United States	Univ of Kansas School of Medicine	Wichita	Kansas
United States	Bowman Gray School of Medicine / Wake Forest Univ	Winston-Salem	North Carolina
United States	Med Ctr of Central Massachusetts	Worcester	Massachusetts
United States	Univ of Massachusetts Med Ctr	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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

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. — View Citation

External Links

•   Click here for more information about Didanosine
•   Click here for more information about Zidovudine