Comparison of ddI Versus Zidovudine in HIV-Infected Patients

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000979
• Other study ID #: ACTG 116
• Secondary ID: 070V1ACTG 116-AA
• Status: Completed
• Phase: Phase 2
• First received: November 2, 1999
• Last updated: March 11, 2011

Study information

• Verified date: January 2003
• 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, 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1500
• Est. primary completion date: October 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 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 Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections

Intervention

Drug:
• Zidovudine

• Didanosine

Locations

Country	Name	City	State
Puerto Rico	San Juan Veterans Administration Med Ctr	San Juan
United States	Johns Hopkins Hosp	Baltimore	Maryland
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	Cook County Hosp	Chicago	Illinois
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	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	Univ TX Galveston Med Branch	Galveston	Texas
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	Texas Children's Hosp / Baylor Univ	Houston	Texas
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee
United States	Children's Hosp of Los Angeles/UCLA Med Ctr	Los Angeles	California
United States	Los Angeles County - USC Med 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	Charity Hosp / Tulane Univ Med School	New Orleans	Louisiana
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 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 Utah School of Medicine	Salt Lake City	Utah
United States	Univ of California / San Diego Treatment Ctr	San Diego	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	Whitman - Walker Clinic	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 (11)

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 — View Citation

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. — View Citation

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. — 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

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

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. Epub 2005 Feb — 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

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

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. — View Citation

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 — View Citation

* Note: There are 11 references in all — Click here to view all references

External Links

•   Click here for more information about didanosine
•   Click here for more information about zidovudine