Clinical trial NCT00000979: Comparison of ddI Versus Zidovudine in HIV-Infected Patients
Official title: Comparison of 2',3'-Dideoxyinosine (ddI) (BMY-40900) and Zidovudine in Therapy of Patients With HIV Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Didanosine
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
First posted: 2001-08-31
Enrollment: 1500
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief 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.

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 (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.

Eligibility criteria: 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hosp of Los Angeles/UCLA Med Ctr
state: California
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: Palo Alto
country: United States
facility: Palo Alto Veterans Adm Med Ctr / Stanford Univ
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: Stanford
country: United States
facility: Stanford Univ School of Medicine
state: California
city: Sylmar
country: United States
facility: Olive View Med Ctr
state: California
city: Sylmar
country: United States
facility: Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Mountain States Regional Hemophilia Ctr / Univ of Colorado
state: Colorado
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Washington
country: United States
facility: Whitman - Walker Clinic
state: District of Columbia
city: Washington
country: United States
facility: George Washington Univ Med Ctr
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: G E Morey Jr
state: Florida
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Hines
country: United States
facility: Edward Hines Veterans Administration Hosp
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Wichita
country: United States
facility: Univ of Kansas School of Medicine
state: Kansas
city: New Orleans
country: United States
facility: Charity Hosp / Tulane Univ Med School
state: Louisiana
city: New Orleans
country: United States
facility: Louisiana Comprehensive Hemophilia Care Ctr
state: Louisiana
city: New Orleans
country: United States
facility: Louisiana State Univ Med Ctr / Tulane Med School
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Univ School of Medicine
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: Boston
country: United States
facility: Harvard (Massachusetts Gen Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Boston Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Med Ctr of Springfield
state: Massachusetts
city: Worcester
country: United States
facility: Med Ctr of Central Massachusetts
state: Massachusetts
city: Worcester
country: United States
facility: Univ of Massachusetts Med Ctr
state: Massachusetts
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Omaha
country: United States
facility: Nebraska Regional Hemophilia Ctr
state: Nebraska
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr/Jacobi Med Ctr
state: New York
city: Bronx
country: United States
facility: Jack Weiler Hosp / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Med Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Bronx Veterans Administration / Mount Sinai Hosp
state: New York
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
state: New York
city: Elmhurst
country: United States
facility: City Hosp Ctr at Elmhurst / Mount Sinai Hosp
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr / Peter Krueger Clinic
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: Mem Sloan - Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: Saint Luke's - Roosevelt Hosp Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: SUNY - Stony Brook
state: New York
city: Syracuse
country: United States
facility: SUNY / State Univ of New York
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Winston-Salem
country: United States
facility: Bowman Gray School of Medicine / Wake Forest Univ
state: North Carolina
city: Cincinnati
country: United States
facility: Holmes Hosp / Univ of Cincinnati Med Ctr
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: Toledo
country: United States
facility: Med College of Ohio
state: Ohio
city: Hershey
country: United States
facility: Milton S Hershey Med Ctr
state: Pennsylvania
city: Philadelphia
country: United States
facility: Univ of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hemophilia Ctr of Western PA / Univ of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Med School
state: Pennsylvania
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Knoxville
country: United States
facility: Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
state: Tennessee
city: Galveston
country: United States
facility: Univ TX Galveston Med Branch
state: Texas
city: Houston
country: United States
facility: Hermann Hosp / Univ Texas Health Science Ctr
state: Texas
city: Houston
country: United States
facility: Texas Children's Hosp / Baylor Univ
state: Texas
city: Salt Lake City
country: United States
facility: Univ of Utah School of Medicine
state: Utah
city: Hampton
country: United States
facility: Dr Stephen L Green
state: Virginia
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
city: Milwaukee
country: United States
facility: Dr Brian Buggy
state: Wisconsin
city: Milwaukee
country: United States
facility: Milwaukee County Med Complex
state: Wisconsin
city: Milwaukee
country: United States
facility: Great Lakes Hemophilia Foundation
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: San Juan Veterans Administration Med Ctr
Study officials:
name: R Dolin
role: STUDY_CHAIR
name: M Fischl
role: STUDY_CHAIR
References:
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.
citation: 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. doi: 10.1097/00005650-199407000-00005.
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.
citation: Schooley RT. Correlation between viral load measurements and outcome in clinical trials of antiviral drugs. AIDS. 1995 Dec;9 Suppl 2:S15-S19.
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. doi: 10.7326/0003-4819-121-4-199408150-00005.
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. doi: 10.1097/00042560-199510020-00009.
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. doi: 10.1097/00042560-199708150-00004.
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 (1988). 1993 Nov;6(11):1212-23.
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 plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS Clinical Trials Group Protocol 116A/116B/117 Team. J Infect Dis. 1996 Oct;174(4):696-703. doi: 10.1093/infdis/174.4.696.
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. doi: 10.1093/infdis/174.4.704.
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. doi: 10.1086/427877. Epub 2005 Feb 18.