Clinical trial NCT00000637: A Randomized Comparative Trial of Zidovudine (AZT) Versus 2',3'-Dideoxyinosine (ddI) Versus AZT Plus ddI in Symptomatic HIV-Infected Children
Official title: A Randomized Comparative Trial of Zidovudine (AZT) Versus 2',3'-Dideoxyinosine (ddI) Versus AZT Plus ddI in Symptomatic HIV-Infected Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Didanosine
Drug Evaluation
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 819
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To compare the effectiveness of treatment with zidovudine (AZT) compared to didanosine (ddI) and compared to the combination of AZT and ddI as determined by survival and disease progression. To compare the relative safety and tolerance of AZT versus ddI versus AZT plus ddI in symptomatic HIV infected children; to compare the virological and immunological parameters in the three treatment groups. AZT has been shown to delay the progression of AIDS in HIV infected individuals. However, bone marrow toxicity is a frequent adverse effect. Also, HIV resistance to AZT sometimes occurs in patients who initially respond to treatment, but later have progression of the disease. Thus, new drug treatments are needed. Studies of ddI in adults and children indicate some effectiveness of the drug. A direct comparison of AZT and ddI treatment in children has not been made. Combination antiviral treatment (AZT plus ddI) may give added therapeutic benefit to children.

Detailed description: AZT has been shown to delay the progression of AIDS in HIV infected individuals. However, bone marrow toxicity is a frequent adverse effect. Also, HIV resistance to AZT sometimes occurs in patients who initially respond to treatment, but later have progression of the disease. Thus, new drug treatments are needed. Studies of ddI in adults and children indicate some effectiveness of the drug. A direct comparison of AZT and ddI treatment in children has not been made. Combination antiviral treatment (AZT plus ddI) may give added therapeutic benefit to children.

Patients are placed by random selection into one of three groups to receive either AZT alone, ddI alone, or AZT and ddI. This is a double-blind study: neither patient nor treating physician knows which group patient is in. If patients are receiving either AZT or ddI alone and they develop drug toxicity (after dose reduction), or if HIV disease progresses, the alternative single drug is offered. If patients receiving both drugs develop drug toxicity (despite dose reduction) or if HIV disease progresses, they discontinue study drug and are offered the best alternative therapy. PER AMENDMENT 6/26/95: Initial monotherapy AZT arm is unblinded and no further crossover therapy for any arm is permitted. Patients who reach crossover criteria on initial blinded ddI or AZT+ddI will be unblinded and permanently discontinued from study drugs.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Allowed:

* Acetaminophen, ibuprofen, or aspirin, but not on a continual basis for \> 72 hours.
* Systemic ketoconazole and fluconazole for acute therapy.

Recommended:

* Prophylaxis for PCP. (Primary prophylaxis with TMP / SMX is encouraged.) IV pentamidine may be used in selected cases if not administered on a weekly basis.

Patients must have the following:

* HIV infection.
* Children randomized prior to their eighteenth birthday are eligible. Co-enrollment in either ACTG 179 or 189 is permitted.

Prior Medication:

Allowed:

* Up to six weeks of antiretroviral or immunomodulator treatment excluding steroids and intravenous immunoglobulin.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

* Active malignancy.
* Pancreatitis or history of pancreatitis within one year prior to study entry associated with compatible symptoms.
* History of uncontrolled seizure disorder.
* Grade 3 or higher peripheral neuropathy.
* Cardiomyopathy.

Concurrent Medication:

Excluded:

* Chemotherapy for malignancy.
* Oral acidifying agents.
* Acetaminophen, ibuprofen, or aspirin on a continual basis for \> 72 hours.
* Ketoconazole or fluconazole for prophylaxis.
* Drugs with potential to cause peripheral neuropathy or pancreatitis should not be given daily for \> 4 weeks.

Patients with the following are excluded:

* Active malignancy.
* Pancreatitis or history of pancreatitis within one year prior to study entry associated with compatible symptoms.
* History of uncontrolled seizure disorder.
* Grade 3 or higher peripheral neuropathy.

Prior Medication:

Excluded:

* Steroids.
* Intravenous immunoglobulin.
* Antiretroviral drugs or specific immunomodulator treatment (excluding steroids and intravenous immunoglobulin) for \> 6 weeks and within 7 days prior to study entry.

Prior Treatment:

Excluded:

* Red blood cell transfusion within four weeks prior to study entry.

Ongoing drug or alcohol use.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham Schl of Med / Pediatrics
state: Alabama
city: Downey
country: United States
facility: Kaiser Permanente / UCLA Med Ctr
state: California
city: La Jolla
country: United States
facility: UCSD Med Ctr / Pediatrics / Clinical Sciences
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial (Pediatric)
state: California
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai / UCLA Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA Med Ctr / Pediatric
state: California
city: Los Angeles
country: United States
facility: Harbor - UCLA Med Ctr / UCLA School of Medicine
state: California
city: Oakland
country: United States
facility: Children's Hosp of Oakland
state: California
city: Pasadena
country: United States
facility: Huntington Memorial Hosp / Children's Hosp of Los Angeles
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: UCSF / Moffitt Hosp - Pediatric
state: California
city: Stanford
country: United States
facility: Stanford Univ School of Medicine / Pediatrics
state: California
city: Denver
country: United States
facility: Children's Hosp of Denver
state: Colorado
city: Farmington
country: United States
facility: Univ of Connecticut Health Ctr
state: Connecticut
city: New Haven
country: United States
facility: Yale Univ Med School
state: Connecticut
city: Washington
country: United States
facility: Georgetown Univ Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Children's Hosp of Washington DC
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ Hosp
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami (Pediatric)
state: Florida
city: Atlanta
country: United States
facility: Emory Univ Hosp / Pediatrics
state: Georgia
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Univ of Illinois College of Medicine / Pediatrics
state: Illinois
city: Chicago
country: United States
facility: Chicago Children's Memorial Hosp
state: Illinois
city: Chicago
country: United States
facility: Univ of Chicago Children's Hosp
state: Illinois
city: Baltimore
country: United States
facility: Univ of Maryland at Baltimore / Univ Med Ctr
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hosp - Pediatric
state: Maryland
city: Boston
country: United States
facility: Children's Hosp of Boston
state: Massachusetts
city: Boston
country: United States
facility: Boston City Hosp / Pediatrics
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Med Ctr of Springfield
state: Massachusetts
city: Worcester
country: United States
facility: Univ of Massachusetts Med Ctr
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hosp of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: St Louis Univ School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson Med School / Pediatrics
state: New Jersey
city: New Brunswick
country: United States
facility: Robert Wood Johnson Med School / Hershey Med Ctr
state: New Jersey
city: Newark
country: United States
facility: Saint Joseph's Hosp and Med Ctr/UMDNJ - New Jersey Med Schl
state: New Jersey
city: Newark
country: United States
facility: Children's Hosp of New Jersey / UMDNJ - New Jersey Med Schl
state: New Jersey
city: Albany
country: United States
facility: Children's Hosp at Albany Med Ctr
state: New York
city: Bronx
country: United States
facility: Lincoln Hosp Ctr
state: New York
city: Bronx
country: United States
facility: Bronx Lebanon Hosp Ctr / Pediatrics
state: New York
city: Bronx
country: United States
facility: Bronx Lebanon Hosp Ctr
state: New York
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Brooklyn
country: United States
facility: King's County Hosp Ctr / Pediatrics
state: New York
city: Brooklyn
country: United States
facility: SUNY - Brooklyn
state: New York
city: Brooklyn
country: United States
facility: SUNY / Health Sciences Ctr at Brooklyn / Pediatrics
state: New York
city: Buffalo
country: United States
facility: Children's Hosp Pact Prog / Children's Hosp of Buffalo
state: New York
city: Great Neck
country: United States
facility: North Shore Univ Hosp
state: New York
city: New Hyde Park
country: United States
facility: Schneider Children's Hosp
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr / Pediatrics
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 College
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: Metropolitan Hosp Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr / Pediatrics
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Med Ctr
state: New York
city: New York
country: United States
facility: Incarnation Children's Ctr / Columbia Presbyterian Med Ctr
state: New York
city: New York
country: United States
facility: Harlem Hosp 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: State Univ of New York at Stony Brook
state: New York
city: Syracuse
country: United States
facility: SUNY Health Sciences Ctr at Syracuse / Pediatrics
state: New York
city: Valhalla
country: United States
facility: Westchester Hosp
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: Cincinnati
country: United States
facility: Cincinnati Children's Hosp / Univ Hosp
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hosp
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hosp of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Saint Christopher's Hosp for Children
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hemophilia Ctr of Western PA / Univ of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hosp / Brown Univ
state: Rhode Island
city: Charleston
country: United States
facility: Med Univ of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: Saint Jude Children's Research Hosp of Memphis
state: Tennessee
city: Dallas
country: United States
facility: Children's Med Ctr of Dallas
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: Seattle
country: United States
facility: Children's Hosp of Seattle
state: Washington
city: Bayamon
country: Puerto Rico
facility: Ramon Ruiz Arnau Univ Hosp / Pediatrics
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico / Univ Children's Hosp AIDS
city: San Juan
country: Puerto Rico
facility: UPR Children's Hosp / UPR School of Medicine
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp
Study officials:
name: Baker C
role: STUDY_CHAIR
name: Englund J
role: STUDY_CHAIR
References:
citation: Raskino C, Pearson DA, Baker CJ, Lifschitz MH, O'Donnell K, Mintz M, Nozyce M, Brouwers P, McKinney RE, Jimenez E, Englund JA. Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team. Pediatrics. 1999 Sep;104(3):e32. doi: 10.1542/peds.104.3.e32.
citation: Grubman S. Pediatric treatment update. GMHC Treat Issues. 1996 Mar;10(3):7-9.
citation: Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring:8-9.
citation: Rogers MF, Mofenson LM, Moseley RR. Reducing the risk of perinatal HIV transmission through zidovudine therapy: treatment recommendations and implications. J Am Med Womens Assoc (1972). 1995 May-Aug;50(3-4):78-82, 93.
citation: Nielsen K, Wei LS, Sim MS, Deveikis A, Keller M, Stiehm ER, Frenkel LM, Bryson YJ. Correlation of clinical progression in human immunodeficiency virus-infected children with in vitro zidovudine resistance measured by a direct quantitative peripheral blood lymphocyte assay. J Infect Dis. 1995 Aug;172(2):359-64. doi: 10.1093/infdis/172.2.359.
citation: Palumbo PE, Raskino C, Fiscus S, Pahwa S, Fowler MG, Spector SA, Englund JA, Baker CJ. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA. 1998 Mar 11;279(10):756-61. doi: 10.1001/jama.279.10.756.
citation: McKinney RE Jr, Wilfert C. Growth as a prognostic indicator in children with human immunodeficiency virus infection treated with zidovudine. AIDS Clinical Trials Group Protocol 043 Study Group. J Pediatr. 1994 Nov;125(5 Pt 1):728-33. doi: 10.1016/s0022-3476(94)70065-6.
citation: James JS. AZT, ddI, and ddC combinations at FDA advisory hearing. Food and Drug Administration. AIDS Treat News. 1996 Apr 5;(no 244):6.
citation: Englund JA, Baker CJ, McKinney RE, Raskino CL, Fowler MG, Lifschitz MC. Results of ACTG 152, a randomized comparative trial of zidovudine (ZDV), didanosine (ddI), and ZDV/ddI combination therapy in symptomatic HIV-infected children. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18:213 (abstract no I150)
citation: Englund JA, Baker CJ, Raskino C, McKinney RE, Petrie B, Fowler MG, Pearson D, Gershon A, McSherry GD, Abrams EJ, Schliozberg J, Sullivan JL. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997 Jun 12;336(24):1704-12. doi: 10.1056/NEJM199706123362403.
citation: Capparelli EV, Englund JA, Connor JD, Spector SA, McKinney RE, Palumbo P, Baker CJ. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol. 2003 Feb;43(2):133-40. doi: 10.1177/0091270002239821.
citation: Chantry CJ, Byrd RS, Englund JA, Baker CJ, McKinney RE Jr; Pediatric AIDS Clinical Trials Group Protocol 152 Study Team. Growth, survival and viral load in symptomatic childhood human immunodeficiency virus infection. Pediatr Infect Dis J. 2003 Dec;22(12):1033-9. doi: 10.1097/01.inf.0000100575.64298.bc.