Clinical trial NCT00000983: The Safety of Different Dose Levels of Zidovudine in HIV-Infected Children
Official title: A Randomized Blinded Trial To Evaluate the Safety and Tolerance of High Versus Low Dose Zidovudine Administered to Children With Human Immunodeficiency Virus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Acquired Immunodeficiency Syndrome
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 400
Sex: ALL
Minimum age (years): 3
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To evaluate and compare differences in tolerance and side effects associated with two different dosages of zidovudine (AZT) when used to treat children with HIV infection. Other goals are to evaluate and compare the degree of change in neurodevelopmental disease and determine whether there are differences in the rate and degree of toxicities associated with one versus the other dosage.

AZT has been shown to decrease the death rate and frequency of opportunistic infections in certain adult patients with symptomatic HIV infection. Thus, it is likely that symptomatic HIV infected children may also benefit from AZT. Studies of the safety and pharmacokinetics (blood levels) in children have indicated that AZT can be given to children in doses that can be tolerated and that can be assumed to be therapeutic. Those currently taking care of infected children no longer feel it is ethical to conduct an AZT/placebo (inactive substance) trial. In addition, given the information learned from studies of adult patients that shows effectiveness of AZT at lower doses, experience with an equivalent lower dose in children needs to be studied.

Detailed description: AZT has been shown to decrease the death rate and frequency of opportunistic infections in certain adult patients with symptomatic HIV infection. Thus, it is likely that symptomatic HIV infected children may also benefit from AZT. Studies of the safety and pharmacokinetics (blood levels) in children have indicated that AZT can be given to children in doses that can be tolerated and that can be assumed to be therapeutic. Those currently taking care of infected children no longer feel it is ethical to conduct an AZT/placebo (inactive substance) trial. In addition, given the information learned from studies of adult patients that shows effectiveness of AZT at lower doses, experience with an equivalent lower dose in children needs to be studied.

All participants are randomized to receive AZT at 1 of 2 doses. Patients are stratified according to whether CD4 cell counts are \> or \< 500 cells/mm3 as well as whether symptoms are mild to moderate or if patients have lymphocytic interstitial pneumonitis (LIP). Medication is dispensed every other week for the first 8 weeks and monthly until week 104, then either monthly or every 3 months. Safety and effectiveness of the treatment program are evaluated at 6-month intervals to assess whether it is appropriate to continue the study as originally designed. Patients are evaluated every 2 weeks for the first 8 weeks, monthly until week 104, every 3 months until week 208, and then every 6 months thereafter.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

AMENDED:

* 03-19-91 Prophylaxis for PCP is recommended according to current practice guidelines. As per published recommendations, primary prophylaxis with TMP / SMX on a M-T-W basis is encouraged.

Allowed:

* Immunoglobulin therapy as single dose exposure prophylaxis or for children with hypogammaglobulinemia.
* Trimethoprim / sulfamethoxazole (TMP / SMX) and parenteral or aerosolized pentamidine for prophylaxis for Pneumocystis carinii pneumonia for children with AIDS and/or CD4+ counts = or \< 500 cells/mm3.
* Systemic ketoconazole and acyclovir, or oral nystatin for acute therapy.
* Aerosol ribavirin for short-term treatment of acute respiratory syncytial virus (RSV).

AMENDED:

* 9/17/90 enrollment is limited to children \< 6 years of age.
* Original design:
* Patients must have the following:
* Parent or guardian available to give written informed consent.
* Laboratory evidence of HIV infection.
* Children \< 15 months of age, with CD4+ cell count \> 500 cells/mm3, who are thought to have acquired HIV through perinatal transmission and whose only laboratory evidence of HIV infection is a positive antibody test, must also have one or more of the laboratory criteria described in Disease Status AND one or more of the disease criteria that are required of children \> 15 months old with CD4+ cell counts \> 500 cells/mm3.

Prior Medication:

Allowed:

* Aerosol ribavirin.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

Previous AIDS-defining opportunistic infection or neoplasms as specified by the CDC surveillance criteria for AIDS.

* Previous unexplained recurrent, serious bacterial infections (two or more within a 2-year period) including sepsis, meningitis, pneumonia, abscess of an internal organ, and bone/joint infections caused by Haemophilus, Streptococcus, or other pyogenic bacteria.
* Qualifying for entrance criteria to zidovudine (AZT) + or - gammaglobulin (ACTG 051).
* Encephalopathy.
* Failure to thrive (defined as a child who crosses two percentile lines on the growth chart or child who is \< fifth percentile and does not follow curve) and/or oral candidiasis for at least 2 months despite appropriate topical therapy.
* Lymphocytic interstitial pneumonitis (LIP) with steroid dependency or requiring supplemental oxygen.
* Preexisting malignancies.

Concurrent Medication:

AMENDED:

* 03-19-91 Prophylaxis with antiviral or antifungals agents, except for PCP prophylaxis is prohibited.
* Drugs that are metabolized by hepatic glucuronidation should be used with caution.

Excluded:

* Prophylaxis for oral candidiasis or otitis media or other infections (sinusitis, urinary tract infections).
* Immunoglobulin therapy not specifically allowed.
* Ketoconazole, acyclovir, or nystatin for prophylaxis.
* Drugs that are metabolized by hepatic glucuronidation and might alter metabolism of zidovudine (AZT).

Patients with the following are excluded:

* Previous AIDS-defining opportunistic infection or neoplasms as specified by the CDC surveillance criteria for AIDS.
* Previous unexplained recurrent, serious bacterial infections (two or more within a 2-year period) including sepsis, meningitis, pneumonia, abscess of an internal organ, and bone/joint infections caused by Haemophilus, Streptococcus, or other pyogenic bacteria.
* Qualifying for entrance criteria to zidovudine (AZT) + or - gammaglobulin (ACTG 051).
* Encephalopathy.
* Failure to thrive (defined as a child who crosses two percentile lines on the growth chart or child who is \< fifth percentile and does not follow curve) and/or oral candidiasis for at least 2 months despite appropriate topical therapy.
* Lymphocytic interstitial pneumonitis (LIP) with steroid dependency or requiring supplemental oxygen.
* Preexisting malignancies.

Prior Medication:

Excluded within 2 weeks of study entry:

* Any other experimental therapy or drugs that cause prolonged neutropenia or significant nephrotoxicity.

Excluded within 1 month of study entry:

* Antiretroviral agents.
* Immunomodulating agents including immunoglobulin, interferon, isoprinosine, and IL-2.

Excluded within 2 months of study entry:

* Systemic ribavirin for retroviral therapy.

Prior Treatment:

Excluded within 1 month of study entry:

* Lymphocyte or red blood cell transfusions.

Active alcohol or drug abuse.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Downey
country: United States
facility: Kaiser Permanente / UCLA Med Ctr
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial (Pediatric)
state: California
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: 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: Oakland
country: United States
facility: Children's Hosp of Oakland
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: Northern California Pediatric AIDS Treatment Ctr / UCSF
state: California
city: Farmington
country: United States
facility: Univ of Connecticut Health Ctr / Pediatrics
state: Connecticut
city: Washington
country: United States
facility: Children's Natl Med Ctr
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Ctr for Special Immunology
state: Florida
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory Univ School of Medicine
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
state: Illinois
city: Chicago
country: United States
facility: Chicago Children's Memorial 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 Med Ctr
state: Massachusetts
city: Worcester
country: United States
facility: Univ of Massachusetts Med Ctr
state: Massachusetts
city: Newark
country: United States
facility: Children's Hosp of New Jersey / UMDNJ - New Jersey Med Schl
state: New Jersey
city: Bronx
country: United States
facility: Lincoln 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: SUNY / Health Sciences Ctr at Brooklyn / Pediatrics
state: New York
city: Jamaica
country: United States
facility: Jewish Hosp Ctr of Long Island / Pediatrics
state: New York
city: New Hyde Park
country: United States
facility: Schneider Children's Hosp / Long Island Jewish Med Ctr
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
state: New York
city: New York
country: United States
facility: Columbia Univ Babies' Hosp
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: Valhalla
country: United States
facility: Westchester Hosp / New York Med College / Pediatrics
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 / North Carolina Baptist Hosp
state: North Carolina
city: Cincinnati
country: United States
facility: Holmes Hosp / Univ of Cincinnati Med Ctr
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hosp
state: Ohio
city: Pittsburgh
country: United States
facility: Hemophilia Ctr of Western PA / Univ of Pittsburgh
state: Pennsylvania
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
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: Bayamon
country: Puerto Rico
facility: Ramon Ruiz Arnau Univ Hosp / Pediatrics
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp
city: San Juan
country: Puerto Rico
facility: UPR Children's Hosp / San Juan City Hosp
Study officials:
name: M Brady
role: STUDY_CHAIR
name: P Weintrub
role: STUDY_CHAIR
References:
citation: Lathey JL, Marschner IC, Kabat B, Spector SA. Deterioration of detectable human immunodeficiency virus serum p24 antigen in samples stored for batch testing. J Clin Microbiol. 1997 Mar;35(3):631-5. doi: 10.1128/jcm.35.3.631-635.1997.
citation: Fiscus SA, Welles SL, Spector SA, Lathey JL. Length of incubation time for human immunodeficiency virus cultures. J Clin Microbiol. 1995 Jan;33(1):246-7. doi: 10.1128/jcm.33.1.246-247.1995.
citation: Brady MT, McGrath N, Brouwers P, Gelber R, Fowler MG, Yogev R, Hutton N, Bryson YJ, Mitchell CD, Fikrig S, Borkowsky W, Jimenez E, McSherry G, Rubinstein A, Wilfert CM, McIntosh K, Elkins MM, Weintrub PS. Randomized study of the tolerance and efficacy of high- versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128). Pediatric AIDS Clinical Trials Group. J Infect Dis. 1996 May;173(5):1097-106. doi: 10.1093/infdis/173.5.1097.
citation: Brady M, McGrath N, Brouwers P, Gelber R, Fowler M, Weintrub P. Controlled trial of tolerance and efficacy of zidovudine (ZDV) at standard and low dose in children (ACTG 128). The Pediatric AIDS Clinical Trials Group. Int Conf AIDS. 1994 Aug 7-12;10(1):79 (abstract no 268B)
citation: Parent D, Ellner J, Hafner R, Williams M, Jacobs P, Hojczyk P. A phase II/III trial of Rifampin (RIF) Ciprofloxach (CIPRO), Clofazimine (CLOF), Ethambutol (ETH), +/- Amikacin (AK) in the treatment (RX) of Disseminated Mycobacterium avium (MA) infection in HIV-infected individuals (PTS). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2:56
citation: Perrier M, Schwarz T, Gonzalez O, Brounts S. Squamous cell carcinoma invading the right temporomandibular joint in a Belgian mare. Can Vet J. 2010 Aug;51(8):885-7.