The Safety of Different Dose Levels of Zidovudine in HIV-Infected Children

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000983
• Other study ID #: ACTG 128
• Secondary ID: 11103
• Status: Completed
• Phase: Phase 2
• Est. completion date: December 1994

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• Est. completion date: December 1994
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 12 Years

Eligibility

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.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Zidovudine

Locations

Country	Name	City	State
Puerto Rico	Ramon Ruiz Arnau Univ Hosp / Pediatrics	Bayamon
Puerto Rico	San Juan City Hosp	San Juan
Puerto Rico	UPR Children's Hosp / San Juan City Hosp	San Juan
United States	Emory Univ School of Medicine	Atlanta	Georgia
United States	Johns Hopkins Hosp - Pediatric	Baltimore	Maryland
United States	Univ of Maryland at Baltimore / Univ Med Ctr	Baltimore	Maryland
United States	Boston Med Ctr	Boston	Massachusetts
United States	Children's Hosp of Boston	Boston	Massachusetts
United States	Albert Einstein College of Medicine	Bronx	New York
United States	Bronx Lebanon Hosp Ctr	Bronx	New York
United States	Lincoln Hosp Ctr / Pediatrics	Bronx	New York
United States	SUNY / Health Sciences Ctr at Brooklyn / Pediatrics	Brooklyn	New York
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Chicago Children's Memorial Hosp	Chicago	Illinois
United States	Cook County Hosp	Chicago	Illinois
United States	Univ of Illinois College of Medicine	Chicago	Illinois
United States	Holmes Hosp / Univ of Cincinnati Med Ctr	Cincinnati	Ohio
United States	Columbus Children's Hosp	Columbus	Ohio
United States	Kaiser Permanente / UCLA Med Ctr	Downey	California
United States	Duke Univ Med Ctr	Durham	North Carolina
United States	Univ of Connecticut Health Ctr / Pediatrics	Farmington	Connecticut
United States	Ctr for Special Immunology	Fort Lauderdale	Florida
United States	Hermann Hosp / Univ Texas Health Science Ctr	Houston	Texas
United States	Texas Children's Hosp / Baylor Univ	Houston	Texas
United States	Jewish Hosp Ctr of Long Island / Pediatrics	Jamaica	New York
United States	Long Beach Memorial (Pediatric)	Long Beach	California
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	Los Angeles County - USC Med Ctr	Los Angeles	California
United States	UCLA Med Ctr / Pediatric	Los Angeles	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Schneider Children's Hosp / Long Island Jewish Med Ctr	New Hyde Park	New York
United States	Bellevue Hosp / New York Univ Med Ctr	New York	New York
United States	Beth Israel Med Ctr / Pediatrics	New York	New York
United States	Columbia Univ Babies' Hosp	New York	New York
United States	Cornell Univ Med College	New York	New York
United States	Harlem Hosp Ctr	New York	New York
United States	Metropolitan Hosp 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	Children's Hosp of New Jersey / UMDNJ - New Jersey Med Schl	Newark	New Jersey
United States	Children's Hosp of Oakland	Oakland	California
United States	Hemophilia Ctr of Western PA / Univ of Pittsburgh	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	Northern California Pediatric AIDS Treatment Ctr / UCSF	San Francisco	California
United States	Westchester Hosp / New York Med College / Pediatrics	Valhalla	New York
United States	Children's Natl Med Ctr	Washington	District of Columbia
United States	Julio Arroyo	West Columbia	South Carolina
United States	Bowman Gray School of Medicine / North Carolina Baptist Hosp	Winston-Salem	North Carolina
United States	Univ of Massachusetts Med Ctr	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Glaxo Wellcome

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (6)

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)

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. — View 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. — View 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. — View 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

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. — View Citation