Trial record 7 of 12 for:    Neurological Complications of AIDS

A Study of Azidothymidine in HIV-Infected Children

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000982
First received: November 2, 1999
Last updated: March 11, 2011
Last verified: October 1996
  Purpose

AMENDED 07/07/93: To evaluate whether continuous infusion AZT will impact neurodevelopmental deficits associated with HIV infection or alter rate of encephalopathy progression in children who have failed to improve or shown progression of these deficits despite optimal AZT therapy.

AMENDED: To assess whether didanosine (ddI) will be better tolerated than AZT administered by either continuous intravenous delivery or oral administration (ddI arm removed per amended version).To determine whether ddI will achieve comparable clinical efficacy as the continuous intravenous route of delivery of AZT, and to assess whether either or both of these regimens are superior to that achieved with an intermittent AZT dosage schedule. To determine whether there are differences in patient or parent (guardian) compliance between the three treatment regimens. Original design: To determine whether the pharmacokinetic profile (bloodstream levels) of zidovudine (AZT) influences its effectiveness on HIV infection in children. That is, the study seeks to find out whether there is a difference in the effect of AZT when given as a continuous intravenous infusion (and, if available, an oral sustained release dose) compared to an intermittent (not continuous) dose given orally every 6 hours. The study also plans to determine (1) whether there are differences in the tolerance and side effects associated with AZT when given on an intermittent schedule as opposed to a steady-state schedule; (2) the extent of variation from patient to patient in AZT levels and whether the plasma and cerebrospinal fluid levels of AZT are related to the degree of therapeutic effectiveness; and (3) whether there are differences in the response of children who acquired HIV infection perinatally (just before, during, or just after the time of birth) versus those who acquired HIV infection by transfusion.

One of the most serious effects of HIV disease in children is neuropsychological deterioration (relating to mental and nervous system functioning). This complication affects the vast majority of HIV infected children. A previous study of continuous intravenous administration of AZT in pediatric patients with HIV infection showed consistent and dramatic improvements of symptoms in all patients that had shown neurodevelopmental deficits or abnormalities. These improvements were seen within 3 to 4 weeks after AZT treatment was started. Neurodevelopmental improvements have been sustained on AZT, usually showing steady improvement which, in some patients, was associated with restoration of pre-HIV intellectual and neurological function. This study also showed an increase in the IQ scores of children receiving continuous infusion of AZT who did not have overt clinical evidence of encephalopathy (disease of the brain). Thus changes in cognitive function may be among the earliest signs of AIDS encephalopathy and underscores the need to start therapies that will treat the central nervous system in patients who appear to be clinically intact. A study comparing continuous infusion to intermittent dosing of AZT showed a significant increase in IQ scores for those children receiving the continuous dose compared to those treated with the intermittent schedule. Although a portable infusion pump allows patients to receive continuous infusion of AZT, a sustained release oral formulation that could provide a continuous release of AZT into the bloodstream would be highly desirable.


Condition Intervention Phase
Encephalopathies
HIV Infections
Drug: Zidovudine
Drug: Didanosine
Phase 2

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: A Randomized Trial To Evaluate the Impact of Maintaining Steady-State Concentrations of Azidothymidine (AZT) Versus an Intermittent Schedule of AZT Delivery in Children With Symptomatic HIV Infection

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 75
Primary Completion Date: September 1996 (Final data collection date for primary outcome measure)
Detailed Description:

One of the most serious effects of HIV disease in children is neuropsychological deterioration (relating to mental and nervous system functioning). This complication affects the vast majority of HIV infected children. A previous study of continuous intravenous administration of AZT in pediatric patients with HIV infection showed consistent and dramatic improvements of symptoms in all patients that had shown neurodevelopmental deficits or abnormalities. These improvements were seen within 3 to 4 weeks after AZT treatment was started. Neurodevelopmental improvements have been sustained on AZT, usually showing steady improvement which, in some patients, was associated with restoration of pre-HIV intellectual and neurological function. This study also showed an increase in the IQ scores of children receiving continuous infusion of AZT who did not have overt clinical evidence of encephalopathy (disease of the brain). Thus changes in cognitive function may be among the earliest signs of AIDS encephalopathy and underscores the need to start therapies that will treat the central nervous system in patients who appear to be clinically intact. A study comparing continuous infusion to intermittent dosing of AZT showed a significant increase in IQ scores for those children receiving the continuous dose compared to those treated with the intermittent schedule. Although a portable infusion pump allows patients to receive continuous infusion of AZT, a sustained release oral formulation that could provide a continuous release of AZT into the bloodstream would be highly desirable.

AMENDED 07/07/93: Children with progressive encephalopathy who have received a minimum of 3 months of oral or intermittent AZT or who have failed to improve following 6 months of optimal AZT will receive continuous infusion AZT via a portable infusion pump.

AMENDED: The oral sustained release has been dropped and is now oral ddI. Added has been a planned stratification for randomization for patients who received any antiretroviral therapy 4 or more weeks prior to study entry. The informed consent was modified to reflect ddI toxicities from adult studies. Computerized Tomography radiation dosimetry is now included.

AMENDED: Dropping the ddI component and open only to children with encephalopathy meaning they are losing milestones, this is equal to a P2 CDC rating . Testing the difference in intermediate vs continuous AZT. 12/1990. Original design: Children are first evaluated for randomization according to whether they have or do not have evidence of neurodevelopmental deficits at the time of the initial pretreatment evaluation. Patients are assigned to 1 of 3 groups, to receive AZT (1) by continuous infusion; (2) by oral, intermittent (every 6 hours) dosing; or (3) by oral sustained-release dosing. If the oral sustained-release formulation is not available when this study begins, it will begin with only the first 2 groups. The sustained release preparation will be evaluated as soon as it is available. Patients will be tested to measure physical or biological improvement in neurodevelopmental function.

  Eligibility

Ages Eligible for Study:   3 Months to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Steroids for children with lymphocytic interstitial pneumonitis (LIP) who are steroid dependent.
  • Maintenance amphotericin B and antituberculosis chemotherapy.
  • Immunoglobulin therapy for children who develop at least three serious bacterial infections while receiving zidovudine (AZT) therapy.
  • Prophylactic therapy for children who have had a previous episode of Pneumocystis carinii pneumonia (PCP) and who are receiving such therapy.

AMENDED 07/07/93:

Only HIV-related encephalopathy patients eligible (i.e., children with progressive encephalopathy who have received a minimum of 3 months of oral or intermittent AZT or who have failed to improve following 6 months of optimal AZT).

ORIGINAL DESIGN:

Eligibility criteria used are similar to those being used in the "Multicenter Trial to Evaluate Oral Retrovir in the Treatment of Children with Symptomatic HIV Infection," currently Protocol 88 C-92a.

Children are included:

  • With overt encephalopathy as well as those who may have a subclinical cognitive impairment.
  • Children must have laboratory evidence of HIV infection as demonstrated by either a positive viral culture (blood or cerebrospinal fluid) or detectable serum P24 antigen or repeatedly positive test for HIV antibody. HIV antibody must be determined by federally licensed ELISA test and confirmed by Western blot.
  • Children with AIDS or ARC must have at least one of the following laboratory criteria indicative of immunologic abnormality:
  • Hypergammaglobulinemia (IgG or IgA) defined as immunoglobulin values greater than upper limit of the age-adjusted normal.
  • Hypogammaglobulinemia (IgG or IgA) defined as immunoglobulin levels less than lower limit of the age-adjusted normal.
  • Absolute depression in CD4+ cells of 500 cells/mm3 or less.
  • Decreased helper/suppressor ratio of 1.0 or less.
  • Depressed in vitro mitogen response to at least one antigen (pokeweed, phytohemagglutinin, concanavalin A, Staphylococcus aureus, tetanus toxoid, Candida).
  • Parent or guardian available to give written informed consent.

Prior Medication:

Allowed within 4 weeks of study entry:

  • Immunoglobulin for thrombocytopenia.

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

  • Serious bacterial, fungal, or parasitic infections requiring parenteral therapy, at the time of study entry.

Concurrent Medication:

Excluded:

  • Clofazimine, ansamycin (or other experimental agents or agents that may modify zidovudine (AZT) toxicity or safety) for active chronic opportunistic infection at time of study entry.
  • Chronic use of drugs that are metabolized by hepatic glucuronidation (and may alter the metabolism of AZT) (e.g., acetaminophen).
  • Prophylaxis for Pneumocystis carinii pneumonia (PCP) for children who have not had a previous episode of PCP, oral candidiasis, or otitis media.
  • Immunoglobulin therapy not specifically allowed.

Patients with the following are excluded:

  • Serious bacterial, fungal, or parasitic infections requiring parenteral therapy, at the time of study entry.
  • Lymphocytic interstitial pneumonitis (LIP) and no additional AIDS-defining indicator disease as specified in the CDC Surveillance Case Definition for AIDS.

Prior Medication:

Excluded within 4 weeks of study entry:

  • Other antiretroviral agents including ribavirin, HPA-23, dideoxycytosine (ddC), soluble CD4, and dideoxyadenosine (ddA) / didanosine (ddI).
  • Immunomodulating agents including steroids, interferon, isoprinosine, and IL-2 not specifically allowed.
  • Immunoglobulin not specifically allowed.
  • Excluded within 2 weeks of study entry:
  • Any other experimental therapy.
  • Drugs that cause prolonged neutropenia or significant nephrotoxicity.

Prior Treatment:

Excluded within 4 weeks of study entry:

  • Lymphocyte transfusion for immune reconstitution.
  • Excluded within 3 months of study entry:
  • Bone marrow transplant.

Risk Behavior:

Excluded:

  • Active alcohol or drug abuse.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000982

Locations
United States, District of Columbia
Children's Hosp of Washington DC / Children's Natl Med Ctr
Washington, District of Columbia, United States, 20010
United States, Florida
Univ of Florida Med Ctr
Jacksonville, Florida, United States, 32209
United States, Maryland
Univ of Maryland at Baltimore / Univ Med Ctr
Baltimore, Maryland, United States, 21201
Natl Cancer Institute / HIV / AIDS Malignancy Branch
Bethesda, Maryland, United States, 20892
Walter Reed / USUHS / Pediatrics
Bethesda, Maryland, United States, 208894799
United States, New York
Children's Hosp at Albany Med Ctr
Albany, New York, United States, 12208
United States, North Carolina
Duke Univ Med Ctr
Durham, North Carolina, United States, 277103499
Sponsors and Collaborators
Investigators
Study Chair: Pizzo PA
  More Information

Additional Information:
No publications provided

ClinicalTrials.gov Identifier: NCT00000982     History of Changes
Other Study ID Numbers: ACTG 103, NCI 89 C-102C
Study First Received: November 2, 1999
Last Updated: March 11, 2011
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Central Nervous System Diseases
Acquired Immunodeficiency Syndrome
Zidovudine

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Anti-HIV Agents
Brain Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Central Nervous System Diseases
Nervous System Diseases
Didanosine
Zidovudine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2014