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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


Phase 2
3 Months
12 Years
Not Enrolling
Both
Encephalopathies, HIV Infections

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Trial Information

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


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.

Inclusion 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.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Pizzo PA

Investigator Role:

Study Chair

Authority:

United States: Federal Government

Study ID:

ACTG 103

NCT ID:

NCT00000982

Start Date:

Completion Date:

Related Keywords:

  • Encephalopathies
  • HIV Infections
  • Central Nervous System Diseases
  • Acquired Immunodeficiency Syndrome
  • Zidovudine
  • HIV Infections
  • Acquired Immunodeficiency Syndrome
  • Brain Damage, Chronic
  • Delirium
  • Encephalitis
  • Hepatic Encephalopathy
  • Neurotoxicity Syndromes

Name

Location

Duke Univ Med CtrDurham, North Carolina  27710
Natl Cancer Institute / HIV / AIDS Malignancy BranchBethesda, Maryland  20892
Children's Hosp of Washington DC / Children's Natl Med CtrWashington, District of Columbia  20010
Univ of Florida Med CtrJacksonville, Florida  32209
Univ of Maryland at Baltimore / Univ Med CtrBaltimore, Maryland  21201
Walter Reed / USUHS / PediatricsBethesda, Maryland  208894799
Children's Hosp at Albany Med CtrAlbany, New York  12208