A Study of Didanosine Use Alone or in Combination With Zidovudine in Infants Exposed to or Infected With HIV

A Phase I Evaluation of the Safety and Toxicity of Zidovudine and Didanosine in Combination in HIV-Infected or Exposed Infants and a Phase II Study of the Effect of Didanosine vs. Combination Therapy With Zidovudine and Didanosine on HIV-1 RNA in Infants With HIV Infection

To determine the pharmacokinetics, safety, and efficacy of didanosine (ddI) alone or in combination with zidovudine (AZT) in HIV-infected infants.

PER AMENDMENT 4/8/97: Part A study objectives are completed. Part B objectives: To assess the safety, toxicity, and tolerability and to compare anti-HIV activity, as measured by change in log10 RNA, of the two study arms.

Early treatment of HIV-infected infants with antiretroviral agents may prevent the early and rapid decline of CD4 count and immunologic function. Combination therapy may be preferred over monotherapy, since resistance to a single agent can develop rapidly. Currently, there is little information on ddI monotherapy in young infants less than 90 days and no information on the use of combination therapy in this population.

Early treatment of HIV-infected infants with antiretroviral agents may prevent the early and rapid decline of CD4 count and immunologic function. Combination therapy may be preferred over monotherapy, since resistance to a single agent can develop rapidly. Currently, there is little information on ddI monotherapy in young infants less than 90 days and no information on the use of combination therapy in this population.

In Part A, a cohort of patients younger than 28 days (was less than 120 days; amended 6/20/95) of age receives open-label ddI monotherapy for 1 week before initiation of AZT/ddI combination therapy. After pharmacokinetic data are obtained, an additional cohort of patients receives ddI at a higher dose. An age-adjusted dose for ddI is determined for use in Part B. (NOTE: As of 2/13/95, Part A has completed accrued for infants 29 to 120 days of age.) Part B patients less than 90 days of age (was less than 180 days of age; amended 6/20/95) are randomized, on a double-blind basis, to receive ddI or AZT/ddI. All patients continue treatment until 12 months after the last patient on Part B is enrolled. PER AMENDMENT 4/8/97: Part A of this protocol is closed with accrual objectives met. Part B of the study will remain open for patient accrual until 6/2/97. Part B is designed as a 2-arm, randomized, double-blind study to assess safety, toxicity and tolerability as well as anti-HIV activity of ddI or AZT/ddI.

Inclusion Criteria

Concurrent Medication:

Recommended:

• PCP prophylaxis.

Allowed:

• Acetaminophen if not on a continual basis.

NOTE:

• Drugs that are metabolized by hepatic glucuronidation or that are associated with occurrence of pancreatitis are allowed but should be used with caution.

Patients must have at least one of the following:

• Documented HIV infection.
• Been born to an HIV-infected woman and receiving AZT.

PER AMENDMENT 4/8/97:

• Number 2 above no longer required with closure of Part A of study.
• Patients must have signed, informed consent of parent or legal guardian.

PER 6/20/95 AMENDMENT, patients in Part A must be less than 28 days of age and those in Part B must be less than 90 days of age.

PER 7/7/94 AMENDMENT, patients in Part A were less than 120 days of age and those in Part B were less than 180 days of age.

NOTE:

• All patients must have been more than 34 weeks gestation at birth.

Prior Medication:

Allowed:

• Prior vaccine therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Pancreatitis.
• Clinically unstable condition.
• Current participation on a vaccine trial or, for Part A, a perinatal trial if of indeterminate infection status.

Concurrent Medication:

Excluded:

• Vaccine therapy.

Patients with the following prior condition are excluded:

• Pancreatitis at any time since birth.

Prior Medication:

Excluded in Part B patients only:

• More than 90 days of prior antiretroviral or immunomodulator therapy, exclusive of therapy received in utero.