Clinical trial NCT00000773: Phase I Safety and Pharmacokinetics Study of Microparticulate Atovaquone (m-Atovaquone; 566C80) in HIV-Infected and Perinatally Exposed Infants and Children
Official title: Phase I Safety and Pharmacokinetics Study of Microparticulate Atovaquone (m-Atovaquone; 566C80) in HIV-Infected and Perinatally Exposed Infants and Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pneumonia, Pneumocystis Carinii
HIV Infections
Keywords: Pneumonia, Pneumocystis carinii
Antifungal Agents
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Biological Availability
atovaquone
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 24
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: PREVENTION

Brief summary: To determine the safety, tolerance, and pharmacokinetics of a new improved microparticulate suspension formulation of atovaquone administered at one of two dose levels (per 09/30/94 amendment, a third dose level was added) daily for 12 days in HIV-infected and perinatally exposed (per 8/9/95 amendment) infants and children who are at risk of developing Pneumocystis carinii pneumonia (PCP).

Atovaquone has shown prophylactic potential in adults in the treatment of PCP but is poorly absorbed in tablet form. To improve the bioavailability of atovaquone, a new formulation has been prepared as a microparticulate suspension. Since studies in adults have demonstrated substantial safety of this drug, evaluation in children is being pursued.

Detailed description: Atovaquone has shown prophylactic potential in adults in the treatment of PCP but is poorly absorbed in tablet form. To improve the bioavailability of atovaquone, a new formulation has been prepared as a microparticulate suspension. Since studies in adults have demonstrated substantial safety of this drug, evaluation in children is being pursued.

Three cohorts of four patients each (ages 2-12 years, 3 months to less than 2 years, and 1 month to less than 3 months) receive atovaquone daily for 12 days. The oldest age group is treated first. In the absence of unacceptable toxicity, the dose of atovaquone is escalated in subsequent 4-patient cohorts representing each of the age stratifications and (per 9/30/94 amendment) in a separate 4-patient cohort aged 3 months to less than 2 years. If two of four patients in a given cohort experience unacceptable toxicity at the initial dose, two additional patients in the same age range are entered. Blood samples are drawn for pharmacokinetic evaluation. Patients are followed to day 24. Per 9/30/94 amendment, patients aged 3 months to less than 2 years of age who received one of the lower doses may re-enroll in the higher dose cohort after a 1-month washout.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Allowed:

* Zidovudine (AZT).
* Dideoxycytidine (zalcitabine; ddC).
* Didanosine (ddI).
* Nonaminoglycoside, nonmacrolide, and nonsulfonamide antibiotics.
* Factor VIII.
* IVIG.

Patients must have:

* AIDS, documented HIV infection, perinatal exposure to HIV, or risk of developing PCP.
* Normal EKG and chest radiograph.
* No blood or protein on urinalysis.
* Consent of parent or guardian.

Prior Medication:

Allowed:

* Prophylactic TMP/SMX if given no less than 3 days prior to study entry.
* Prophylactic aerosolized pentamidine (or a single intravenous dose of 4.0 mg/kg pentamidine) if given no less than 7 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Anticipated organ system or laboratory abnormalities (other than immune system abnormalities) from the primary disease and its treatment during the study.
* Acute or chronic infections requiring treatment during the study. NOTE:
* Thrush and herpes labialis are allowed if these conditions do not require treatment.
* Diarrhea or vomiting.

Concurrent Medication:

Excluded:

* Trimethoprim/sulfamethoxazole.
* Sulfadoxine and pyrimethamine (Fansidar).
* Primaquine.
* Aspirin.
* Amphotericin B.
* Aminoglycoside antibiotics.
* Sulfonamides.
* Dapsone.
* Benzodiazepines.
* Rifampin.
* Erythromycin, clarithromycin, and azithromycin.
* Digitalis.
* Para-aminosalicylic acid (PAS).
* Isoniazid.
* Anticoagulants.
* Any other investigational therapies.

Patients with the following prior condition are excluded:

* History of G6PD deficiency.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Pediatric AIDS CRS
state: California
city: Chicago
country: United States
facility: Chicago Children's CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane/LSU Maternal/Child CRS
state: Louisiana
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: San Juan
country: Puerto Rico
facility: Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS
Study officials:
name: Hughes W
role: STUDY_CHAIR
name: Dorenbaum A
role: STUDY_CHAIR
References:
citation: Dorenbaum A, Sadler BM, Xu J, Van Dyke RB, Wei LJ, Moye J, McNamara J, Yogev R, Diaz C, Hughes W. Phase I safety and pharmacokinetics (PK) study of micronized atovaquone (m-ATQ) in HIV exposed or infected infants and children. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:117 (abstract no 288)