Clinical trial NCT00012519: Ritonavir and Indinavir in Children Failing Other Anti-HIV Treatment
Official title: A Phase I/II Trial of Ritonavir and Indinavir in Children Failing Other Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: Dose-Response Relationship, Drug
Drug Therapy, Combination
HIV Protease Inhibitors
Ritonavir
Indinavir
Anti-HIV Agents
Viral Load
Pharmacokinetics
Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2001-08-31
Enrollment: 29
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Both ritonavir (RTV) and indinavir (IDV) are approved by the FDA to treat HIV, but IDV has not been approved for use in children and the doses for the combination of the two drugs has not been studied in children. The purpose of this study is to find a combination of RTV and IDV that is safe, well tolerated, and produces drug levels in the blood of children that are comparable to effective drug levels in the blood of adults. The effectiveness of the drug combination in decreasing the amount of virus in the body will also be studied. The children enrolled in this study will have high HIV viral loads despite taking anti-HIV drugs.

Detailed description: Combination regimens of RTV and IDV in adults offer the benefit of two potent antiretroviral agents, convenience of twice-daily dosing, unrestricted timing of meals, and fewer renal complications. There are limited, largely anecdotal data from children suggesting that initial virologic response can also be attained in children given IDV with RTV, but there are not sufficient pharmacokinetic data to define appropriate dose regimens. This study will evaluate the clinical feasibility of a combination RTV and IDV regimen for children.

Patients will be stratified on the basis of age/Tanner stage and ability to swallow intact capsules. Patients will be randomized to either Balanced Dose or Low Dose RTV treatment arms. Patients in the Balanced Dose Arm will receive RTV and IDV in approximately equal doses. The Low Dose RTV Arm will receive a dosing ratio of RTV:IDV of approximately 1:3. Patients will have scheduled study visits every 4 weeks for 6 months, then every 3 months for approximately 18 months. Study visits will consist of a medical history, physical exam, and blood and urine tests. Patients will have intensive pharmacokinetic analysis at Week 4 (or 2 weeks after a stable dose of study drugs has been reached) and Week 16. Study visits that include pharmacokinetic analysis will last 9 to 13 hours.

At each study visit, patients will be closely assessed for drug toxicity and virologic response. At the end of the study, patients with good virologic response and no evidence of toxicity may choose to enter a 48 week extension phase and continue taking the combination regimen.

Eligibility criteria: Inclusion Criteria

* HIV infection
* HIV RNA levels \> 10,000 copies/ml within 30 days prior to study entry
* Anti-HIV drug therapy failure while on the same anti-HIV drugs for more than 16 weeks
* Body size above a certain limit (body surface area \> 0.48 m2)
* Acceptable methods of contraception
* Consent of parent or legal guardian

Exclusion Criteria

* Unable to determine HIV genotypic resistance
* HIV resistant to IDV or RTV at study screening
* Previously received IDV and RTV at the same time
* Need treatment with any medication prohibited by the study
* Glucocorticoids for more than 14 days at study entry
* Cancer requiring chemotherapy
* Drugs affecting the immune system, other than IVIG, within 3 months of study entry
* Certain abnormal laboratory results at study entry
* Pregnant or breast-feeding
* Unable to be followed at a PACTG center during the trial

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Gainesville
country: United States
facility: Univ. of Florida College of Medicine-Dept of Peds, Div. of Immunology, Infectious Diseases & Allergy
state: Florida
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Chicago
country: United States
facility: Chicago Children's CRS
state: Illinois
city: New York
country: United States
facility: Metropolitan Hosp. Ctr.
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: New York
country: United States
facility: Harlem Hosp. Ctr. NY NICHD CRS
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Med. Univ., Dept. of Peds.
state: New York
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hosp. CRS
state: Texas
city: Richmond
country: United States
facility: VCU Health Systems, Dept. of Peds
state: Virginia
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
name: Ellen Chadwick
role: STUDY_CHAIR
name: Ram Yogev
role: STUDY_CHAIR
name: Stephen Pelton
role: STUDY_CHAIR
name: Elaine Abrams
role: STUDY_CHAIR
References:
citation: Saah AJ, Winchell GA, Nessly ML, Seniuk MA, Rhodes RR, Deutsch PJ. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrob Agents Chemother. 2001 Oct;45(10):2710-5. doi: 10.1128/AAC.45.10.2710-2715.2001.
citation: van Rossum AM, de Groot R, Hartwig NG, Weemaes CM, Head S, Burger DM. Pharmacokinetics of indinavir and low-dose ritonavir in children with HIV-1 infection. AIDS. 2000 Sep 29;14(14):2209-10. doi: 10.1097/00002030-200009290-00022. No abstract available.
citation: Chadwick EG, Rodman JH, Samson P, Fenton T, Abrams EJ, Nowak B, Pelton SI, Lavoie S, Knapp K, Bambji M, Yogev R, PACTG 1013 Team. Antiviral Activity, Tolerance and Pharmacokinetics of Indinavir with Two Doses of Ritonavir as Salvage Therapy in Children. 10th Conference on Retroviruses and Oppurtunistic Infections. Feb 2003. Abstract 875.