A Phase I/II, Multicenter, Open-Label, PK, Safety and Efficacy Study to Evaluate Raltegravir in HIV-1 Infected Youth

Phase 1

Conditions: HIV
MedDRA version: 20.0Level: PTClassification code 10020161Term: HIV infectionSystem Organ Class: 10021881 - Infections and infestations
Therapeutic area: Diseases [C] - Virus Diseases [C02]

Registration Number: EUCTR2009-015884-15-Outside-EU/EEA

Lead Sponsor: The National Institute of Allergy and Infectious Diseases (NIAID) and The Eunice Kennedy Shriver NICHD

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: A

Sex: All

Target Recruitment: 138

Inclusion Criteria

•Age = 4 weeks (defined as 30 days) to <19 years at study entry.
•Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. The same method may be used at both time points. All samples tested must be whole blood, serum or plasma.
Subjects < 18 months of age. The first test may be any of the following:
- One HIV DNA PCR
- One HIV RNA PCR (quantitative >5,000 copies/mL or qualitative)
- One HIV culture (prior to August 2009)
- One total HIV nucleic acid
Subjects > 18 months of age. The first test may be any of the following:
- Two rapid antibody tests from different manufacturers or based on different principles and epitopes
- One rapid antibody test AND one [enzyme immunoassay (EIA) OR Western blot (WB) OR immunofluorescence OR chemiluminescence]
- One EIA AND one [WB OR immunofluorescence OR chemiluminescence]
- One HIV DNA PCR
- One HIV RNA PCR (quantitative >5,000 copies/mL or qualitative)
- One HIV culture (prior to August 2009)
- One total HIV nucleic acid
If the first test(s) is positive, a second sample collected and tested in an NIH-approved laboratory participating in an appropriate external quality assurance program using any of the tests listed above (except for qualitative RNA assays ).

•Cohorts I, IIA, IIB, and III: On unchanged therapeutic regimen for at least 12 weeks, or treatment experienced (not including therapy to interrupt maternal-infant transmission) but on no treatment for =4 weeks prior to entry. Dose adjustments for growth are permitted with team approval. Formula substitutions (substituting single agents for fixed dose combinations and vice versa of the same ARV) are permitted. Substitutions within class of one antiretroviral for another for toxicity management are allowed within the last 12 weeks.
Cohort IV: Candidate subjects must have received therapy to either interrupt maternal-infant transmission and/or to treat HIV infection.
Cohort V: Candidate subjects must have received therapy to interrupt maternal-infant transmission, but have not received other anti-HIV therapies.
Subjects must have:
- =1 log drop in HIV RNA within 12 weeks prior to the screening visit
OR
- screening HIV RNA is =25,000 copies/mL.
If a subject does not immediately qualify (i.e., there is >1 log drop or HIV RNA is <25,000 copies/mL), then the screening HIV RNA may be repeated within 4-6 weeks.
- If the difference between the screening and repeat HIV RNA is =0.5 log, or if the repeat viral load is higher than original, then the subject is eligible.
- If the difference between the screening and repeat HIV RNA is >0.5 log and the repeat viral load is lower than original, then the subject is not eligible.
Please note that the criteria requiring =1 log drop in HIV RNA within 12 weeks prior to screening or HIV RNA = 25,000 DO NOT APPLY to potential subjects who have not received ARV therapy for =4 weeks prior to entry.
•HIV RNA =1,000 copies/mL at screening.
•Demonstrated ability or willingness to take assigned raltegravir preparation.
•Parent/legal guardian or subject able and willing to provide signed informed consent when applicable.
•Female subjects who are sexually active and potentially able to become pregnant must use two methods of birth control while on study and for three months after stopping study drug. Hormonal birth control alone (e.g., pills, shots, or slow release inserts placed under/on the skin) would not be considered adequate. An

Exclusion Criteria

•Known = Grade 3 of any of the following laboratory tests within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, AST, ALT, lipase, serum creatinine.
•Clinical evidence of pancreatitis.
•Treatment for active tuberculosis (TB) infection or disease.
•History of lactic acidosis in 3 months prior to study entry. (Confirmed lactate levels = 2.0 x ULN in subjects with ALT and AST values >2.5 x ULN with no easily discernable etiology (e.g., acute Hepatitis A, B, C or chronic hepatitis B or C), or in subjects who have new and persistent, otherwise unexplained findings of nausea, vomiting, abdominal pain, abdominal distention, unexplained fatigue and dyspnea.)
•Applicable only to subjects enrolling on Stage II, whose stable background regimen includes atazanavir:
a) Subject has total bilirubin = Grade 4 within 30 days of study entry.
b) Subject has total bilirubin value < Grade 4 but direct bilirubin or concurrent transaminase values are >1.5 x ULN and subject is symptomatic, within 30 days prior to study entry.
•Stage I mini-cohort (initial 4 subjects) only: Current or anticipated use of antiretroviral regimen that includes atazanavir, tenofovir or tipranavir during Stage I. Any other commercially available antiretroviral drugs are acceptable.
•Stage I subjects enrolling after initial 4 subjects: Use of atazanavir, tenofovir or tipranavir prior to completion of the intensive PK. Subjects may optimize therapy using any of these ARVs after completion of intensive PK. If the cohort of 10 fails the PK and/or safety criteria and a dose adjustment is required, subjects whose optimized regimen includes atazanavir, tenofovir or tipranavir will be replaced with a subject whose stable background regimen does not include these ARVs.
•Diagnosis of a new CDC Stage C (per 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less than 13 Years of Age) criteria or opportunistic or bacterial infection diagnosed within 30 days prior to screening and not considered clinically stable.
•Prior treatment with another experimental HIV integrase inhibitor.
•Subject has used immunosuppressive therapy within 30 days prior to beginning raltegravir study treatment. Short courses of corticosteroids (e.g. prednisone or equivalent up to 2 mg/kg/day for two weeks) are permitted.
•Current or anticipated use of any disallowed medications (see Section 4.4).
•Any history of malignancy.
•Subject is currently participating in or has participated in a study with a compound or device that is not commercially available within 30 days of signing informed consent.
•Subjects who are pregnant or breastfeeding. (Infants who are receiving
breastmilk are allowed to enroll.)
•Subject is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study.
•Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator’s opinion, would compromise the outcome of this study.
•For Cohort IV and Cohort V, subject’s caregiver is unable to access clean water supply (as defined by local standards) to re-suspend raltegravir oral granules.