| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
•In Stage I, to evaluate the short term safety and tolerability of raltegravir in infants, children and adolescents.
•In Stage I, to evaluate the steady state plasma concentration profiles and pharmacokinetic parameters of raltegravir in infants, children and adolescents. Raltegravir will be added to a stable background therapy which will then be optimized for Cohorts I, II and III (≥2 to <19 years) after obtaining the PK samples. Raltegravir will be initiated simultaneously with a new background regimen in Cohort V (≥4 weeks to <6 months). Subjects in Cohort IV (≥6 months to <2 years) may use either approach.
•In Stage II, chronic dosing, to evaluate the safety and tolerability of raltegravir at the selected dose in combination with optimized background therapy (OBT) in children and adolescents in the age groups ≥4 weeks to <6 months, ≥6 months to <2 years, ≥2 to <6 years, ≥6 to <12 years and ≥12 to <19 years, as assessed by review of the accumulated safety data over 24 weeks.
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| E.2.2 | Secondary objectives of the trial |
•In chronic dosing, to evaluate the safety and tolerability of raltegravir at the selected dose in combination with optimized background therapy (OBT) in study subjects, as assessed by review of the accumulated safety data over 48 weeks.
•To evaluate the antiretroviral activity of raltegravir at study weeks 24 and 48 at the selected dose in combination with OBT in study subjects, as measured by the proportion of subjects achieving HIV RNA below 400 copies/mL, or maintaining a 1-log drop in HIV RNA from baseline.
•To evaluate the immunological activity of raltegravir at the selected dose in combination with OBT in study subjects, as measured by changes in CD4 cell count and changes in CD4 % over 24 and 48 weeks.
•To describe pediatric raltegravir exposure over time, using a population pharmacokinetic modeling approach.
•To develop and implement a raltegravir dried blood spot (DBS) method to be used for pharmacokinetic evaluations in the younger cohorts of P1066.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 effective, medically accepted barrier method of contraception (e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm (excluding nonoxynol-9), intrauterine device [IUD], others) also must be used during the study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission. Use of an IUD may increase the risk of pelvic inflammatory disease.
•Males participating in the study must not participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.
•Subjects will be re-registered within the same cohort if a dose change is recommended by the team.
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| E.4 | Principal 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Toxicity Endpoint:
Termination from treatment due to a suspected adverse drug reaction (SADR)
attributable to the study medication
Death, adverse events of grade 3 or 4 severity
2.Pharmacokinetic Endpoints
Intensive PK: Pharmacokinetic parameters will be determined from plasma concentration-time profiles. Calculated pharmacokinetic parameters will be: area-under-thecurve (AUCtau), maximum plasma concentration (Cmax), time to Cmax (Tmax), and minimum plasma concentration (Cmin).
Population PK: data will be pooled to build a population pharmacokinetic model to assess pediatric raltegravir exposure and possible changes in exposure during the course of the study.
Dried blood spot (DBS) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Plasma HIV RNA PCR (copies/ml)
CD4 count and percent
Genotypic and phenotypic resistance measures
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Botswana |
| Brazil |
| South Africa |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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