SCHEMA IMPAACT P1093

Phase I/II Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in

HIV-1 Infected Infants, Children and Adolescents

DESIGN:                                Phase I/II, multi-center, open-label, non-comparative intensive PK and safety study

SAMPLE SIZE:                      Approximately 160 HIV-1 infected infants, children and adolescents to provide a minimum of 120 evaluable* subjects:

Stage I – a minimum of 10 subjects, per cohort

Stage II – a minimum of 60 evaluable subjects across all cohorts

*Evaluable is defined as having been treated exclusively on the dose determined to be optimal for a given age cohort and having either completed 24 (or 48) weeks of exposure to the study drug or having been classified as a safety failure, due to a study drug related adverse event occurring during the first 24 (or 48) weeks of treatment.

POPULATION:                      HIV infected infants, children and adolescents aged ≥ 4 weeks to < 18 years of age.

STRATIFICATION:              All subjects enrolled into the study will be stratified at screening into one of nine age specific cohorts as follows:

Cohort I:         Adolescents ≥ 12 to <18 years of age

(Film-coated Tablets)

Cohort IIA:    Children ≥ 6 to <12 years of age

(Film-coated Tablets)

Cohort IIB:     Children ≥ 6 to <12 years of age

(Granules for suspension)

Note: Dispersible tablets may also be evaluated in this cohort if requested by regulatory authorities.

Cohorts III:    Children ≥ 2 to < 6 years of age

(Granules for suspension)

Cohort III-DT: Children ≥ 2 to < 6 years of age

(Dispersible Tablets)

Cohort IV:      Children ≥ 6 months to < 2 years of age

(Granules for suspension)

Cohort IV-DT: Children ≥ 6 months to < 2 years of age

(Dispersible Tablets)

Cohort V:        Infants > 4 weeks to < 6 months of age

(Granules for suspension)

Cohort V-DT: Infants > 4 weeks to < 6 months

(Dispersible Tablets)

REGIMEN:                            Three different dolutegravir (DTG) formulations will be evaluated as follows: film-coated tablets; a granule formulation for suspension; and dispersible tablets. The final dose for each formulation and each age cohort will be selected based on real-time PK evaluations and safety to achieve exposure similar to that observed in adults treated with 50 mg QD.

See Sections 5.0-5.4 for details on DTG drug regimens, formulations, drug supply and handling.

TREATMENT DURATION:  Stages I and II: 48 Weeks

Long Term Safety Follow-up: All subjects who successfully complete 48 weeks of DTG treatment will continue to receive DTG for a minimum of three years as part of long term safety follow-up. (See Section 6.3 and Appendix IE for details).

HYPOTHESIS:                      DTG will be generally well tolerated and demonstrate an acceptable safety profile, adequate PK and antiviral activity when used concurrently with an optimized background therapy (OBT) in HIV-1 infected infants, children and adolescents.

OBJECTIVES:

PRIMARY OBJECTIVES

1.   To select a dose for each formulation of DTG for chronic dosing in infants, children and adolescents that achieves similar exposure to the DTG 50 mg once daily dose in adults.

2.   To determine the safety and tolerability of DTG in HIV-1 infected infants, children and adolescents at 24 and 48 weeks.

3.   To evaluate the steady-state pharmacokinetics of DTG in combination with other antiretrovirals (OBT) in treatment-experienced and/or treatment-naïve HIV-1 infected infants, children and adolescents and to determine the dose of DTG that achieves a targeted AUC24 (primary PK endpoint) and C24h (secondary PK endpoint) in this population.

SECONDARY OBJECTIVES

1.   To evaluate the antiviral activity of DTG in combination with an OBT by measuring virologic response in infants, children and adolescents at 24 and 48 weeks.

2.   To evaluate the effect on immunologic response from baseline to 24 and 48 weeks.