Study To Evaluate Emtricitabine/Tenofovir Alafenamide (F/TAF) in Human Immunodeficiency Virus 1 (HIV-1) Infected Children and Adolescents Virologically Suppressed on a 2- Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (2-NRTI)-Containing Regimen

Study Overview
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Brief Summary
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The primary objective of this study is to confirm the TAF dose and to evaluate the pharmacokinetics (PK) of TAF, safety, and tolerability of F/TAF in HIV-1 infected children and adolescents virologically suppressed (defined as having < 50 copies/mL of HIV-1 ribonucleic acid [RNA] for a period of at least 6 months) while on a stable NRTI containing regimen.

Detailed Description
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Cohorts 2, 3, and 4 will be on a boosted protease inhibitor (PI) or any other 3rd antiretroviral (ARV) agent and will switch their current 2-NRTI-containing regimen to open-label F/TAF while continuing their boosted PI or 3rd agent through 48 weeks. A minimum of 10 participants each in Groups 1 and 2 of Cohort 2, and Cohorts 3 and 4, who are on boosted-atazanavir (ATV) as their 3rd ARV agent will be enrolled. Participants in Cohort 2, Group 1 receive boosted PI agents only. Cohorts 2, 3, and 4 will be enrolled by cohort into a two-part study (Parts A and B). After completion of 48 weeks, all participants will be given the option to participate in an extension phase of the study. Gilead will provide F/TAF until a) The participant turns 18 years old and F/TAF is commercially available for use in adults in the country in which the participant is enrolled or b), F/TAF becomes commercially available for pediatric use in the country in which the participant is enrolled or c), Gilead Sciences elects to terminate development of F/TAF in the applicable country.

Official Title
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A Phase 2/3, Open-Label, Multi-Cohort Switch Study to Evaluate Emtricitabine/Tenofovir Alafenamide (F/TAF) in HIV-1 Infected Children and Adolescents Virologically Suppressed on a 2-NRTI-Containing Regimen

Conditions
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HIV-1

Intervention / Treatment
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* Drug: F/TAF
* Drug: 3rd ARV agent
* Drug: Boosted PIs


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: HIV-1 infected male and female adolescents and children aged 1 month to < 18 years at baseline/Day 1 (according to requirements of the enrolling cohort) Must be able to give written assent prior to any screening evaluations Parent or guardian able to give written informed consent prior to any screening evaluations and willing to comply with study requirements Body weight at screening as follows: Cohort 1: ≥ 35 kg Cohort 2, Group 1: ≥ 25 kg Cohort 2, Group 2: 17 kg to < 25 kg Cohort 3: to be updated per a protocol amendment Cohort 4: to be updated per a protocol amendment Currently on a stable 2-NRTI containing regimen that includes a 3rd ARV agent for ≥ 6 consecutive months prior to screening Plasma HIV-1 RNA levels < 50 copies/mL for ≥ 6 consecutive months preceding the screening visit No opportunistic infection within 30 days of study entry (at baseline/Day 1) A negative serum β-human chorionic gonadotropin (HCG) pregnancy test is required for females of childbearing potential only Key Exclusion Criteria: An acquired immunodeficiency syndrome (AIDS) - indicator condition with onset within 30 days prior to screening Life expectancy of < 2 years Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline/Day 1 Evidence of active pulmonary or extra-pulmonary tuberculosis disease within 3 months of the screening visit Active hepatitis C virus (HCV) infection defined as positive for HCV antibody and having detectable HCV RNA Positive hepatitis B surface antigen or other evidence of active hepatitis B virus (HBV) infection. Have any serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with treatment, assessment, or compliance with the protocol. Pregnant or lactating females Have history of significant drug sensitivity or drug allergy Have previously participated in an investigational trial involving administration of any investigational agent, other than tenofovir, within 30 days prior to the study dosing NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F/TAF+3rd ARV agent (Cohort 1)<br>Participants between 12 to < 18 years of age and ≥ 35 kg in body weight will switch their current 2-NRTI containing regimen to F/TAF (200/25 mg for unboosted 3rd agent and 200/10 mg for boosted 3rd agent) while continuing on their 3rd ARV agent for 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: F/TAF+3rd ARV agent (Cohort 2, Group 1, Part A)<br>Participants between 6 to < 12 years of age and ≥ 25 kg in body weight must be on a boosted protease inhibitor (PI) as their 3rd ARV agent and will switch their current 2-NRTI regimen to F/TAF 200/25 mg while continuing on their boosted PI for 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: Boosted PIs<br>* Boosted PIs of the participant's pre-existing regimen may include one of the following: ATV, LPV, or DRV.<br>|
| Experimental: F/TAF+3rd ARV agent (Cohort 2, Group 2, Part A)<br>Participants between 2 to < 12 years of age and between 17 kg to < 25 kg in body weight must be on a boosted protocol specified 3rd ARV agent and will switch their current 2-NRTI containing regimen to F/TAF 120/15 mg while continuing their 3rd ARV agent for 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: FTC/TAF+3rd ARV agent (Cohort 3, Part A)<br>Participants between 2 to < 6 years of age will receive F/TAF plus a 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: FTC/TAF+3rd ARV agent (Cohort 4, Part A)<br>Participants between 1 month to < 2 years of age will receive F/TAF plus a 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: F/TAF+3rd ARV agent (Cohort 2, Group 1, Part B)<br>Screening will be initiated for Part B following confirmation of TAF dose in Part A. Approximately 10 additional total participants will be enrolled across all Part B cohorts and will receive F/TAF while continuing their 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: F/TAF+3rd ARV agent (Cohort 2, Group 2, Part B)<br>Screening will be initiated for Part B following confirmation of TAF dose in Part A. Approximately 10 additional total participants will be enrolled across all Part B cohorts and will receive F/TAF while continuing their 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: FTC/TAF+3rd ARV agent (Cohort 3, Part B)<br>Screening will be initiated for Part B following confirmation of TAF dose in Part A. Approximately 10 additional total participants will be enrolled across all Part B cohorts and will receive F/TAF while continuing their 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: FTC/TAF+3rd ARV agent (Cohort 4, Part B)<br>Screening will be initiated for Part B following confirmation of TAF dose in Part A. Approximately 10 additional total participants will be enrolled across all Part B cohorts and will receive F/TAF while continuing their 3rd ARV agent through 48 weeks. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|
| Experimental: FTC/TAF +3rd ARV agent (Extension Phase)<br>After completion of 48 weeks, all participants will be given the option to participate in an extension phase of the study. Gilead will provide F/TAF until a) the participant turns 18 and F/TAF is commercially available for use in adults in the country in which the participant is enrolled or, b) F/TAF becomes commercially available for pediatric use in the country in which the participant is enrolled or, c) Gilead Sciences elects to terminate development of F/TAF in the applicable country. | Drug: F/TAF<br>* F/TAF tablets administered orally once daily<br>Drug: 3rd ARV agent<br>* A 3rd antiretroviral (ARV) agent of the participant's pre-existing regimen may include one of the following: boosted atazanavir (ATV), boosted lopinavir (LPV), boosted darunavir (DRV), unboosted efavirenz (EFV), unboosted nevirapine (NVP), unboosted raltegravir (RAL), or unboosted dolutegravir (DTG).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter (Cohort 1): AUCtau of Tenofovir Alafenamide (TAF) | AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): AUCtau of TAF | AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Through Week 24 | An AE is any untoward medical occurrence in a clinical study participant which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The TEAEs were defined as any AEs with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. | Baseline through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter (Cohort 1): Cmax of TAF, FTC, and TFV | Cmax is defined as the maximum concentration of drug. | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): Cmax of TAF, FTC, and TFV | Cmax is defined as the maximum concentration of drug. | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| PK Parameter (Cohort 1): Clast of TAF | Clast is defined as the last observable concentration of drug. | Any time at Week 2 visit | 
| PK Parameter (Cohort 2) : Clast of TAF | Clast is defined as the last observable concentration of drug. | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| PK Parameter (Cohort 1): CL/F of TAF | CL/F is defined as the apparent oral clearance following administration of the drug. | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): CL/F of TAF | CL/F is defined as the apparent oral clearance following administration of the drug. | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| PK Parameter (Cohort 1): Vz/F of TAF | Vz/F is defined as the apparent volume of distribution of the drug. | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): Vz/F of TAF | Vz/F is defined as the apparent volume of distribution of the drug. | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| PK Parameter (Cohort 1): AUCtau of FTC and TFV | AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): AUCtau of FTC and TFV | AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| PK Parameter (Cohort 1): Ctau of FTC and TFV | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Any time at Week 2 visit | 
| PK Parameter (Cohort 2): Ctau of FTC and TFV | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Any time at Week 2 or Week 4 visit, or within 7 days after the completion of Week 2 or Week 4 visits | 
| Percentage of Participants Experiencing TEAEs and SAEs Through Week 48 | An AE is any untoward medical occurrence in a clinical study participant which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The TEAEs were defined as any AEs with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. | Baseline through Week 48 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24, as Defined by the United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defined a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48, as Defined by the US FDA-Defined Snapshot Algorithm | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defined a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. | Week 48 | 
| Change From Baseline in CD4+ Cell Count at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in CD4+ Cell Count at Week 48 |  | Baseline, Week 48 | 
| Change From Baseline in CD4 Percentage at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in CD4 Percentage at Week 48 |  | Baseline, Week 48 | 
| Percentage of Participants With Palatability of F/TAF Formulation | Palatability was reported based on the product taste of being normal or abnormal. Missing data were reported separately. | Week 2 (for Cohort 1), Week 2 and Week 4 (for Cohort 2) | 
| Percentage of Participants With Acceptability of F/TAF Formulation | Acceptability was reported based on the the product size and shape. Missing data were reported separately. | Baseline up to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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emtricitabine, FTC, tenofovir, TDF, antiretroviral, adolescents, children, pediatric