Study of Cobicistat-Boosted Atazanavir (ATV/co), Cobicistat-Boosted Darunavir (DRV/co) and Emtricitabine/Tenofovir Alafenamide (F/TAF) in Children With HIV

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical study is to learn more about the safety and dosing of study drugs, cobicistat-boosted Atazanavir (ATV/co), cobicistat-boosted darunavir (DRV/co) and emtricitabine/tenofovir alafenamide (F/TAF), in children (age ≥ 4 weeks to < 18 years) with HIV.

Official Title
-----------------
A Phase 2/3, Multicenter, Open-label, Multicohort Study Evaluating Pharmacokinetics (PK), Safety, and Efficacy of Cobicistat-boosted Atazanavir (ATV/co) or Cobicistat-boosted Darunavir (DRV/co) and Emtricitabine/Tenofovir Alafenamide (F/TAF) in HIV-1 Infected, Virologically Suppressed Pediatric Participants

Conditions
-----------------
Acquired Immune Deficiency Syndrome (AIDS), HIV Infections

Intervention / Treatment
-----------------
* Drug: ATV
* Drug: DRV
* Drug: Cobicistat
* Drug: BR
* Drug: F/TAF
* Drug: LPV/r
* Drug: Third Unboosted Drug
* Drug: Cobicistat TOS
* Drug: F/TAF TOS


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: HIV-1 infected, virologically suppressed males and females Age ≥ 4 weeks to < 18 years (according to requirements of enrolling Cohort). Body weight at screening ≥ 25 to < 40 kg (Cohort 2); ≥ 14 to < 25 kg (Cohort 3); ≥ 3 to < 25 kg (Cohort 4); ≥ 3 to < 14 kg (Cohort 5) Stable antiretroviral (ARV) regimen for a minimum of 3 months prior to the screening visit. Participants enrolled prior to implementation of Amendment 7: 2 NRTIs and ATV/r once daily or DRV/r once daily or twice daily. Participants enrolled after the implementation of Amendment 9: Cohorts 2, 3 and 4 (Group 1): 2 NRTIs plus a third agent per local prescribing guidelines. Participants will switch from their current third agent to ATV or DRV at Day 1. Participants taking DRV must be on once-daily dosing or must switch to once daily at or prior to Day 1. Cohort 4 (Group 1), participants may also switch their current third agent to LPV/r at Day 1. Participants will switch their NRTI backbone to F/TAF. Cohort 4 (Groups 2 to 4) and Cohort 5 (Groups 1 to 3): 2 NRTIs plus a third agent per local prescribing guidelines or treatment naive. Participants on treatment will switch from their current third agent to ATV or LPV/r (Cohort 4 [Groups 2 to 4]), or to a third unboosted agent (Cohort 5 [Groups 1 to 3]). Participants will switch their NRTI backbone to F/TAF. Participants undergoing dose modifications to their ARV regimen for growth or switching medication formulations are considered to be on a stable ARV regimen. Documented plasma HIV-1 RNA for ≥ 3 months preceding the screening visit: Participants enrolled after the implementation of Amendment 9: For Cohorts 2, 3, and 4 (Group 1), virologically suppressed ≥ 3 months preceding the screening visit: HIV-1 RNA < 50 copies/mL on a stable regimen (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) For Cohorts 4 (Groups 2 to 4) and Cohort 5 (Groups 1 to 3), on an ARV regimen irrespective of plasma HIV-1 RNA copies or treatment naive; a participant is considered treatment naive if ARVs were given for prevention of mother-to-child transmission but not for HIV treatment For virologically suppressed participants, unconfirmed virologic elevations of HIV-1 RNA ≥ 50 copies/mL (transient detectable viremia, or blip) prior to screening are acceptable. If the lower limit of detection of the local HIV-1 RNA assay is < 50 copies/mL (eg, < 20 copies/mL), the plasma HIV-1 RNA level cannot exceed 50 copies/mL on 2 consecutive HIV-1 RNA tests. Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) ≥ 90 mL/min/1.73m2 using the Schwartz formula. If ≥ 1 year old, eGFR greater than or equal to the minimum normal value for age using the Schwartz Formula. If < 1 year old as follows: Age Minimum Value for eGFR (mL/min/1.73 m2) > 28 days to ≤ 95 days 30, ≥ 96 days to ≤ 6 months 39, > 6 to < 12 months 49 Participants must not have documented or suspected resistance to applicable study drugs including FTC, TFV, ATV, DRV, or LPV. Participants < 14 kg (Cohorts 4 [Groups 2 to 4] and 5 [Groups 1 to 3]) with M184V/I AND HIV-1 RNA < 50 copies/mL will be allowed. Positive confirmatory HIV test (confirmatory nucleic acid-based testing if < 18 months of age). Cohort 4 (Groups 2 to 4) and Cohort 5 (Groups 1 to 3): Last dose of nevirapine or efavirenz, if applicable, ≥ 14 days prior to enrollment. Note: Other protocol defined Inclusion/Exclusion criteria do apply.

Ages Eligible for Study
-----------------
Minimum Age: 4 Weeks
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Part A and Part B<br>Participants ages 12 to <18 years old will receive cobicistat 150 mg with either ATV or DRV plus background regimen (BR). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: DRV<br>* Tablets administered once daily according to dosing recommendations per product monograph<br>* Other names: Prezista®;Drug: Cobicistat<br>* Tablets administered orally once daily with food<br>* Other names: Tybost®;Drug: BR<br>* Background Regimen (BR) include Food and Drug Administration (FDA)-approved nucleos(t)ide reverse transcriptase inhibitors (NRTIs) including zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), lamivudine (3TC), and emtricitabine (FTC).<br>|
| Experimental: Cohort 2 (Group 1)<br>After Protocol Amendment 9, Cohort 2 weight range will be modified to ≥ 25 to < 40 kg. Group 1 will be the current weight/age range for Cohort 2, participants aged 6 to <12 years old and ≥ 25 to < 35 kg. They will receive cobicistat (co) 150 mg and emtricitabine/tenofovir alafenamide (F/TAF) 20/25 mg with either ATV or DRV. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: DRV<br>* Tablets administered once daily according to dosing recommendations per product monograph<br>* Other names: Prezista®;Drug: Cobicistat<br>* Tablets administered orally once daily with food<br>* Other names: Tybost®;Drug: F/TAF<br>* Tablets administered orally once daily<br>* Other names: Descovy®;|
| Experimental: Cohort 2 (Group 2)<br>After Protocol Amendment 9, Cohort 2 weight range will be modified to ≥ 25 to < 40 kg. Group 2 will be the new weight range for Cohort 2, participants aged 6 to <12 years old and ≥ 35 to < 40 kg. They will receive cobicistat (co) 150 mg and emtricitabine/tenofovir alafenamide (F/TAF) 20/25 mg with DRV | Drug: DRV<br>* Tablets administered once daily according to dosing recommendations per product monograph<br>* Other names: Prezista®;Drug: Cobicistat<br>* Tablets administered orally once daily with food<br>* Other names: Tybost®;Drug: F/TAF<br>* Tablets administered orally once daily<br>* Other names: Descovy®;|
| Experimental: Cohort 3<br>Participants ages ≥ 2 years old will receive cobicistat 90 mg and F/TAF 120/15 mg with either ATV or DRV. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: DRV<br>* Tablets administered once daily according to dosing recommendations per product monograph<br>* Other names: Prezista®;Drug: Cobicistat<br>* Tablets administered orally once daily with food<br>* Other names: Tybost®;Drug: F/TAF<br>* Tablets administered orally once daily<br>* Other names: Descovy®;|
| Experimental: Cohort 4 (Group 1)<br>Participants age ≥ 4 weeks old weighing 14 to < 25 kg will receive cobicistat tablet for oral suspension (TOS) 90 mg, once daily and F/TAF TOS 120/15 mg, once daily with either ATV or DRV or lopinavir boosted by ritonavir (LPV/r). Minimum age and weight for ATV is ≥ 3 months and ≥ 5 kg, minimum age and weight for DRV is ≥ 3 years and ≥ 15 kg; participants receiving LPV/r will not receive cobicistat TOS. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: DRV<br>* Tablets administered once daily according to dosing recommendations per product monograph<br>* Other names: Prezista®;Drug: LPV/r<br>* Solution administered orally<br>Drug: Cobicistat TOS<br>* Tablets for oral suspension<br>* Other names: Tybost®;Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 4 (Group 2)<br>Participants age ≥ 4 weeks old weighing 10 to < 14 kg will receive cobicistat TOS 30 mg (twice daily) and F/TAF TOS 60/7.5 mg, once daily with either ATV or LPV/r. Minimum age and weight for ATV is ≥ 3 months and ≥ 5 kg, respectively; participants receiving LPV/r will not receive cobicistat TOS. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: LPV/r<br>* Solution administered orally<br>Drug: Cobicistat TOS<br>* Tablets for oral suspension<br>* Other names: Tybost®;Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 4 (Group 3)<br>Participants age ≥ 4 weeks old weighing 6 to < 10 kg will receive cobicistat TOS 30 mg (twice daily) and F/TAF TOS 30/3.75 mg, once daily with either ATV or LPV/r. Minimum age and weight for ATV is ≥ 3 months and ≥ 5 kg, respectively; participants receiving LPV/r will not receive cobicistat TOS. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: LPV/r<br>* Solution administered orally<br>Drug: Cobicistat TOS<br>* Tablets for oral suspension<br>* Other names: Tybost®;Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 4 (Group 4)<br>Participants age ≥ 4 weeks old weighing 3 to < 6 kg will receive cobicistat TOS 30 mg (twice daily) and F/TAF TOS 15/1.88 mg, once daily with either ATV or LPV/r. Minimum age and weight for ATV is ≥ 3 months and ≥ 5 kg, respectively; participants receiving LPV/r will not receive cobicistat TOS. | Drug: ATV<br>* Capsules administered once daily according to dosing recommendations per product monograph<br>* Other names: Reyataz®;Drug: LPV/r<br>* Solution administered orally<br>Drug: Cobicistat TOS<br>* Tablets for oral suspension<br>* Other names: Tybost®;Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 5 (Group 1)<br>Participants ages ≥ 4 weeks old weighing ≥ 10 to < 14 kg will receive F/TAF TOS 60/7.5 mg, once daily with the third unboosted drug. | Drug: Third Unboosted Drug<br>* ATV (administered orally), DRV (administered orally), and LPV/r (administered orally) would be general list but unspecified for sites.<br>Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 5 (Group 2)<br>Participants ages ≥ 4 weeks old weighing ≥ 6 to < 10 kg will receive F/TAF TOS 30/3.75 mg, once daily with the third unboosted drug. | Drug: Third Unboosted Drug<br>* ATV (administered orally), DRV (administered orally), and LPV/r (administered orally) would be general list but unspecified for sites.<br>Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|
| Experimental: Cohort 5 (Group 3)<br>Participants ages ≥ 4 weeks old weighing ≥ 3 to < 6 kg will receive F/TAF TOS 15/1.88 mg, once daily with the third unboosted drug. | Drug: Third Unboosted Drug<br>* ATV (administered orally), DRV (administered orally), and LPV/r (administered orally) would be general list but unspecified for sites.<br>Drug: F/TAF TOS<br>* Tablets for oral suspension<br>* Other names: Descovy®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: AUCtau of ATV, DRV, TAF, and TFV | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). AUCtau for ATV (Cohorts 1 Part A, 2, 3, and 4 [Groups 2 to 4]); DRV (Cohorts 1 Part A, 2, and 3); TAF (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 [Groups 1 to 3] taking F/TAF); and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 [Groups 1 to 3] taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| Percentage of Participants Experiencing Treatment Emergent Adverse Events (AEs) Through Week 24 |  | First dose date up to Week 24 plus 30 days (Cumulative data through Week 24) | 
| Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities Through Week 24 |  | First dose date up to Week 24 plus 30 days (Cumulative data through Week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: Ctau of ATV, DRV, TAF, and TFV | Ctau is defined as the observed drug concentration at the end of the dosing interval. Ctau for ATV (cohorts 1, 2, 3, and 4 (Groups 2 to 4)), DRV (cohorts 1, 2, and 3), COBI (except Cohort 5), FTC and TFV (cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: Cmax of ATV, DRV, COBI, TAF, FTC and TFV | Cmax is defined as the maximum observed concentration of drug. Cmax for ATV (Cohorts 1, 2, 3, and 4 [Groups 2 to 4]) and DRV (Cohorts 1, 2, and 3); for COBI (except Cohort 5); for TAF, FTC and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: CL/F of ATV, DRV, COBI, TAF, FTC and TFV | CL/F is defined as the apparent oral clearance following administration of the drug. CL/F for ATV (Cohorts 1, 2, 3, and 4 [Groups 2 to 4]) and DRV (Cohorts 1, 2, and 3); for COBI (except Cohort 5); for TAF, FTC and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: Vz/F of COBI, TAF, FTC and TFV | Vz/F is defined as the apparent volume of distribution of the drug. Vz/F for COBI (Except Cohort 5); for TAF (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF); for FTC and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: AUCtau of COBI, FTC and TFV | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). AUCtau for COBI (Except Cohort 5); for FTC and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: AUClast of TAF, FTC and TFV | AUClast is defined as area under the concentration versus time curve from time zero to the last quantifiable concentration. AUClast for TAF (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF); for FTC and TFV (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| PK Parameter: Clast of TAF | Clast is defined as the the last observed quantifiable concentration of the drug in plasma. Clast for TAF (Cohorts 2, 3, 4 [Groups 1 to 4] and 5 taking F/TAF) will be reported. | Predose on Day 1, and postdose up to Week 48 | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | First dose date up to Week 48 plus 30 days (Cumulative data through Week 48) | 
| Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values |  | First dose date up to Week 48 plus 30 days (Cumulative data through Week 48) | 
| Percentage of Participants with HIV-1 RNA < 50 Copies/mL at Week 24 and as Defined by the US FDA-defined Snapshot Algorithm |  | Week 24 | 
| Percentage of Participants with HIV-1 RNA < 50 Copies/mL at Week 48 and as Defined by the US FDA-defined Snapshot Algorithm |  | Week 48 | 
| Change from Baseline in CD4+ Cell Counts (cells/μL) at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in CD4+ Cell Counts (cells/μL) at Week 48 |  | Baseline, Week 48 | 
| Change from Baseline in Percentage of CD4+ Cells at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in Percentage of CD4+ Cells at Week 48 |  | Baseline, Week 48 | 
| Acceptability of COBI and F/TAF as Measured by Palatability Score |  | Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Pediatrics, Adolescents, HIV-1, Treatment experienced