Two Part Study to Evaluate Pharmacokinetics, Safety, and Antiviral Activity of Elvitegravir Administered With a PI/r Background Regimen for ARV Treatment-Experienced Pediatric Participants

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the safety, tolerability and steady-state PK and confirm the dose of EVG/r in HIV-1 infected, antiretroviral treatment-experienced children 4 weeks to <18 years of age. The study consists of 2 parts: Part A and Part B. Part A will enroll participants with suppressed viremia (HIV-1 RNA < 50 copies/mL) or failing a current antiretroviral (ARV) regimen (HIV-1 RNA > 1,000 copies/mL only for participants in Cohort 2, Part A) to evaluate the steady state PK and confirm the dose of EVG. Part B will enroll participants who are failing a current ARV regimen (HIV-1 RNA > 1,000 copies/mL) to evaluate the safety, tolerability, and antiviral activity of EVG. The study consists of 4 age cohorts with each cohort including 2 parts (Part A and Part B) with the exception of the adolescent age cohort (Cohort 1: 12 to < 18 years old) containing Part B only.

Official Title
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A Phase 2/3 Multicenter, Open-Label, Multicohort, Two-Part Study Evaluating the Pharmacokinetics (PK), Safety, and Antiviral Activity of Elvitegravir (EVG) Administered With a Background-Regimen (BR) Containing a Ritonavir-Boosted Protease Inhibitor (PI/r) in HIV-1 Infected, Antiretroviral Treatment-Experienced Pediatric Subjects

Conditions
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HIV Infections, Acquired Immune Deficiency Syndrome (AIDS)

Intervention / Treatment
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* Drug: EVG
* Drug: Background regimen


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals must meet all of the following inclusion criteria to be eligible for participation in this study. Individuals with screening results that do not meet eligibility criteria will not be allowed to rescreen. HIV-1 infected male and female individuals 4 weeks (gestational age of at least 44 weeks) to less than 18 years of age at Baseline. Individuals are able to provide written assent if they have the ability to read and write. Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements. Body weight at screening greater than 5kg, 10.6kg, or 15kg dependent upon age cohort Adequate renal function Adequate hematologic function Hepatic transaminases (AST and ALT) less than or equal to 5 x upper limit of normal (ULN) Total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin Negative serum pregnancy test Individuals with evidence of suppressed viremia Individuals failing a current antiretroviral regimen at study entry Male and female individuals of childbearing potential must agree to utilize highly effective contraception methods while on study treatment or agree to abstain from heterosexual intercourse of reproductive potential throughout the study period and for 30 days following the last dose of study drug Must be willing and able to comply with all study requirements. Key Exclusion Criteria: Participants who meet any of the following exclusion criteria are not to be enrolled in this study. Individuals with CD4+ cell counts at Screening of less than 50, 75, or 200 cells/mm3 dependent on age cohort An AIDS defining condition with onset within 30 days prior to screening Life expectancy of less than 1 year For Individuals with HIV-1 RNA greater than 1,000 copies/mL at screening, prior treatment of any duration with an integrase strand transfer inhibitor. An ongoing serious infection requiring systemic antibiotic therapy at the time of screening. Evidence of active pulmonary or extra-pulmonary tuberculosis disease Anticipated requirement for rifamycin treatment while participating in the study. Have any serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with Individual's treatment, assessment, or compliance with the protocol. Individuals experiencing decompensated cirrhosis A history of or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Pregnant or lactating females. Current alcohol or substance abuse judged by the Investigator to potentially interfere with individual's compliance. Have history of significant drug sensitivity or drug allergy. Known hypersensitivity to the study drug, the metabolites, or formulation excipients. Have previously participated in an investigational trial involving administration of any investigational agent within 30 days prior to the study dosing. Participation in any other clinical trial without prior approval from sponsor is prohibited while participating in this trial. Individuals receiving ongoing therapy with any medication that is not to be taken with EVG or a component of the BR, including drugs not to be used with ritonavir Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 4 Weeks
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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (12 to < 18 years of age)<br>Part A: No participants will be enrolled in Part A, as PK data is currently available for this age group. Part B: Participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. | Drug: EVG<br>* Tablet (s) or tablet (s) for oral suspension (if unable to swallow) will be administered orally once daily<br>* Other names: Vitekta®;Drug: Background regimen<br>* Background regimen may consist of the following ritonavir (RTV)-boosted PIs (PI/r): lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. For participants < 2 months old, only lopinavir/r is allowed. Use of additional antiretrovirals in background therapy may be allowed.<br>|
| Experimental: Cohort 2 (6 to < 12 years of age)<br>Part A: Participants with HIV-1 RNA < 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days. Participants with HIV-1 RNA > 1,000 copies/mL will receive EVG along with a newly constructed background regimen that includes a Pl/r for 48 weeks. Participants with HIV-1 RNA > 1,000 copies/mL can continue after Week 48. Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. Participants who complete the 48-week follow-up in both Part A and Part B will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. | Drug: EVG<br>* Tablet (s) or tablet (s) for oral suspension (if unable to swallow) will be administered orally once daily<br>* Other names: Vitekta®;Drug: Background regimen<br>* Background regimen may consist of the following ritonavir (RTV)-boosted PIs (PI/r): lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. For participants < 2 months old, only lopinavir/r is allowed. Use of additional antiretrovirals in background therapy may be allowed.<br>|
| Experimental: Cohort 3 (2 to < 6 years of age)<br>Part A: Participants with HIV-1 RNA < 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days. Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. | Drug: EVG<br>* Tablet (s) or tablet (s) for oral suspension (if unable to swallow) will be administered orally once daily<br>* Other names: Vitekta®;Drug: Background regimen<br>* Background regimen may consist of the following ritonavir (RTV)-boosted PIs (PI/r): lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. For participants < 2 months old, only lopinavir/r is allowed. Use of additional antiretrovirals in background therapy may be allowed.<br>|
| Experimental: Cohort 4 (4 weeks to < 2 years of age)<br>Part A: Participants with HIV-1 RNA < 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days. Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. | Drug: EVG<br>* Tablet (s) or tablet (s) for oral suspension (if unable to swallow) will be administered orally once daily<br>* Other names: Vitekta®;Drug: Background regimen<br>* Background regimen may consist of the following ritonavir (RTV)-boosted PIs (PI/r): lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. For participants < 2 months old, only lopinavir/r is allowed. Use of additional antiretrovirals in background therapy may be allowed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: AUCtau of EVG | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose and up to 12 hours postdose on Day 10 | 
| Pharmacokinetic (PK) Parameter: Cmax of EVG at Day 10 | Cmax is defined as the maximum concentration of drug. | Predose and up to 12 hours postdose on Day 10 | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events |  | Baseline up to the last dose date plus 30 days (maximum exposure: 173.6 weeks for participants age 6 to < 18 Years Screening HIV-1 RNA > 1000 copies/mL and 2.0 weeks for participants age 6 to < 12 Years Screening HIV-1 RNA < 50 copies/mL) | 
| Percentage of Participants Experiencing Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each subject. The criteria used to grade laboratory results were as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), and Grade 4 (life-threatening). | Baseline up to the last dose date plus 30 days (maximum exposure: 173.6 weeks for participants age 6 to < 18 Years Screening HIV-1 RNA > 1000 copies/mL and 2.0 weeks for participants age 6 to < 12 Years Screening HIV-1 RNA < 50 copies/mL) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: Ctau of EVG | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Predose and up to 12 hours postdose on Day 10 | 
| Pharmacokinetic (PK) Parameter: CL/F of EVG | CL/F is defined as the apparent oral clearance following administration of the drug. | Predose and up to 12 hours postdose on Day 10 | 
| Pharmacokinetic (PK) Parameter: Vz/F of EVG | Vz/F is defined as the apparent volume of distribution of the drug. | Predose and up to 12 hours postdose on Day 10 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 as Defined by the FDA Snapshot Algorithm | The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines 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 FDA Snapshot Algorithm | The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines 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 | 
| Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL at Week 24 as Defined by the FDA Snapshot Algorithm | The percentage of participants achieving HIV-1 RNA < 400 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines 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 Plasma HIV-1 RNA < 400 Copies/mL at Week 48 as Defined by the FDA Snapshot Algorithm | The percentage of participants achieving HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines 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 Plasma Log₁₀ HIV-1 RNA at Week 24 |  | Baseline to Week 24 | 
| Change From Baseline in Plasma Log₁₀ HIV-1 RNA at Week 48 |  | Baseline to Week 48 | 
| Change From Baseline in CD4 Cell Count at Week 24 |  | Baseline to Week 24 | 
| Change From Baseline in CD4 Cell Count at Week 48 |  | Baseline to Week 48 | 
| Change From Baseline in CD4 Percentage at Week 24 |  | Baseline to Week 24 | 
| Change From Baseline in CD4 Percentage at Week 48 |  | Baseline to Week 48 | 
| Tanner Stage Evaluation by Sex at Week 24 | Tanner Stage (pubic hair and breasts for females; pubic hair and genitalia for males) at Week 24 visit was summarized using frequency count and percentage. Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). | Week 24 | 
| Tanner Stage Evaluation by Sex at Week 48 | Tanner Stage (pubic hair and breasts for females; pubic hair and genitalia for males) at Week 48 visit was summarized using frequency count and percentage. Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). | Week 48 | 
| Age of First Menses | Age of first menses for female participants. | Baseline through end of study (maximum exposure: 173.6 weeks for participants age 6 to < 18 Years with Screening HIV-1 RNA > 1000 copies/mL and 2.0 weeks for participants age 6 to < 12 Years with Screening HIV-1 RNA < 50 copies/mL) | 
| Palatability of Oral Suspension Formulation of EVG in Appropriate Age Group |  | Up to Week 48 | 
| Adherence to EVG | Adherence was calculated as the number of pills taken divided by number of pills prescribed multiplied by 100. | Baseline up to the last dose date (maximum exposure: 173.6 weeks for participants age 6 to < 18 Years Screening HIV-1 RNA > 1000 copies/mL and 2.0 weeks for participants age 6 to < 12 Years Screening HIV-1 RNA < 50 copies/mL) | 

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