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

Phase 2

Terminated

Conditions: Acquired Immune Deficiency Syndrome (AIDS)
HIV Infections

Interventions: Drug: EVG
Drug: Background regimen

Registration Number: NCT01923311

Lead Sponsor: Gilead Sciences

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 31

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1 (12 to < 18 years of age)	Background regimen	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.
Cohort 2 (6 to < 12 years of age)	Background regimen	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.
Cohort 3 (2 to < 6 years of age)	Background regimen	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.
Cohort 4 (4 weeks to < 2 years of age)	Background regimen	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.
Cohort 1 (12 to < 18 years of age)	EVG	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.
Cohort 2 (6 to < 12 years of age)	EVG	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.
Cohort 3 (2 to < 6 years of age)	EVG	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.
Cohort 4 (4 weeks to < 2 years of age)	EVG	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.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetic (PK) Parameter: AUCtau of EVG	Predose and up to 12 hours postdose on Day 10	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Pharmacokinetic (PK) Parameter: Cmax of EVG at Day 10	Predose and up to 12 hours postdose on Day 10	Cmax is defined as the maximum concentration of drug.
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	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)	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Plasma Log₁₀ HIV-1 RNA at Week 48	Baseline to Week 48
Pharmacokinetic (PK) Parameter: Ctau of EVG	Predose and up to 12 hours postdose on Day 10	Ctau is defined as the observed drug concentration at the end of the dosing interval.
Pharmacokinetic (PK) Parameter: CL/F of EVG	Predose and up to 12 hours postdose on Day 10	CL/F is defined as the apparent oral clearance following administration of the drug.
Pharmacokinetic (PK) Parameter: Vz/F of EVG	Predose and up to 12 hours postdose on Day 10	Vz/F is defined as the apparent volume of distribution of the drug.
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
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 as Defined by the FDA Snapshot Algorithm	Week 24	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.
Change From Baseline in Plasma Log₁₀ HIV-1 RNA at Week 24	Baseline to Week 24
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the FDA Snapshot Algorithm	Week 48	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.
Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL at Week 24 as Defined by the FDA Snapshot Algorithm	Week 24	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.
Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL at Week 48 as Defined by the FDA Snapshot Algorithm	Week 48	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.
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	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).
Tanner Stage Evaluation by Sex at Week 48	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).
Age of First Menses	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)	Age of first menses for female participants.
Palatability of Oral Suspension Formulation of EVG in Appropriate Age Group	Up to Week 48
Adherence to EVG	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)	Adherence was calculated as the number of pills taken divided by number of pills prescribed multiplied by 100.

Trial Locations

Locations (11): Be Part Yoluntu Centre
🇿🇦
Cape Town, South Africa
Universita degli Studi di Pavia - Fondazione IRCCS Policlinico San Matteo
🇮🇹
Pavia, Italy
Joint Clinical Research Centre
🇺🇬
Kampala, Uganda
Thai Red Cross AIDS Research Centre (HIV-NAT)
🇹🇭
Bangkok, Thailand
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
Hospital Universitario De Getafe
🇪🇸
Getafe, Madrid, Spain
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Rahima Moosa Mother and Child Hopsital
🇿🇦
Johannesburg, South Africa
Siriraj Hospital
🇹🇭
Bangkok, Thailand
Hospital 12 de Octubre
🇪🇸
Madrid, Spain