Acquired Immunodeficiency Syndrome, HIV Infections
Conditions
Keywords
Adolescents, HIV-1, HIV, Treatment Naive
Brief summary
The primary objectives of this study are to evaluate the steady-state pharmacokinetics (PK) and confirm the dose of the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) single-tablet regimen (STR) (Part A) and to evaluate the safety and tolerability of EVG/COBI/FTC/TDF STR through Week 48 (Part B) in HIV-1 infected, antiretroviral (ARV) treatment-naive adolescents. A total of 50 adolescent participants (12 to \< 18 years of age) will be enrolled to receive EVG/COBI/FTC/TDF as follows: * Part A: Twelve to 16 eligible participants will be enrolled to evaluate steady-state PK, and confirm the dose, with the intent to enroll at least 4 participants 12 to \< 15 and at least 4 participants 15 to \< 18 years of age. * Part B: Following confirmation of EVG exposure in at least 12 participants from Part A, 34 to 38 participants in addition to those enrolled in Part A will be enrolled to evaluate the safety, tolerability, and antiviral activity of EVG/COBI/FTC/TDF STR.
Interventions
DRUGEVG/COBI/FTC/TDF
150/150/200/300 mg STR administered orally once daily with food
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * 12 years to \< 18 years of age at baseline * 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 * Plasma HIV-1 RNA levels of ≥ 1,000 copies/mL * CD4+ cell count \> 100 cells/µL * Weight ≥ 35 kg (77 lbs) * Screening genotype report must show sensitivity to FTC and TDF * Able to swallow oral tablets * Adequate renal function * Clinically normal ECG * Documented screening for active pulmonary tuberculosis per local standard of care within 6 months of a screening visit * Hepatic transaminases ≤ 5 x upper limit of normal * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Individuals with a positive Hepatitis B surface antigen screening test can participate in the study, providing that alternate therapy (other than TDF) for chronic Hepatitis B infection is available as a part of local standard of care * Adequate hematologic function * Negative serum pregnancy test for all females * Males and females of childbearing potential must agree to utilize highly effective contraception methods while on study treatment or agree to abstain from heterosexual intercourse throughout the study period and for 30 days following the last dose of study drug * Males must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of investigational medicinal product * Must be willing and able to comply with all study requirements * Life expectancy ≥ 1 year Key
Exclusion criteria
* A new AIDS-defining condition diagnosed within the 30 days prior to screening * Prior treatment with any approved or investigational or experimental anti HIV-1 drug for any length of time (other than that given for prevention of mother-to-child transmission) * Evidence of active pulmonary or extra-pulmonary tuberculosis disease within 3 months of the screening visit * Anticipated to require rifamycin treatment for mycobacterial infection while participating in the study. Note: prophylactic Isoniazid (INH) therapy for latent tuberculosis (TB) treatment is allowed. * Individuals experiencing decompensated cirrhosis * Pregnant or lactating females * Have any serious or active medical or psychiatric illness which would interfere with treatment, assessment, or compliance with the protocol. This would include uncontrolled renal, cardiac, hematological, hepatic, pulmonary, endocrine, central nervous, gastrointestinal, vascular, metabolic, immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment within 30 days prior to the study dosing. * Current alcohol or substance abuse that will potentially interfere with compliance * Have history of significant drug sensitivity or drug allergy * Known hypersensitivity to the study drugs, the metabolites or formulation excipients * Have been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening or expected to receive these agents during the study * A history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma * 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 * Receiving ongoing therapy with any disallowed medications, including drugs not to be used with EVG, COBI, FTC, TDF or individuals with any known allergies to the excipients of EVG/COBI/FTC/TDF STR tablets Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| For Part A, Pharmacokinetic (PK) Parameter: AUCtau of EVG | Predose, 2, 4, 4.5, 5, 8, and 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). |
| Incidence of Treatment-Emergent Serious Adverse Events (SAEs) and All Treatment-Emergent Adverse Events (AEs) | Up to Week 48 plus 30 days | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For Part A, PK Parameter: AUCtau of FTC, TFV, and COBI | Predose, 2, 4, 4.5, 5, 8, and 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). |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Weeks 24 and 48 | — |
| Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Weeks 24 and 48 | — |
| For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI | Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10 | Ctau is defined as the observed drug concentration at the end of the dosing interval. |
| Change From Baseline in CD4+ Cell Count at Weeks 24 and 48 | Baseline; Weeks 24 and 48 | — |
| Change From Baseline in CD4 Percentage at Weeks 24 and 48 | Baseline; Weeks 24 and 48 | — |
| Change From Baseline in Plasma log10 HIV-1 RNA at Weeks 24 and 48 | Baseline; Weeks 24 and 48 | — |
| For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI | Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10 | Cmax is defined as the maximum concentration of drug. |
Countries
South Africa, Thailand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, South Africa, and Thailand. The first participant was screened on 06 December 2012. The last study visit occurred on 29 January 2018.
Pre-assignment details
56 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| EVG/COBI/FTC/TDF EVG/COBI/FTC/TDF (150/150/200/300 mg) STR administered orally once daily with food for 48 weeks, followed by EVG/COBI/FTC/TDF (150/150/200/300 mg) during the optional extension phase | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Non- Compliance with Study Drug | 3 |
| Overall Study | Withdrew Consent | 1 |
Baseline characteristics
| Characteristic | EVG/COBI/FTC/TDF |
|---|---|
| Age, Continuous | 15 years STANDARD_DEVIATION 1.5 |
| CD4 Cell Count | 399 cells/µL STANDARD_DEVIATION 127.6 |
| CD4 Cell Count Category ≤ 199 cells/µL | 2 Participants |
| CD4 Cell Count Category 200 ≥ and ≤ 349 cells/µL | 16 Participants |
| CD4 Cell Count Category 350 ≥ and ≤ 499 cells/µL | 22 Participants |
| CD4 Cell Count Category ≥ 500 cells/µL | 10 Participants |
| HIV-1 RNA | 4.60 log10 copies/mL STANDARD_DEVIATION 0.551 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 40 Participants |
| HIV-1 RNA Category > 100,000 copies/mL | 10 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants |
| Race/Ethnicity, Customized Black | 34 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 47 Participants |
| Race/Ethnicity, Customized Not Permitted | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 1 Participants |
| Region of Enrollment South Africa | 22 Participants |
| Region of Enrollment Thailand | 14 Participants |
| Region of Enrollment United States | 14 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 50 |
| other Total, other adverse events | 46 / 50 |
| serious Total, serious adverse events | 5 / 50 |
Outcome results
Primary
For Part A, 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).
Time frame: Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10
Population: PK Substudy Analysis Set: all enrolled and treated participants from Part A who had evaluable steady-state pharmacokinetic profiles of the respective analyte of interest at the Day 10 intensive PK visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVG/COBI/FTC/TDF | For Part A, Pharmacokinetic (PK) Parameter: AUCtau of EVG | 31620.9 ng•h/mL | Standard Deviation 13978.07 |
90% CI: [1.0479, 1.62]
Primary
Incidence of Treatment-Emergent Serious Adverse Events (SAEs) and All Treatment-Emergent Adverse Events (AEs)
Time frame: Up to Week 48 plus 30 days
Population: Safety Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVG/COBI/FTC/TDF | Incidence of Treatment-Emergent Serious Adverse Events (SAEs) and All Treatment-Emergent Adverse Events (AEs) | SAEs | 4 Participants |
| EVG/COBI/FTC/TDF | Incidence of Treatment-Emergent Serious Adverse Events (SAEs) and All Treatment-Emergent Adverse Events (AEs) | AEs | 45 Participants |
Secondary
Change From Baseline in CD4+ Cell Count at Weeks 24 and 48
Time frame: Baseline; Weeks 24 and 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | Change From Baseline in CD4+ Cell Count at Weeks 24 and 48 | Change at Week 24 | 178 cells/µL | Standard Deviation 165.4 |
| EVG/COBI/FTC/TDF | Change From Baseline in CD4+ Cell Count at Weeks 24 and 48 | Change at Week 48 | 229 cells/µL | Standard Deviation 245.3 |
Secondary
Change From Baseline in CD4 Percentage at Weeks 24 and 48
Time frame: Baseline; Weeks 24 and 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | Change From Baseline in CD4 Percentage at Weeks 24 and 48 | Change at Week 24 | 7.4 percentage | Standard Deviation 4.7 |
| EVG/COBI/FTC/TDF | Change From Baseline in CD4 Percentage at Weeks 24 and 48 | Change at Week 48 | 8.1 percentage | Standard Deviation 5.34 |
Secondary
Change From Baseline in Plasma log10 HIV-1 RNA at Weeks 24 and 48
Time frame: Baseline; Weeks 24 and 48
Population: Full Analysis Set: all participants who were enrolled in the study and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | Change From Baseline in Plasma log10 HIV-1 RNA at Weeks 24 and 48 | Change at Week 24 | -3.08 log10 copies/mL | Standard Deviation 0.922 |
| EVG/COBI/FTC/TDF | Change From Baseline in Plasma log10 HIV-1 RNA at Weeks 24 and 48 | Change at Week 48 | -3.16 log10 copies/mL | Standard Deviation 0.705 |
Secondary
For Part A, PK Parameter: AUCtau of FTC, TFV, and COBI
AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Time frame: Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10
Population: PK Substudy Analysis Set: all enrolled and treated participants from Part A who had evaluable steady-state pharmacokinetic profiles of the respective analyte of interest at the Day 10 intensive PK visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: AUCtau of FTC, TFV, and COBI | FTC | 15136.5 ng•h/mL | Standard Deviation 4702.06 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: AUCtau of FTC, TFV, and COBI | TFV | 4450.7 ng•h/mL | Standard Deviation 1312.27 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: AUCtau of FTC, TFV, and COBI | COBI | 11884.8 ng•h/mL | Standard Deviation 11220.94 |
Secondary
For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI
Cmax is defined as the maximum concentration of drug.
Time frame: Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10
Population: PK Substudy Analysis Set: all enrolled and treated participants from Part A who had evaluable steady-state pharmacokinetic profiles of the respective analyte of interest at the Day 10 intensive PK visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI | EVG | 2624.3 ng/mL | Standard Deviation 1239.64 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI | FTC | 2217.4 ng/mL | Standard Deviation 664.64 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI | TFV | 438.5 ng/mL | Standard Deviation 170.69 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Cmax of EVG, FTC, TFV, and COBI | COBI | 1500.4 ng/mL | Standard Deviation 975.29 |
Secondary
For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI
Ctau is defined as the observed drug concentration at the end of the dosing interval.
Time frame: Predose, 2, 4, 4.5, 5, 8, and 12 hours postdose on Day 10
Population: PK Substudy Analysis Set: all enrolled and treated participants from Part A who had evaluable steady-state pharmacokinetic profiles of the respective analyte of interest at the Day 10 intensive PK visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI | EVG | 579.3 ng/mL | Standard Deviation 455.2 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI | FTC | 102.6 ng/mL | Standard Deviation 30.85 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI | TFV | 86.6 ng/mL | Standard Deviation 23.58 |
| EVG/COBI/FTC/TDF | For Part A, PK Parameter: Ctau of EVG, FTC, Tenofovir (TFV), and COBI | COBI | 39.7 ng/mL | Standard Deviation 68.52 |
Secondary
Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis
Time frame: Weeks 24 and 48
Population: Full Analysis Set: all participants who were enrolled in the study and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EVG/COBI/FTC/TDF | Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Week 48 | 92.0 percentage of participants |
| EVG/COBI/FTC/TDF | Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Week 24 | 94.0 percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis
Time frame: Weeks 24 and 48
Population: Full Analysis Set: all participants who were enrolled in the study and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EVG/COBI/FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Week 24 | 88.0 percentage of participants |
| EVG/COBI/FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 24 and 48 as Defined by the FDA Snapshot Analysis | Week 48 | 88.0 percentage of participants |