| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus (HIV-1) Infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus (HIV-1) Infections |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this study are:
•To evaluate the steady-state PK and confirm the dose of EVG/r in HIV-1 infected, antiretroviral treatment-experienced subjects 4 weeks to less than 18 years of age.
•To evaluate the safety and tolerability of EVG/r in HIV-1 infected, antiretroviral treatment-experienced subjects 4 weeks to <18 years of age. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is:
•To evaluate the antiviral activity of EVG/r in HIV-1 infected, antiretroviral treatment-experienced subjects 4 weeks to <18 years of age who are failing their current HAART regimen |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) HIV-1 infected male and female subjects 4 weeks (gestational age of at least 44 weeks) to < 18 years of age at the Baseline visit (according to Cohort).
2) Subjects are able to provide written assent if they have the ability to read and write.
3) Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements.
4) Body weight at screening as follows:
•Cohort 2 – greater than 15 kg
•Cohort 3 – greater than 10.6 kg
•Cohort 4 – greater than 5 kg
5) Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) ≥ 90 mL/min/1.73m2 using the Schwartz Formula.
6) Adequate hematologic function defined as:
•Absolute neutrophil count ≥ 500 cells/mm3 (Note: Subjects with chronic neutropenia, defined as having an ANC of < 500/mm3 documented at least twice within 6 months of screening, and in whom, according to the investigator, there is no evidence of active opportunistic serious infection or clinically relevant immune dysfunction related to neutrophenia can enroll in the study contingent upon approval from the Gilead Medical Monitor.)
•Hemoglobin > 8.5 g/dL (9.5 g/dL for infants less than 35 days of age)
•Platelets > 50,000/mm3
7) Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN)
8) Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
9) Subjects 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 to the subjects as a part of local standard of care.
10) Negative serum β-HCG pregnancy test for female subjects (of childbearing potential only).
11) For subjects with evidence of suppressed viremia (Part A only):
•Plasma HIV-1 RNA concentration (at least 2 consecutive measurements) at an undetectable level according to the assay being used for at least 3 months prior to screening, and HIV-1 RNA <50 copies/mL (Roche COBAS TaqMan v2.0) at screening.
•Stable antiretroviral regimen including one of the following PI/r for at least 3 months prior to screening: lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. Subjects undergoing dose modifications to their antiretroviral regimen for growth or switching medication formulations are considered to be on a stable antiretroviral regimen.
12) For subjects failing a current antiretroviral regimen at study entry (Parts A Cohort 2 only and B):
•HIV-1 RNA >1,000 copies/mL at screening
•Prior treatment for HIV-1 infection, defined as 6 months of antiretroviral treatment experience (with the exception of Cohort 4 where less than 6 months of treatment experience is acceptable) and at least 1 documented resistance mutation as defined by current IAS-USA Guidelines. These resistance gene mutations must be documented in a historical genotype report(s), or in the genotype report at screening provided by Gilead Sciences.
•Stable antiretroviral regimen (or no antiretroviral regimen) for at least 30 days prior to screening. Subjects undergoing dose modifications to their antiretroviral regimen for growth or switching medication formulations are considered to be on a stable antiretroviral regimen.
•Screening genotype must show full sensitivity to EVG.
•Ability to construct a BR that must contain one of the following fully active PI/r: lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. (Fully active is defined by genotypic analysis.)
•Genotypic sensitivity score (GSS) of at least 2 (including the fully active PI/r and EVG).
•No opportunistic infection within 30 days of study entry.
13) Male and female subjects 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; highly effective methods normally utilize two separate forms of contraception, one of which must be an effective barrier contraceptive method. Pre-pubertal females (Tanner Stages 1 and 2 are not considered to be of childbearing potential, unless onset of menarche has occurred. )
•Female subjects who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing. It is recommended that an oral contraceptive contain at least 30 μg of ethinyl estradiol if administered with EVG.
14) Must be willing and able to comply with all study requirements. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Subjects with the following CD4+ cell counts:
•For Cohorts 1 and 2: Screening CD4+ cell count < 50 cells/mm3
•For Cohort 3: Screening CD4+ cell count < 75 cells/mm3
•For Cohort 4: Screening CD4+ cell count < 200 cells/mm3
2) An acquired immunodeficiency syndrome (AIDS)-defining condition with onset within 30 days prior to screening
3) Life expectancy of < 1 year
4) For subjects with HIV-1 RNA >1,000 copies/mL at screening, prior treatment of any duration with an integrase strand transfer inhibitor.
5) An ongoing serious infection requiring systemic antibiotic therapy at the time of screening.
6) Evidence of active pulmonary or extra-pulmonary tuberculosis disease:
•Within 3 months of the Screening visit for all subjects 6 months of age or older
•At any time for subjects younger than 6 months
7) Anticipated requirement for rifamycin treatment while participating in the study. Note: prophylactic isoniazid therapy for latent TB is allowed.
8) Active HCV infection. Note: subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll.
9) Have any serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include uncontrolled renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (e.g., diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment within 30 days prior to the study dosing.
10) Subjects experiencing decompensated cirrhosis (eg, ascites, encephalopathy)
11) A history of or ongoing malignancy other than cutaneous Kaposi’s sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Subjects with biopsy confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Baseline and are not anticipated to require systemic therapy during the study.
12) Pregnant or lactating subjects.
13) Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance.
14) Have history of significant drug sensitivity or drug allergy.
15) Known hypersensitivity to the investigational medicinal product (IMP), the metabolites, or formulation excipients.
16) Have previously participated in an investigational trial involving administration of any investigational agent within 30 days prior to the study dosing.
17) Participation in any other clinical trial without prior approval from sponsor is prohibited while participating in this trial.
18) Subjects 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 (refer to prescribing information for drugs used as part of the BR); examples include the following-see protocol: (Administration of any of the following medications must be discontinued at least 30 days prior to the Baseline/Day 1 visit and for the duration of the study) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of this study are:
•Pharmacokinetic (PK) parameters AUCtau and Cmax of EVG
•Safety and tolerability through Week 48 as assessed by the the incidence of
treatment-emergent AEs and treatment-emergent laboratory abnormalities
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic (PK) parameters AUCtau and Cmax of EVG- timepoint of evaluation Day 10
Incidence of treatment-emergent AEs and treatment-emergent laboratory abnormalities- timepoint through to week 48
|
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are:
•PK parameters Ctau, CL/F, and Vz/F of EVG
•The percentage of subjects with plasma HIV 1 RNA <50 and <400 copies/mL at Weeks 24 and 48 as defined by the FDA snapshot analysis, respectively
•The change from baseline in plasma log10 HIV 1 RNA (copies/mL), in CD4+ cell count (cells/μL), and CD4 percentage at Weeks 24 and 48
•Tanner Stages at Weeks 24 and 48, and age of first menses.
•Palatability of oral suspension formulation of EVG in appropriate age group
•Adherence to EVG |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation are;
•PK parameters Ctau, CL/F, and Vz/F of EVG- timepoint Day 10
•The percentage of subjects with plasma HIV 1 RNA <50 and <400 copies/mL at Weeks 24 and 48 as defined by the FDA snapshot analysis, respectively
•The change from baseline in plasma log10 HIV 1 RNA (copies/mL), in CD4+ cell count (cells/μL), and CD4 percentage at Weeks 24 and 48
•Tanner Stages at Weeks 24 and 48, and age of first menses.
•Palatability of oral suspension formulation of EVG in appropriate age group- through to week 48
•Adherence to EVG- through to week 48 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Italy |
| South Africa |
| Spain |
| Thailand |
| Uganda |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Part A subjects with suppressed viremia, the end of study is defined as the completion of Day 10 & the 30-Day Follow-up visit.
For subjects failing a current antiretroviral regimen, the end of study is defined as the completion of 48 weeks on study drug & the 30-Day Follow-up visit.
For extension phase end of trial is when a) subject turns 18 & EVG is available for use in adults or b) the age appropriate EVG formulation becomes available or c) Sponsor elects to terminate development of EVG. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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