| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| human immunodeficiency virus-1 (HIV-1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| human immunodeficiency virus-1 (HIV-1) |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| 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 |
-To evaluate the pharmacokinetics (PK) of tenofovir alafenamide (TAF) and confirm the TAF dose in HIV-1 infected children and adolescents virologically suppressed on a 2 NRTI-containing regimen.
-To evaluate the safety and tolerability of emtricitabine/tenofovir alafenamide (F/TAF) through Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the PK of tenofovir (TFV) and emtricitabine (FTC).
-To evaluate the safety, tolerability, and efficacy of F/TAF through Week 48. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. HIV-1 infected male and female pediatric patients aged 1 month to < 18 years at Baseline/Day 1 (according to requirements of the enrolling cohort)
2. Subject is able to give written assent prior to any screening evaluations if they have the ability to read and write
3. Parent or guardian able to give written informed consent prior to any screening evaluations and willing to comply with study requirements
4. A negative serum β-HCG pregnancy test is required for female subjects of childbearing potential only
5. Body weight at screening as defined in protocol
6. Currently on a stable 2-NRTI-containing regimen that includes a 3rd ARV agent for ≥ 6 consecutive months prior to screening.
7. Plasma HIV-1 RNA levels < 50 copies/mL for ≥ 6 consecutive months preceding the screening visit (measured at least twice using the same assay) and not experienced two consecutive HIV-1 RNA above detectable levels after achieving a confirmed (two consecutive) HIV-1 RNA below detectable levels on the current regimen in the past year.
8. Estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73m2 by (Schwartz) formula
9. All male subjects and those female subjects of childbearing potential or those who reach childbearing potential during study participation (as defined in Appendix 5 of the protocol) 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. See Appendix 5 of the protocol for definition of females of childbearing potential.
10. 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.
11. Adequate hematologic function
12. Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN)
13. For subjects on all 3rd ARV agents except ATV, total bilirubin ≤ 1.5 mg/dL or normal direct bilirubin
14. For subjects on ATV, total bilirubin ≤ 3.0 mg/dL or normal direct bilirubin
15. Normal ECG (or if abnormal, determined by the investigator to be not clinically significant)
16. Must be willing and able to comply with all study requirements
17. No opportunistic infection within 30 days of study entry (at Baseline/Day 1)
18. Subject is able to swallow a tablet |
|
| E.4 | Principal exclusion criteria |
1. An acquired immunodeficiency syndrome (AIDS) - indicator condition with onset within 30 days prior to screening
2. Life expectancy of < 2 years.
3. Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Baseline/Day 1
4. Evidence of active pulmonary or extra-pulmonary tuberculosis disease within 3 months of the screening visit
5. Anticipated requirement for rifamycin treatment while participating in the study.
6. Active HCV infection defined as positive for HCV antibody and having detectable HCV RNA.
7. Positive Hepatitis B surface antigen or other evidence of active HBV infection.
8. Subjects with a historical genotype that have documented resistance to TFV or FTC, including, but not limited to, the presence of reverse transcriptase mutations K65R, K70E, M184V/I, or 3 or more thymidine analog-associated mutations (TAMs) that include M41L or L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R).
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 or active tuberculosis), 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 Baseline/Day 1).
10. Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy).
11. A history 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 screening 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 excipient.
16. Have previously participated in an investigational trial involving administration of any investigational agent, other than TDF, 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 of the following medications in the table 4.1 of the protocol, including drugs not to be used with FTC, TAF or their 3rd ARV agent (refer to the individual agents Prescribing Information). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The PK parameter AUCtau for TAF
- Incidence of treatment-emergent SAEs and all treatment-emergent adverse events |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- PK endpoint: at Week 2 (Intensive Pharmacokinetic assessment [IPK]) for Cohort 1; at Week 2 or Week 4 visit or within 7 days after the completion of Week 2 or Week 4 visit for Cohort 2 part A
- Safety endpoint: through Week 24 |
|
| E.5.2 | Secondary end point(s) |
- PK parameters of Cmax, Clast, Cl/F, and Vz /F for TAF, AUCtau, Cmax, and Ctau for FTC and TFV
- Incidence of treatment-emergent SAEs and all treatment-emergent adverse events
- The percentage of subjects with HIV-1 RNA < 50 copies/mL
- The change from baseline in CD4+ cell count (cells/μL) and CD4+ percentage
- The palatability and acceptability of the age-appropriate F/TAF formulation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK endpoint: at Week 2 (IPK) for Cohort 1; at Week 2 or Week 4 visit or within 7 days after the completion of Week 2 or Week 4 visit for Cohort 2 part A
- Safety endpoint: through Week 48
- Efficacy endpoint (HIV-1 RNA): at Weeks 24, 48 and 96
- Efficacy endpoint (CD4+ cell count): at Weeks 24, 48 and 96 |
|
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Panama |
| South Africa |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 11 |
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