| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus (HIV-1) Infection |
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| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus (HIV-1) Infection |
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| 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 |
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| 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 |
Cohorts 1, 2 & 3:
Part A: To evaluate the steady state PK of BIC and confirm dose of the B/F/TAF 50/200/25 mg FDC and dose of B/F/TAF 30/120/15 mg FDC
Parts A & B: To evaluate safety and tolerability of adult strength and low dose B/F/TAF FDC through Week 24
Cohort 4:
Group 1: To evaluate the safety and tolerability of B/F/TAF 30/120/15 mg FDC TOS through Week 24
Group 2:
To evaluate the steady state PK of BIC and TAF and confirm the dose of B/F/TAF 15/60/7.5 mg FDC TOS
To evaluate the safety and tolerability of the B/F/TAF 15/60/7.5 mg FDC TOS through Week 24
Group 3:
To evaluate the steady state PK of BIC and TAF and confirm the dose of B/F/TAF 7.5/30/3.75 mg FDC TOS
To evaluate the safety and tolerability of B/F/TAF 7.5/30/3.75 mg FDC TOS through Week 24
Group 4:
To evaluate the steady state PK of BIC and TAF and confirm the dose of B/F/TAF 3.75/15/1.88 mg FDC TOS
To evaluate the safety and tolerability of the B/F/TAF 3.75/15/1.88 mg FDC TOS through Week 24
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|
| E.2.2 | Secondary objectives of the trial |
Cohorts 1, 2 & 3:
To evaluate safety and tolerability of adult strength and low dose B/F/TAF FDC through Week 48
To evaluate antiviral activity of adult strength and the low dose B/F/TAF FDC through Weeks 24 and 48
Cohort 4:
Group 1:
To evaluate safety and tolerability of B/F/TAF 30/120/15 mg FDC TOS through Week 48
To evaluate antiviral activity of B/F/TAF 30/120/15 mg FDC TOS through Weeks 24 and 48
Group 2:
To evaluate safety and tolerability of the B/F/TAF 15/60/7.5 mg FDC TOS through Week 48
To evaluate antiviral activity of the B/F/TAF 15/60/7.5 mg FDC TOS through Weeks 24 and 48
Group 3:
To evaluate safety and tolerability of B/F/TAF 7.5/30/3.75 mg FDC TOS through Week 48
To evaluate antiviral activity of B/F/TAF 7.5/30/3.75 mg FDC TOS through Weeks 24 and 48
Group 4:
To evaluate safety and tolerability of the B/F/TAF 3.75/15/1.88 mg FDC TOS through Week 48
To evaluate antiviral activity of the low dose B/F/TAF 3.75/15/1.88 mg FDC TOS through Weeks 24 and 48
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|
| 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) Age ≥ 1 month to < 18 years (according to requirements of enrolling Cohort)
2) Subject is able to provide written assent if they have the ability to read and write (if applicable per their local institutional guidelines and local country regulations)
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 for Cohort 1: ≥ 35 kg (77 lbs); Cohort 2 ≥ 25 kg (55 lbs); Cohort 3: ≥ 14 to < 25 kg (≥ 31 to < 55 lbs); Cohort 4: Group 1: ≥ 14 to < 25 kg (≥ 31 to < 55 lbs), Group 2: ≥ 10 to < 14 kg (≥ 22 to < 31 lbs), Group 3: ≥ 6 to < 10 kg (≥ 13 to < 22 lbs), Group 4: ≥ 3 to < 6 kg (≥ 6.6 to < 13 lbs)
5) Confirmed HIV infection if < 18 months of age (positive nucleic acid based test result to be provided)
6) Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) ≥ 90 mL/min/1.73 m2 (≥ 1.5 mL/sec/1.73 m2) for children ≥ 1 year of age using the Schwartz Formula.
Adequate renal function: eGFR ≥ the minimum normal values for children < 1 year of age using the Schwartz Formula.
7) Adequate hematologic function defined as: a) Absolute neutrophil count > 500 cells/mm3 (> 0.50 GI/L), b) Hemoglobin > 8.5 g/dL (≥ 85 g/L), c) Platelets ≥ 50,000/mm3 (≥ 50 GI/L)
8) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
9) Total bilirubin ≤ 1.5 mg/dL (≤ 26 μmol/L), or normal direct bilirubin
10) Documented plasma HIV-1 RNA < 50 copies/mL on a stable regimen (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for ≥ 6 months preceding the Screening visit for Cohorts 1, 2 and 3 and Cohort 4 Group 1. For Cohort 4, Groups 2-4: treatment naive or on ARV treatment for ≥ 1 month. Antiretrovirals used for Prevention of Mother-to-Child Transmission (PMTCT) are allowed for naive or ART treated patients.
Unconfirmed virologic elevations of ≥ 50 copies/mL (transient detectable viremia, or “blip”) prior to screening are acceptable. If the lower limit of detection of the local HIV-1 RNA assay is < 50 copies/mL (eg, < 20 copies/mL), the plasma HIV-1 RNA level cannot exceed 50 copies/mL on two consecutive HIV-1 RNA tests.
11) Stable antiretroviral regimen of 2 NRTIs in combination with a third agent for a minimum of 6 months prior to the screening visit. Subjects undergoing dose modifications to their antiretroviral regimen for growth or who are switching medication formulation(s) are considered to be on a stable antiretroviral regimen (Cohorts 1, 2, 3 and Cohort 4 Group 1).
Stable ARV treatment of 2 NRTIs in combination with a third agent for a minimum of 1 month prior to the screening visit or treatment naive (Cohort 4 Groups 2, 3 and 4 only) (patient is considered treatment naive if ARVs were given for prevention of mother-to-child transmission only and not for HIV treatment)
12) Plasma HIV-1 RNA < 50 copies/mL at the screening visit (Cohorts 1, 2, 3 and Cohort 4 Group 1). No threshold for HIV RNA levels for Cohort 4 Groups 2, 3 and 4.
13) Life expectancy ≥ 1 year
14) Have no documented or suspected resistance to FTC, TFV, or INSTIs including, but not limited to, the reverse transcriptase resistance mutations K65R. Subjects with M184V/I AND HIV-1 RNA < 50 copies/mL may be enrolled in Cohort 4. Subjects in Cohort 4 with HIV-1 RNA > 50 copies/mL should have documentation of no FTC, TFV, or INSTI resistance by plasma testing at screening (> 400 copies/mL) or historical genotype (if > 50 copies/mL but < 400 copies/mL).
15) A negative serum β-HCG pregnancy test is required for female subjects of childbearing potential only
16) Female and male subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
17) 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
18) Male subjects must refrain from sperm donation throughout the study period
19) Must be willing and able to comply with all study requirements
20) Lactating females must agree to discontinue nursing before the IMP is administered. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Cohorts 1, 2, 3 and Cohort 4 Group 1: CD4+ cell count < 200 cells/ mm3. Cohort 4 Groups 2, 3 and 4: CD4+ cell count < 750 cells/mm3 for ≥1 to <12 months of age and < 500 cells/mm3 for ≥12 to <24 months of age.
2) An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to screening
3) An ongoing serious infection requiring systemic antibiotic therapy at the time of screening
4) Evidence of active pulmonary or extra-pulmonary tuberculosis within 3 months
5) Acute hepatitis in the 30 days prior to study entry
6) Hepatitis B virus (HBV) surface antigen (HBsAg) positive
7) Hepatitis C virus (HCV) antibody positive with detectable HCV RNA. Children < 18 months of age born to an HCV positive mother and/or HCV antibody positive will need to have 2 negative HCV RNA tests 6 months apart with the first test occurring no earlier than 2 months of age. In this situation, the earliest such a patient can be screened for study eligibility is at 8 months of age.
8) 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 Day 1.
9) Subjects experiencing decompensated cirrhosis (eg, ascites, encephalopathy)
10) 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 Day 1 and are not anticipated to require systemic therapy during the study
11) Females who are pregnant (as confirmed by positive serum pregnancy test)
12) Females who are breastfeeding
13) ≤ 2 months of age and gestational age (GA) ≤ 37 weeks (Cohort 4 Groups 2, 3 and 4)
14) Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance
15) Have history of significant drug sensitivity or drug allergy
16) Known hypersensitivity to the investigational medicinal product (IMP), the metabolites, or formulation excipients
17) Participation in any other clinical trial, including observational studies without prior approval from sponsor is prohibited while participating in this trial
18) Cohort 4 Groups 2, 3, and 4: Last dose of nevirapine (NVP) or efavirenz (EFV), if applicable, ≥ 14 days prior to enrolment
19) Subjects receiving ongoing therapy with any medication that is not to be taken with the study drug. Administration of any of the following medications must be discontinued at least 30 days prior to the Day 1 visit and for the duration of the study, with the exception of the subject’s prior ARV treatment regimen, which must be continued until their scheduled Day 1 visit.
- Antiarrhythmic agent: dofetilide
- Anticonvulsants: phenobarbital, phenytoin, carbamazepine, oxcarbazepine
- Antimycobacterials: rifampin, rifapentine, rifabutin
- Antiretrovirals: any antiretroviral drug that is not part of the study regimen
- GI Motility Agents: cisapride
- Herbal/Natural supplements: St. John’s Wort, Echinaccea |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of this study are:
- The steady state PK parameters AUCtau and Ctau (Ctrough) for BIC at Week 2 (all cohorts) or Week 4 (Cohort 1 and 2 Part A subjects only)
- The steady state PK parameters AUClast and Cmax for TAF at Week 2 (Cohort 4 Groups 2, 3 and 4 only)
- Incidence of treatment-emergent AEs, and treatment-emergent laboratory abnormalities through Week 24 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 2 or 4 and Week 24 respectively, as defined above |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are:
- The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by the US FDA-defined snapshot algorithm
- Change from baseline in CD4 cell counts and percentages at Weeks 24 and 48
- PK parameters of AUClast, Cmax, Tmax, T1/2, apparent CL and apparent Vz for BIC, as applicable; AUCtau, AUClast, Cmax, Ctau, Tmax, T1/2, apparent CL and apparent Vz for TAF and FTC, as applicable
- Incidence of treatment-emergent AEs, and treatment-emergent laboratory abnormalities through week 48
- Acceptability and palatability of adult B/F/TAF formulation |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 24 and 48 respectively, as defined above |
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| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Acceptability and tolerability |
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| 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 |
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 |
| South Africa |
| Thailand |
| Uganda |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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