| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
Cohort 1:
-SS PK and confirm dose of ATV/co or DRV/co in HIV-1 infected
virologically suppressed adolescents ≥ 25 kg (12 to < 18 years of age)
-safety and tolerability of ATV/co or DRV/co through 24 weeks, in
population above mentioned
Cohort 2:
-evaluate SS PK and confirm the dose of ATV/co or DRV/co in HIV-1
infected pediatric patients ≥ 25 kg to < 35 kg (6 to < 12 years of age)
-evaluate SS PK and confirm dose of F/TAF in population above
mentioned
-evaluate safety and tolerability of ATV/co, DRV/co and F/TAF through
24 weeks in population above mentioned
Cohort 3:
-evaluate SS PK and confirm the dose of ATV/co or DRV/co of HIV-1
infected pediatric patients ≥ 14 kg to < 25 kg (≥ 3 years of age)
-evaluate SS PK and confirm the dose of F/TAF in population above
mentioned
-evaluate safety and tolerability of ATV/co, DRV/co and F/TAF through
24 weeks in population above mentioned
|
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1:
-efficacy of ATV/co or DRV/co through 24 weeks in HIV-1 infected
virologically suppressed adolescents ≥ 25 kg (12 to < 18 years of age)
-safety, tolerability and efficacy of ATV/co or DRV/co through 48 weeks,
in population above mentioned
Cohort 2:
-efficacy of ATV/co, DRV/co and F/TAF through 24 weeks in HIV-1
infected pediatric patients ≥ 25 kg to < 35 kg (6 to < 12 years of age)
-safety, tolerability and efficacy of ATV/co, DRV/co and F/TAF through
48 weeks, in population above mentioned
Cohort 3:
-efficacy of ATV/co, DRV/co and F/TAF through 24 weeks in HIV-1
infected pediatric patients ≥ 14 kg to < 25 kg (≥ 3 years of age)
-safety, tolerability and efficacy of ATV/co, DRV/co and F/TAF through
48 weeks in population above mentioned
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Age 3 to < 18 years (according to requirements of enrolling Cohort)
2) Participants 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) A negative serum -HCG pregnancy test is required for female subjects of childbearing potential only
5) Body weight at screening is as follows:
Cohort 1: 12 years to <18 years, ≥ 25 kg
Cohort 2: 6 years to <12 years, ≥ 25 kg to < 35 kg
Cohort 3: ≥ 3 years, ≥ 14 kg to < 25 kg
6) Adequate renal function: Estimated Glomerular Filtration Rate (eGFR)
≥ 90 mL/min/1.73 m2 using the Schwartz Formula:
Schwartz Formula (mL/min/1.73 m2) = k x L/SCr (k is a proportionality
constant, L is height in centimeters (cm) and SCr is serum creatinine
(mg/dL). The value of k is 0.55 for children (≥ 2 to < 12 years old) and
adolescent girls (≥ 12 years old) and 0.70 for adolescent boys (≥ 12
years old).
7) Male and female subjects of childbearing potential, or who reach
childbearing potential during study participation, must agree to utilize
highly effective contraception methods while on study treatment or
agree to abstain from heterosexual intercourse throughout the study
period. Pre-pubertal females (Tanner stages 1 and 2) are not considered
to be of childbearing potential, unless onset of menarche has occurred.
8) Adequate hematologic function defined as:
a) Absolute neutrophil count ≥ 500 cells/mm3 (Subjects with neutrophil
count of < 500/mm3 documented at least twice within 6 months of
screening, and whom, according to the investigator, have no evidence of
immunosuppression associated with low neutrophil count, can enroll in
the study contingent upon approval from the Gilead study Medical
Monitor)
b) Hemoglobin > 8.5 g/dL
c) Platelets ≥ 50,000/mm3
9) Adequate hepatic function defined as:
a) Transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN)
b) Total bilirubin ≤ 1.5 mg/dL or a normal direct bilirubin
10) Stable antiretroviral regimen for a minimum of 3 months prior to the
screening visit.
11) Documented plasma HIV-1 RNA for ≥ 3 months preceding the
Screening visit
Participants enrolled after the implementation of Amendment 8:
Virologically suppressed ≥ 3 months preceding the Screening visit: 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)
Viremic: HIV-1 RNA ≥ 50 copies/mL and on a stable regimen
For virologically suppressed subjects, 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.
12) Must be willing and able to comply with all study requirements
|
|
| E.4 | Principal exclusion criteria |
1) 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) An ongoing serious infection requiring systemic antibiotic therapy at
the time of screening
5) Evidence of active pulmonary or extra-pulmonary tuberculosis (TB)
disease, within 3 months of the Screening visit
6) Anticipated requirement for rifamycin treatment while participating in
the study Note: prophylactic isoniazid therapy for latent TB is allowed
7) Active HCV infection. Subjects with positive HCV antibody, and
without detectable HCV RNA are permitted to enroll
8) Positive Hepatitis B (HBV) surface antigen or other evidence of active
HBV infection. Note: Subjects with positive HBV surface antibody, and no
evidence of active HBV infection are permitted to enroll
9) Subjects with clinically significant abnormal ECGs
10) 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 (including diabetes), central nervous,
gastrointestinal (including ulcers), vascular, metabolic (including thyroid
disorders and adrenal disease), immunodeficiency disorders, active
infection, or malignancies that are clinically significant or require
treatment within 30 days prior to Day 1
11) Subjects experiencing decompensated cirrhosis (eg, ascites,
encephalopathy, etc.)
12) A history of, or ongoing, malignancies 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
13) Pregnant or lactating subjects
14) Current alcohol or substance abuse judged by the Investigator to
potentially interfere with subject compliance
15) A History of significant drug sensitivity or drug allergy
16) Known hypersensitivity to the investigational medicinal product
(IMP), its metabolites, or formulation excipient
17) Have previously participated in a clinical trial involving
administration of any investigational agent within 30 days prior to Day 1
18) Participation in any other clinical trial, including observational
studies, without prior approval from sponsor is prohibited while
participating in this trial
19) Participants receiving ongoing therapy with any medication that is
not to be taken with COBI, F/TAF, a component of the current
antiretroviral regimen, or drugs not to be used with ritonavir (refer to
prescribing information for drugs used as part of the antiretroviral
regimen). Administration of any of the following medications (Table 4-1)
must be discontinued for:
-Drug Class - Agents Disallowed:
-Acid Reducing Agents (H2-receptor antagonists [H2RAs] and Proton
Pump Inhibitors [PPIs]) - H2-receptor antagonists and Proton pump
inhibitors
should not be used in patients less than 6 years of age, and/or less than
40 kg receiving ATV
-Alpha Adrenergic Receptor Antagonists - Alfuzosin
-Antibacterials - Telithromycin
-Anticonvulsants - Phenobarbital, Phenytoin, Carbamazepine,
Oxcarbazepine
-Antifungals - Voriconazole
-Antihistamines - Astemizole, Terfenadine
-Antimycobacterials - Rifampin, Rifapentine, Rifabutin
-Antiretrovirals - Any antiretroviral drug that is not part of the study
regimen
-Antiarrhythmics - Amiodarone, quinidine, dronedarone
-Antipsychotics - Lurasidone
-Antivirals - Cidofovir, Ganciclovir, Valganciclovir
-Calcium Channel Blockers - Bepridil
-Direct Oral Anticoagulants (DOACs) - Apixaban, Rivaroxaban
-Ergot Derivatives - Ergotamine, Ergonovine, Dihydroergotamine,
Methylergonovine - Ergometrine
-GI Motility Agents - Cisapride
-Herbal/Natural Supplements - St. John's Wort, Echinacea
-Lipid-modifying agents - Simvastatin, Lovastatin, Cerivastatin
-Neuroleptics - Pimozide
-Oral contraceptives - Drospirenone when coadministered with ATV/co
-Sedatives/Hypnotics - Midazolam, Triazolam
-Phosphodiesterase-5 inhibitor - Sildenafil for pulmonary arterial
hypertension
-Topoisomerase inhibitors - Irinotecan
-Other - Probenecid |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- PK parameters of AUCtau of ATV and DRV for each cohort; AUCtau of
TAF for Cohorts 2 and 3 taking F/TAF.
- The incidence of treatment-emergent AEs and treatment-emergent
laboratory abnormalities through week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Day 10
- Throughout duration of study |
|
| E.5.2 | Secondary end point(s) |
- PK parameters of Ctau, Cmax, and CL/F for ATV and DRV; AUCtau, Ctau,
Cmax CL/F, and Vz/F for COBI; Cmax, Clast, CL/F, and Vz/F for TAF;
AUCtau, Cmax, and Ctau for FTC and TFV
- The incidence of treatment-emergent AEs and treatment-emergent
laboratory abnormalities through Week 48
- The percentage of participants with HIV-1 RNA < 50 copies/mL at
Week 24 and as defined by the US FDA-defined snapshot algorithm
- The change from baseline in CD4+ cell counts (cells/μL), and CD4+
percentages at Weeks 24 and 48
- Acceptability and palatability of COBI and F/TAF in each cohort, as
applicable |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Day 10
-Weeks 12, 24, 48 and every 12 weeks thereafter
-Throughout duration of study
-Weeks 24 and 48, and every 12 weeks thereafter
-Weeks 24 and 48, and every 12 weeks thereafter in subjects < 5 years old
-Day 1, day 10, Week 24 and 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Argentina |
| Panama |
| South Africa |
| Thailand |
| United Kingdom |
| United States |
| Zimbabwe |
|
| 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.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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