E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Long term infection with hepatitis B virus |
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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 | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
To evaluate the relative bioavailability of a pediatric oral granule formulation of tenofovir alafenamide (TAF) relative to the adult tablet formulation |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of a single dose of a pediatric oral granule formulation of TAF in healthy subjects |
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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) Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
2) Be aged 18 through 45 years of age, inclusive at screening
3) Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug
4) Have a calculated body mass index (BMI) of >= 19.0 and <= 30.0 kg/m2 at screening
5) Have a creatinine clearance (CLcr) mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening.
6) Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission (unless permanently sterile or greater than 2 years postmenopausal)
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
8) Male subjects must refrain from sperm donation from clinic admission (eg, Day -1), throughout the study period, and continuing for at least 7 days following the last dose of study drug
9) Subjects have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 7 days following the last dose of study drug.
10) Screening laboratory and 12-lead ECG evaluations must be without clinically significant abnormalities as assessed by the investigator
11) Have liver disease or liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin equal to or below the upper limit of normal at screening
12) Must be willing and able to comply with all study requirements
13) Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will not be enrolled in this study:
1) Be a lactating female
2) Have received any study drug within 30 days prior to study dosing
3) Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
4) Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody
5) Have poor venous access that limits phlebotomy
6) Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications
7) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
8) Have a history of any of the following:
A) Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticarial
B) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
C) Known hypersensitivity to the study drugs their metabolites or to formulation excipients
D) Significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years
E) Syncope, palpitations, or unexplained dizziness
F) Implanted defibrillator or pacemaker
G) Liver disease, including Gilbert disease
H) Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment.
I) Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary.
9) Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including 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
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints are the following plasma PK parameters of TAF and TFV: AUClast, AUCinf, and Cmax. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Intensive pharmacokinetic (PK) blood sampling will occur relative to dosing of TAF at the following time points:
Days 1 and 13: predose (≤ 5 min), 5 min, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hours postdose. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are the incidences of AEs and laboratory abnormalities.
Additional PK parameters calculated may include: %AUCexp, Tmax, Clast, Tlast, z, CL/F, t1/2, and Vz/F. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Days -1, 1, 13, 19 and Early Termination Visit |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
E.8.4 | Will this trial be conducted at multiple sites globally? | No |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of this study will be the last subject’s last observation (or visit). |
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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 days | 57 |