Chronic Hepatitis B Infection

Primary Objectives:  To assess the safety and tolerability of RO7020322 compared to placebo after single-ascending and multiple-ascending oral doses in healthy subjects.  To assess the safety and tolerability of RO7020322 compared to placebo after multiple oral doses in chronically HBV infected patients.

RO7020322

RO7020322

Capsule

1 mg, 10 mg, 100 mg

SAFETY OUTCOME MEASURES
A detailed medical history and a complete physical examination will be performed at the time
points indicated in the schedule of assessment (SoA).

Inclusion Criteria
Healthy subjects must meet the following criteria for study entry:
1. Healthy male and female subjects (of non-childbearing-potential). Healthy status is defined
by absence of evidence of any active or chronic disease following a detailed medical and
surgical history, concomitant drug use (including hormonal supplements), a complete
physical examination including vital signs, 12-lead ECG, hematology, blood chemistry,
serology and urinalysis.
2. 18 to 65 years of age, inclusive.
3. A Body Mass Index (BMI) between 18 to 30 kg/m2
inclusive and a body weight of at least
50 kg.
4. All males must agree to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agree to refrain from donating sperm, as defined below:
a) With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and up to the
follow-up period to avoid exposing the embryo. Men must refrain from donating
sperm during this same period.
b) The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the healthy subject.
Periodic abstinence and withdrawal are not acceptable methods of contraception.
5. Women should be of non-childbearing potential. A woman is considered to be of
childbearing potential if she is post-menarcheal but has not reached a post-menopausal
state ( 12 continuous months of amenorrhea with no identified cause other than
menopause, confirmed by follicle-stimulating hormone [FSH], or amenorrhea for at least
24 months if on hormone replacement therapy), and has not undergone surgical sterilization
(removal of ovaries and/or uterus).
6. Able to participate and willing to give written informed consent and to comply with the study
restrictions.
7. Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1
and agree to remain as non-smoker during the study.
Chronic hepatitis B infected patients must meet the following criteria for study entry:
1. Adult male and female patients, aged 18-65 years.
2. A BMI between 18 to 32 kg/m2
inclusive.
3. Chronic hepatitis B infection.
4. Positive test for HBsAg for more than 6 months prior to randomization.
5. HBsAg titer  103
IU/mL at screening.
6. On entecavir or tenofovir treatment for at least 6 months prior to randomization and will
remain on stable treatment during the study.
7. HBV DNA below detection for at least the preceding 6 months.
8. Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 days prior
to first study treatment within normal ranges or judged to be not clinically significant by
Principal Investigator (PI) and Medical Monitor.
9. Alanine transaminase (ALT), aspartate aminotransferase (AST), -glutamyltransferase
(GGT), and alkaline phosphatase (ALP) at screening  1.5 x upper limit of normal (ULN);
normal values for tuberculosis (TB) and prothrombin time (PT)/International Normalized
Ratio (INR)/activated partial thromboplastin time (aPTT) tests at screening (except for
patients with Gilbert’s syndrome TB  47 mol/L [2.75 mg/dL]).
10. Liver biopsy, fibroscan
or equivalent test obtained within the past 6 months demonstrating
liver disease consistent with chronic HBV infection without evidence of bridging fibrosis or
cirrhosis.
11. All males must agree to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
c) With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and up to the
follow-up period to avoid exposing the embryo. Men must refrain from donating
sperm during this same period.
d) The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence and withdrawal are not acceptable methods of contraception.
12. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use non-hormonal contraceptive methods that result in a failure
rate of  1% per year during the treatment period and for at least until the end of the
follow-up period.
13. A woman is considered to be of childbearing potential if she is post-menarcheal, has not
reached a post-menopausal state ( 12 continuous months of amenorrhea with no identified
cause other than menopause), and has not undergone surgical sterilization (removal of
ovaries and/or uterus). Examples of non-hormonal contraceptive methods with a failure rate
of  1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine
devices.
14. The reliability of sexual abstinence should be evaluated in relation to the duration of the
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
acceptable methods of contraception.
15. Ability and willingness of patient or legal guardian/representative to provide written informed
consent.

Exclusion criteria
Healthy subjects who meet any of the following criteria will be excluded from study entry:
1. Women who are lactating.
2. Any suspicion or history of alcohol and/or other substance abuse or dependence in the past
6 months.
3. Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone,
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or positive
cotinine test at Day -1.
4. Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus
(HIV) 1 and 2.
5. Confirmed (e.g., two consecutive triplicate measurements) average systolic blood pressure
(SBP)  140 or  90 mmHg, and diastolic blood pressure (DBP)  90 or  45 mmHg at
screening.
6. Confirmed (e.g., two consecutive triplicate measurements) average resting pulse rate (PR)
 90 or  45 beats per minute (bpm) at screening.
7. A personal history of unexplained blackouts or faints, or known risk factors for Torsade de
Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal ECG, including
arrhythmias or marked QT abnormalities (QTcF  300 msec or  450 msec at screening).
8. ECG morphology at screening that renders measurement of QT interval imprecise (e.g.,
neuromuscular artifact that cannot be readily eliminated, indistinct QRS onset, low amplitude
T-wave, merged T- and U-waves, prominent U-waves, arrhythmias, etc.).
9. Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right or left
bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Clinically significant abnormalities (as judged by the Investigator) in the physical examination
and in the laboratory test results (including hepatic and renal panels, complete blood count,
chemistry panel and urinalysis) at screening and on Day-1.
12. Participation in an investigational drug or device study within 90 days prior to screening or 5
times the half-life of the investigational drug (whichever is longer).
13. Donation of blood over 500 mL within three months prior to screening.
14. Concomitant disease or condition (including allergic reactions against any drug, or multiple
allergies) that could interfere with, or treatment of which might interfere with, the conduct of
the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the
healthy subject in this study.
15. Any major illness within the one month preceding the screening visit, or any febrile illness
within the two weeks preceding the screening visit.
16. Any prescribed or over the counter medication including herbal remedies taken within
2 weeks prior to first study drug administration or within 6 times the elimination half-life of the
medication prior to first study drug administration (whichever is longer) with the exception of
hormone replacement therapy (HRT) which is allowed throughout the study. Paracetamol
(up to 2 g per day) and vitamins.
17. Coffee (or tea) consumption of  5 cups per day or  1.5 liter/day methylxanthine containing
drinks or more than 250 g/day of chocolate.
18. Alcohol consumption averaging more than 2 units per day (1 unit is 330 mL of beer, 125 mL
of wine or 25 mL of spirits, for further guidance).
19. Hypersensitivity to the excipients of the study drug.
20. Healthy subjects under judicial supervision, guardianship or curatorship.
Chronic hepatitis B infected patients who meet any of the following criteria will be excluded from
study entry:
1. Women who are pregnant (positive pregnancy test) or lactating.
2. History or other evidence of bleeding from esophageal varices.
3. Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification or clinical
evidence such as ascites or varices).
4. History or other evidence of a medical condition associated with chronic liver disease other
than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease,
toxin exposure, thalassemia, non-alcoholic steatohepatitis, etc.).
5. Documented history or other evidence of metabolic liver disease within one year of
randomization.
6. Positive test for hepatitis A (IgM anti-HAV), hepatitis C, or HIV.
7. Documented history of infection with hepatitis D virus.
8. Expected to need systemic antiviral therapy other than that provided by the study at any time
during their participation in the study, with the exception of oral therapy for Herpes simplex
virus (HSV) I or HSV II.
9. History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP)  13 ng/mL at
screening.
10. History of immunologically-mediated disease (e.g., inflammatory bowel disease, idiopathic
thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia,
scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other
autoimmune disease).
11. History of clinically significant and not adequately controlled cardiovascular, endocrine,
gastrointestinal, renal, ocular, pulmonary, or neurological disease.
12. Evidence of an active or suspected cancer or a history of malignancy other than adequately
treated basal cell carcinoma.
13. History of having received (in the last 6 months) or currently receiving any systemic
anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic
corticosteroids).
14. History of organ transplantation.
15. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or
multiple drug allergies (non-active hay fever is acceptable).
16. Significant acute infection (e.g., influenza, local infection) or any other clinically significant
illness within 2 weeks of randomization.
17. Clinically relevant ECG abnormalities on screening ECG including arrhythmias or marked
QT abnormalities (QTcF  300 msec or  450 msec at screening).
18. Any of the following laboratory parameters at screening:
a) White blood cells (WBC)  3,000 cells/ mm3
b) Neutrophil count  1500 cells/mm3
c) Platelet count  140,000 cells/mm3
d) PT  14 seconds, aPTT  40 seconds, INR  1.2
e) Hemoglobin (Hgb)  12 g/dL in females or  13 g/dL in males.
19. Abnormal renal function including serum creatinine  ULN or calculated creatinine
clearance  70 mL/min (using the Cockcroft Gault formula).
20. Participation in an investigational drug or device study within 30 days prior to randomization.
21. Donation or loss of blood over 500 mL within 3 months prior to starting study medication.
22. Administration of any blood product within 3 months of randomization.
23. History or evidence of alcohol abuse (consumption of more than 2 standard drinks per day
on average; 1 standard drink = 10 grams of alcohol) and/or drug abuse within one year of
randomization; positive test result for drugs of abuse at screening.
24. Patients under judicial supervision, guardianship or curatorship.
25. Medical or social conditions that would potentially interfere with the patient’s ability to comply
with the study visit schedule or the study assessments.