HEPATITIS B VIRUS(HBV) INFECTION

Primary:  To assess the safety and tolerability of 12-week treatment with RO6864018 administered orally to virologically suppressed entecavir treated chronic HBV patients.

RO6864018

RO6864018

Capsule

200mg/Capsule

Primary Outcome Measures :
1. Safety: Percentage of Participants with Adverse Events [ Time Frame: Baseline up to approximately 36 weeks ]

Secondary Outcome Measures :
1. Pharmacodynamics: Peripheral Blood Levels of Interferon (IFN)-Alpha in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
2. Pharmacodynamics: Peripheral Blood Levels of IFN-Alpha in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
3. Pharmacodynamics: Peripheral Blood Levels of IFN-Gamma-Induced Protein (IP)-10 in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
4. Pharmacodynamics: Peripheral Blood Levels of IP-10 in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
5. Efficacy: Quantitative HBV Deoxyribonucleic Acid (DNA) Level in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up; and at any point that breakthrough occurs (up to 36 weeks) ]
6. Efficacy: Quantitative HBV DNA Level in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up; and at any point that breakthrough occurs (up to 36 weeks) ]
7. Efficacy: Quantitative Hepatitis B Surface Antigen (HBsAg) Level in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
8. Efficacy: Quantitative HBsAg Level in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
9. Efficacy: Percentage of Participants with Loss of HBsAg in QOD Dosing Cohorts [ Time Frame: Baseline; on Day 7 of Week 12; then at Week 36 during follow-up ]
10. Efficacy: Percentage of Participants with Loss of HBsAg in QWk Dosing Cohorts [ Time Frame: Baseline; on Day 7 of Week 12; then at Week 36 during follow-up ]
11. Efficacy: Percentage of Participants with Loss of Hepatitis B Envelope Antigen (HBeAg) in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
12. Efficacy: Percentage of Participants with Loss of HBeAg in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
13. Efficacy: Percentage of Participants with HBsAg Seroconversion in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Week 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
HBsAg Seroconversion = antibody to HBsAg (Anti-HBs) Positive Status and Loss of HBsAg

14. Efficacy: Percentage of Participants with HBsAg Seroconversion in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
HBsAg Seroconversion = anti-HBs Positive Status and Loss of HBsAg

15. Efficacy: Percentage of Participants with HBeAg Seroconversion in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Week 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
HBeAg Seroconversion = antibody to HBeAg (anti-HBe) Positive Status and Loss of HBeAg

16. Efficacy: Percentage of Participants with HBeAg Seroconversion in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
HBeAg Seroconversion = anti-HBe Positive Status and Loss of HBeAg

17. Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of RO6864018 Metabolite in QOD Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 ]
18. Pharmacokinetics: Cmax of RO6864018 Metabolite in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
19. Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) of RO6864018 Metabolite in QOD Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 ]
20. Pharmacokinetics: Tmax of RO6864018 Metabolite in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
21. Pharmacokinetics: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUCinf) of RO6864018 Metabolite in QOD Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 ]
22. Pharmacokinetics: AUCinf of RO6864018 Metabolite in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
23. Pharmacokinetics: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of RO6864018 Metabolite in QOD Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 ]
24. Pharmacokinetics: AUClast of RO6864018 Metabolite in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
25. Pharmacokinetics: Half-life (t1/2) of RO6864018 Metabolite in QOD Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 ]
26. Pharmacokinetics: T1/2 of RO6864018 Metabolite in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
27. Pharmacodynamics: Peripheral Blood Levels of Neopterin in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
28. Pharmacodynamics: Peripheral Blood Levels of Neopterin in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
29. Pharmacodynamics: Peripheral Blood Levels of Tumor Necrosis Factor (TNF)-Alpha in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
30. Pharmacodynamics: Peripheral Blood Levels of TNF-alpha in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
31. Pharmacodynamics: Peripheral Blood Levels of Interleukin (IL)-6 in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
32. Pharmacodynamics: Peripheral Blood Levels of IL-6 in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
33. Pharmacodynamics: Peripheral Blood Levels of IL-10 in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
34. Pharmacodynamics: Peripheral Blood Levels of IL-10 in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
35. Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
36. Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
37. Efficacy: Percentage of Participants with Development of Anti-HBe in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
38. Efficacy: Percentage of Participants with Development of Anti-HBe in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
39. Efficacy: Percentage of Participants with Development of Anti-HBs in QOD Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
40. Efficacy: Percentage of Participants with Development of Anti-HBs in QWk Dosing Cohorts [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
41. Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QWk Cohorts [ Time Frame: QWk: Baseline; pre-dose (0 hours) and post-dose (6 and 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12, and Day 7 of Week 12; then Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
42. Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QOD Cohorts [ Time Frame: Baseline; pre-dose; post-dose (6 and 24 hours) on Days 1, 3, and 7 for Week 1, Day 1 of Weeks 3, 5, 7, Day 6 of Week 12; then Weeks 16, 20, 24, 28, 32, 36 during follow-up ]
43. Pharmacodynamics: Percentage of T Cells, B Cells, and NK Cells (TBNK) [ Time Frame: For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up ]
44. Pharmacodynamics: Percentage of Myeloid Cells [ Time Frame: For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up ]
45. Pharmacodynamics: Percentage of Plasmacytoid Dendritic Cells [ Time Frame: For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up ]
46. Pharmacokinetics: Cmax of Entecavir in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]
47. Pharmacokinetics: AUCinf of Entecavir in QWk Dosing Cohorts [ Time Frame: Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 ]

Inclusion criteria
Patients must meet the following criteria for study entry:
1. Adult male and female patients, age 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 ≥ 250 IU/mL at screening;
6. On any nucleoside/nucleotide analogue treatment for
1 – 3 years with ongoing entecavir treatment at
randomization and for at least 6 months prior to
randomization;
7. HBV DNA < 90 IU/mL or below a detection level
acceptable by both the sponsor and the investigator
for at least the preceding 6 months; HBV DNA
undetectable at screening by Roche Cobas assay;
8. HBeAg positive at randomization and for at least 6
months prior to randomization;
9. Screening laboratory values (hematology, chemistry,
urinalysis) obtained up to 28 days prior to first study
treatment within acceptable range or judged to be not
clinically significant by PI and medical monitor;
10. ALT ≤ 1.5 x ULN from 2 measurements separated by
at least 14 days during the 6 months prior to
randomization (one of the ALT measurements can be
done at screening); ALT at screening ≤ 1.5 x ULN;
normal values for AST, TB, GGT, ALP, PT(INR)/aPTT
tests at screening (for patients with Gilbert’s
syndrome TB ≤47 µmol/L [2.75 mg/dL]);
11. 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;
12. For women who are not postmenopausal (i.e. ≥ 12
months of non-therapy-induced amenorrhea,
confirmed by follicle stimulating hormone [FSH], if not
on hormone replacement) or surgically sterile
(absence of ovaries and/or uterus) agreement to
remain abstinent or use combined contraceptive
methods that result in a failure rate of < 1% per year
during the treatment period and at least through week
12 after last dose.
a. Abstinence is only acceptable if it is in line with
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;
b. Examples of contraceptive methods with an
expected failure rate of < 1% per year include
male sterilization, hormonal implants, proper
use of combined oral or injected hormonal
contraceptives, and certain intrauterine
devices. Alternatively, two methods (e.g., two
barrier methods such as a condom and a
cervical cap) may be combined to achieve a
failure rate of < 1% per year, barrier methods
must always be supplemented with the use of
a spermicide;
13. All males must use a barrier method of contraception
during the treatment period and at least through 7
days after the last dose;
14. Ability and willingness of subject or legal
guardian/representative to provide written informed
consent;
15. Negative pregnancy test on Day -1 for women of child
bearing potential.

Exclusion criteria
1. Pregnant (positive pregnancy test) or lactating
women;
2. Documented history of HBV genotype D;
3. History or other evidence of bleeding from
esophageal varices;
4. Decompensated liver disease (e.g., Child-Pugh
Class B or C clinical classification or clinical evidence
such as ascites or varices);
5. 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, nonalcoholic steatohepatitis, etc.);
6. Documented history or other evidence of metabolic
liver disease within one year of randomization;
7. Positive test for Hepatitis A (IgM anti-HAV), Hepatitis
C, or human immunodeficiency virus;
8. Documented history of infection with hepatitis D, E,
or G virus;
9. 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 HSV I or HSV II;
10. History of or suspicion of hepatocellular carcinoma or
alpha fetoprotein ≥ ULN at screening;
11. 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);
12. History of clinically significant cardiovascular,
endocrine, gastrointestinal, renal, ocular, pulmonary,
psychiatric or neurological disease;
13. History of significant psychiatric disease, especially
major depression (significant psychiatric disease is
defined as treatment with an antidepressant
medication or a major tranquilizer at therapeutic
doses for major depression or psychosis,
respectively, or any history of the following: a suicide
attempt, hospitalization for psychiatric disease, or a
period of disability due to a psychiatric disease);
14. Evidence of an active or suspected cancer or a
history of malignancy other than adequately treated
basal cell carcinoma;
15. History of having received or currently receiving any
systemic anti-neoplastic (including radiation) or
immune-modulatory treatment (including systemic
oral or inhaled corticosteroids; eye drop-containing
and infrequent inhaled corticosteroids are
permissible) ≤ 4 weeks prior to the first dose of study
drug or the expectation that such treatment will be
needed at any time during the study;
16. History of organ transplantation;
17. History of thyroid disease; also, patients with
clinically significant elevated thyroid stimulating
hormone (TSH) concentrations at screening;
18. Any confirmed significant allergic reactions (urticaria
or anaphylaxis) against any drug, or multiple drug
allergies (non-active hay fever is acceptable);
19. Significant acute infection (e.g. influenza, local
infection) or any other clinically significant illness
within 2 weeks of randomization;
20. Clinically relevant ECG abnormalities on screening
ECG;
21. Any of the following laboratory parameters at
screening
a. 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. Hgb < 12 g/dl in females or 13 g/dl in males
22. Abnormal renal function including serum creatinine >
upper limit of normal or calculated creatinine
clearance <70 ml/min (using the Cockcroft Gault
formula);
23. Positive results for anti-nuclear antibody (ANA), antimitochondrial antibody (AMA), anti-smooth muscle
antibody (ASMA) and thyroid peroxidase antibody;
24. Participation in an investigational drug or device
study within 30 days prior to randomization;
25. Donation or loss of blood over 500 mL within 3
months prior to starting study medication;
26. Administration of any blood product within 3 months
of randomization;
27. 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;
28. Subjects under judicial supervision, guardianship or
curatorship;
29. Medical or social conditions that would potentially
interfere with the subject’s ability to comply with the
study visit schedule or the study assessments.