Activity of NCO-48 Fumarate in Treatment-Naive Adults With Chronic Hepatitis B

Study Overview
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Brief Summary
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This is an open-label study evaluating multiple doses of NCO-48 Fumarate versus tenofovir alafenamide (TAF).

Detailed Description
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This is a randomized, open-label, active comparator, multiple oral dose study to evaluate the safety, tolerability, pharmacokinetics, and anti-hepatitis B virus (HBV) activity of NCO-48 Fumarate in treatment-naive adults with chronic HBV infection. This study will evaluate the safety, viral kinetics, and antiviral activity of 2 different doses of NCO-48 Fumarate over 28 days of therapy. In addition, the study will evaluate the antiviral activity of an optimal dose of NCO-48 Fumarate versus 25 mg tenofovir alafenamide (TAF) over 28 days of therapy.

Official Title
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Randomized, Open-Label, Active Comparator, Multiple Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-Hepatitis B Virus (HBV) Activity of NCO-48 Fumarate in Treatment-Naive Adults With Chronic HBV Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: NCO-48 Fumarate 4 mg
* Drug: NCO-48 Fumarate 20 mg
* Drug: Tenofovir Alafenamide 25 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male and female subjects between 18 and 65 years of age Female subjects of non-childbearing potential must be surgically sterile or postmenopausal at the Screening Visit Female subjects of childbearing potential who are sexually active with a non-sterile male partner must be using a medically acceptable form of birth control for the duration of the study and for 30 days after the last dose of study drug and must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test upon admission to the study site HBV treatment-naive or treatment-experienced with (pegylated or non pegylated) interferon alpha (must have ended at least 6 months prior to the Screening Visit) Screening plasma HBV DNA ≥ 2x10^3 IU/mL Positive for serum hepatitis B surface antigen for more than 6 months Estimated creatinine clearance (CLCr) ≥ 70 mL/min Serum transaminase activity (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] levels) <10 x the upper limit of normal Compensated liver disease with normal prothrombin time/international normalized ratio, hematology, albumin, bilirubin (unless subject has Gilbert's disease). Serum AST and/or ALT levels may be normal or elevated Body mass index within the range of 18.5 to 35 kg/m2, inclusive, and body weight >45 kg Normal vital signs, without any clinically significant abnormalities at the Screening Visit Subjects who have normal or abnormal clinically insignificant clinical laboratory assessments as considered by the Investigator from pre-treatment blood tests to assess hematology, liver (except for serum AST and/or ALT levels) and renal biochemistry, urinalysis, and drug screen Normal 12-lead electrocardiogram (ECG), with no clinically significant abnormalities of rate, rhythm, or conduction and including normal heart rate-corrected QT interval segment time at the Screening Visit Exclusion Criteria: Received treatment with TFV disoproxil fumarate or TAF (including clinical study experience) Positive for hepatitis C virus (HCV) or human immunodeficiency virus (HIV) History or presence of asthma or other pulmonary disease, thyroid disease, or other liver disease Hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of study drug, or would place the subject at increased risk Abnormal laboratory values that are considered clinically significant Have used medication, other than topical products without significant systemic absorption, hormonal contraceptives, or hormone replacement therapy and thyroid medication for at least 6 months Unwilling to refrain from consumption of alcohol within 48 hours prior to each dose of study drug and during the inpatient period, or have a history of significant alcohol abuse within 1 year prior to Screening Positive urine drug screen, or positive alcohol breath test at Screening or upon admission to the study site Use of illicit drugs within 3 months prior to the Screening Visit or hard drugs within 1 year prior to the Screening Visit, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction Women who are breastfeeding or have a positive pregnancy test at the Screening Visit or at any time during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: After Screening procedures, eligible subjects will be randomized 1:1:1 to receive either open-label NCO-48 Fumarate 4 mg (2 x 2 mg) or 20 mg (2 x 10 mg), or open-label TAF 25 mg for 28 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NCO-48 Fumarate 4 mg<br>Eligible subjects will be randomized 1:1:1 to receive either open-label NCO-48 Fumarate 4 mg or 20 mg, or open-label TAF 25 mg for 28 days. | Drug: NCO-48 Fumarate 4 mg<br>* 2 x 2mg NCO-48 Fumarate over 28 days of therapy<br>|
| Experimental: NCO-48 Fumarate 20 mg<br>Eligible subjects will be randomized 1:1:1 to receive either open-label NCO-48 Fumarate 4 mg or 20 mg, or open-label TAF 25 mg for 28 days. | Drug: NCO-48 Fumarate 20 mg<br>* 2 x 10 mg NCO-48 Fumarate over 28 days of therapy<br>|
| Active Comparator: Tenofovir alafenamide 25 mg<br>Eligible subjects will be randomized 1:1:1 to receive either open-label NCO-48 Fumarate 4 mg or 20 mg, or open-label TAF 25 mg for 28 days. | Drug: Tenofovir Alafenamide 25 mg<br>* 25 mg over 28 days of therapy<br>* Other names: Vemlidy ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatitis B virus (HBV) DNA | Time-weighted average change from baseline through Week 4 in plasma HBV DNA (log10 IU/mL) for NCO-48 Fumarate 4 and 20-mg. | Up to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HBV DNA for tenofovir alafenamide (TAF) | Comparing the short-term antiviral activity of NCO-48 Fumarate with TAF 25 mg. This is measured by time-weighted average change from baseline through Week 4 in plasma HBV DNA (log10 IU/mL) for TAF. | Up to Week 4 | 
| Incidence of Treatment-Emergent Adverse Events | Safety and tolerability is measured by the incidence of treatment-emergent adverse events. | Up to week 4 | 
| NCO-48 Fumarate Area Under the Concentration -Time Curve (AUC) | Blood samples are to be collected at designated time points for the determination of the NCO-48 Fumarate AUC. | Up to week 4 | 
| NCO-48 Fumarate Maximum Plasma Concentration (Cmax) | Blood samples are to be collected at designated time points for the determination of the NCO-48 Fumarate Cmax. | Up to week 4 | 
| Tenofovir (TFV) Area under the Concentration-Time Curve (AUC) | Blood samples are to be collected at designated time points for the determination of TFV AUC. | Up to week 4 | 
| TFV Maximum Plasma Concentration (Cmax) | Blood samples are to be collected at designated time points for the determination of TFV Cmax. | Up to week 4 |