| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis B Virus Infection |
|
| 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 |
|
| 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 safety and tolerability of combination treatment with VBR, AB-729, and nucleos(t)ide reverse transcriptase inhibitor (NrtI) |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of Cohort 1 are:
• To evaluate the effect of adding VBR and AB-729 to NrtI on reduction in and loss of HBsAg
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV DNA levels
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV RNA levels
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing other HBV antigens (ie, HBcrAg)
• To evaluate the effect of adding VBR and AB-729 to NrtI on HBsAg seroconversion
• To evaluate the effect of adding VBR and AB-729 to NrtI on normalization of ALT
• To evaluate the off-treatment durability of response to treatment with VBR and AB-729
• To evaluate the PK of VBR and AB-729 when coadministered with NrtI |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional intensive PK substudy.
An optional intensive PK substudy of AB-729 will be performed after the first 60 mg subcutaneous dose on Day 1 and after the last dose at Week 40. The plasma PK parameters to be estimated are listed in Section 10.4.6. Blood samples will be collected at the following timepoints: predose, and at 0.5 (±3 min), 1 (±6 min), 2 (±10 min), 4 (±10 min), and 6 (±10 min)-hours postdose.
Single PK blood samples will be collected from all subjects receiving AB-729 at Weeks 8, 16, 24, and 32 at 2 hours (±1 hour) postdose for sparse PK analysis of AB-729 (Table 9).
A sparse PK sample will also be collected at Day 1 and Week 40 at 2 hours (±1 hour) postdose from those subjects who do not participate in the optional intensive PK substudy. |
|
| E.3 | Principal inclusion criteria |
1.Willing and able to provide Informed Consent
2. Male or female between the ages 18 and 50 years (inclusive) at Screening
3. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive) at Screening
4. Female subjects of child-bearing potential (Appendix 2) must be non-pregnant and have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1 predose
5. cHBV defined as HBV infection documented for ≥6 months prior to Screening
6. Must be HBeAg negative at least 3 months prior to the Screening Visit (historical documentation) AND at the Screening Visit to be eligible
7. Virologically suppressed on NrtI therapy with nonquantifiable HBV DNA for at least 6 months prior to and including Screening
8. On a stable NrtI regimen of entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) for >12 months
9. HBsAg ≥100 IU/mL at Screening
10. Lack of bridging fibrosis or cirrhosis as documented by the following:
• Fasting FibroScan® ≤8 kPa within 3 months prior to Screening (including the Screening visit) or other Sponsor-approved hepatic imaging method within 6 months prior to Screening (eg, Meta-analysis of Histological Data in Viral Hepatitis [METAVIR] F0-F2 or equivalent)
or
• Liver biopsy results (eg, METAVIR F0-F2 or equivalent) within 1 year prior to Screening
If results from liver biopsy and FibroScan® are available, then the diagnostic method reporting the most advanced liver disease will be used to determine eligibility for the study
11. Agreement to comply with protocol-specified contraceptive requirements (Appendix 2)
12. In good general health, except for cHBV, in the opinion of the Investigator
13. Able to take oral medication, be willing to receive subcutaneous injections of AB-729, and in the opinion of the Investigator, be willing to adhere to study treatment and procedures |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will not be eligible for Cohort 1 of the study:
1. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis D virus (HDV), acute hepatitis A virus (HAV), or acute hepatitis E virus (HEV)
2. Females who are lactating or wish to become pregnant during the course of the study
3. History of liver transplant or evidence of advanced liver disease, cirrhosis, or hepatic decompensation (including jaundice, ascites, portal hypertension, gastrointestinal bleeding esophageal varices, hepatic encephalopathy) at any time prior to, or at the time of Screening
4. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per day on average [1 standard drink=14 grams of alcohol]) or illicit drug abuse within 3 years prior to Screening
5. Clinically significant diseases or conditions, such as cardiac disease, including poorly-controlled or unstable hypertension; pulmonary disease; chronic or recurrent renal or urinary tract disease; liver disease other than cHBV; endocrine disorder; autoimmune disorder; poorly controlled diabetes mellitus; neuromuscular, musculoskeletal, or mucocutaneous conditions requiring frequent treatment, seizure disorders requiring treatment; ongoing infection or other medical conditions requiring frequent medical management or pharmacologic or surgical treatment that, in the opinion of the Investigator or the Sponsor, makes the subject unsuitable for study participation
6. History of hepatocellular carcinoma (HCC)
History of malignancy other than HCC unless the subject’s malignancy has been in complete remission off chemotherapy and without additional medical or surgical interventions during the 3 years before Screening
8. History or presence at Screening of electrocardiogram (ECG) abnormalities deemed clinically significant, in the opinion of the Investigator
9. History of hypersensitivity or idiosyncratic reaction to any components or excipients of the investigational drugs
10. History of any significant food or drug-related allergic reactions such as anaphylaxis or Stevens-Johnson syndrome
11. The following are exclusionary laboratory results at Screening:
a. Platelet count <100,000/mm3
b. Albumin <3 g/dL
c. Direct bilirubin >1.2× ULN
d. ALT ≥5× ULN
e. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN but <100 ng/mL, the subject is eligible if hepatic imaging prior to initiation of study drug reveals no lesions indicative of possible HCC
f. INR >1.5× ULN
g. Estimated creatinine clearance (CrCl) <50 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight at Screening
h. Any other laboratory abnormality deemed clinically significant by the Investigator
12. Current or prior use of prohibited concomitant medications from 28 days prior to Day 1 (Section 6.3.1)
13. Current or prior treatment for cHBV with:
• Lamivudine, telbivudine or adefovir (any duration)
• HBV core inhibitor (any duration)
• siRNA or other oligonucleotide therapeutic (any duration)
• Interferon in the 6 months prior to Screening
• Any investigational agent for cHBV in the 6 months prior to Screening
14. Participation in another clinical study of a drug or device whereby the last investigational drug/device administration is within 60 days or 5 half-lives prior to the first study drug administration, whichever is longer |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with AEs, premature treatment discontinuation due to AEs, and abnormal laboratory results |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of Cohort 1 are:
• Mean change in log10 HBsAg from Baseline at each timepoint
• Proportion of subjects with HBsAg <LLOQ at each timepoint
• Proportion of subjects with HBV DNA TND (<5 IU/mL) at Week 48
• Proportion of subjects with HBV RNA <LLOQ at Week 48
• Mean change in log10 HBV RNA from Baseline at each timepoint
• Mean change in log10 HBcrAg from Baseline at each timepoint
• Proportion of subjects with HBsAg seroconversion at Week 48
• Proportion of subjects with abnormal ALT at Baseline who have normal ALT (by central laboratory and American Association for the Study of Liver Diseases [AASLD] criteria) at each timepoint
• Proportion of subjects achieving Treatment Stopping Criteria at end of treatment (EOT)
• Proportion of subjects who remain off-treatment at end of study (EOS)
• Analysis of VBR and AB-729 drug concentrations, NrtI concentrations may be analyzed, as needed |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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 | No |
| 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Australia |
| Canada |
| New Zealand |
| Bulgaria |
|
| 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
|
| The study will end when the last subject completes the last visit of the follow-up period or is considered “lost to follow-up,” whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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