A PHASE II, RANDOMISED, ADAPTIVE, OPEN-LABEL PLATFORM TRIAL TO EVALUATE EFFICACY AND SAFETY OF MULTIPLE COMBINATION THERAPIES IN PARTICIPANTS WITH CHRONIC HEPATITIS B
- Conditions
- chronic diseaseviral infection10047438
- Registration Number
- NL-OMON50813
- Lead Sponsor
- Covance
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 6
Informed Consent
1. Able and willing to provide written informed consent and to comply with the
study
protocol according to International Council for Harmonization (ICH) and local
regulations.
Age
2. Participants must be between 18 and 65 years of age, inclusive, at the time
of
signing the informed consent.
Weight
3. Body mass index between 18 and 32 kg/m2 inclusive.
Type of Participants and Disease Characteristics
4. Participants with CHB infection (HBsAg positive for **6 months) who are on
NUC
(entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy
for *12 months, having received the same NUC therapy for** 3 months prior to
screening.
5. HBV DNA below the LLOQ or < 20 IU/mL for > 6 months prior to screening and
confirmed at screening.
6. Alanine transaminase (ALT) **1.5 x upper limit of normal (ULN) for > 6
months prior
to screening, and confirmed at screening
7. Screening laboratory values (hematology, chemistry, urinalysis) within normal
range, or judged not clinically significant by the Investigator and Medical
Monitor.
Sex
8. Male and female participants:
The contraception and abstinence requirements are intended to prevent exposure
of
an embryo to the study treatment. The reliability of sexual abstinence for
enrollment
eligibility needs to be evaluated in relation to the duration of the clinical
study and
the preferred and usual lifestyle of the participant. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal
are
not acceptable methods of preventing fetal/embryonic drug exposure.
The following contraception requirements must be followed unless otherwise
stated
in the respective appendix of each treatment arm.
a) Female Participants:
A female participant is eligible to participate if she is not pregnant (see
Appendix 5),
not breastfeeding, and at least one of the following conditions applies:
* Woman of non-childbearing potential (WONCBP), as defined in Appendix 5.
* Woman of childbearing potential (WOCBP), who:
* Agrees to remain abstinent (refrain from heterosexual intercourse) or use
highly effective contraceptive methods that result in a failure rate of <1% per
year during the treatment period and for at least 6 months after the final dose
of
study treatment. Examples of contraceptive methods with a failure rate of <1%
per year include bilateral tubal occlusion, male sterilization, established
proper
use of hormonal contraceptives that inhibit ovulation, hormone-releasing
intrauterine devices, and copper intrauterine devices (see Appendix 5).
* Has a negative pregnancy test at screening (Day -14 to -7). In addition, WOCBP
must be willing to undergo a urine pregnancy test every 3 months until the end
of
study.
b) Male Participants:
During the treatment period and for at least 6 months after the final dose of
study
treatment, agree to:
* Remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures such as a condom plus an additional contraceptive
method that together result in a failure rate of <1% per year, with a partner
who is a woman of childbearing potential (WOCBP, as defined in Section 1
in Appendix 5).
* With pregnant female partner, remain abstinent (refrain from heterosexual
intercourse) or use contraceptive
Medical Conditions
1. Pregnant (positive pregnancy test) or lactating women.
2. Co-infection with other pathogens such as hepatitis A (HAV), hepatitis C
(HCV),
hepatitis D (HDV), hepatitis E (HEV), or human immunodeficiency virus (HIV).
3. History of cirrhosis or current evidence of significant liver fibrosis or
cirrhosis (F3 or
above on liver biopsy, *7.4 kPa on transient elastography, >1.32 m/s on acoustic
radiation force impulse [ARFI] elastography, or >3.13 kPa on magnetic resonance
[MR]
elastography), or decompensated liver disease (e.g., ascites, hepatic
encephalopathy). Liver biopsy or transient elastography/ARFI/MR result must be
obtained within 6 months prior to randomization.
4. History of or suspicion of hepatocellular carcinoma (HCC) (e.g, elevated *-
fetoprotein
[AFP] levels, suggestive lesions on abdominal ultrasound or other imaging,
etc.).
5. Thyroid disease poorly controlled on prescribed medications or clinically
relevant
abnormal thyroid function tests (thyroid-stimulating hormone [TSH], free
triiodothyronine [FT3], free thyroxin [FT4]) at screening, as judged by the
Investigator and Medical Monitor.
6. Clinically significant disease other than CHB that, in the opinion of the
Investigator,
makes the participant unsuitable for the study.
7. Pre-existing cardiac disease that in the opinion of the investigator would
increase
the risk for the patient to participate to the study.
8. History of alcohol abuse and/or drug abuse within one year of randomization.
9. History of having received (in the last 6 months) or currently receiving any
systemic antineoplastic
(including radiation) or immunosuppressive (including biologic
immunosuppressors) or immune modulating treatment (including non-biological oral
immune modulating drugs; e.g., methotrexate > 25 mg per week,
azathioprine > 3.0 mg/kg/day or 6-mercaptopurine > 1.5 mg/kg/day) for malignant
or
non-malignant disorders.
10. Currently taking, or have received within 3 months of Day 1, systemic
corticosteroids at a
high-dose (e.g., 40 mg prednisolone per day for) > 7 days, or a low-dose (e.g.,
20 mg
prednisolone per day) for > 14 days.
Diagnostic Assessments
11. Electrocardiogram (ECG) with clinically significant abnormalities,
including QTcF
interval (QT corrected using Fridericia*s formula) *450 msec for males and *470
msec for females at screening.
12. Laboratory parameters at screening:
a) Hemoglobin <12 g/dL (females) or <13 g/dL (males); platelets normal (LLN); international normalized ratio (INR) >1.1.
b) Albumin <3 g/dL; total bilirubin >ULN (exception: Gilbert*s disease).
c) Positive results for anti-mitochondrial antibodies (AMA >1:80), antinuclear
antibody (ANA >1:80), anti*smooth muscle antibody (ASMA >1:40), or
antithyroperoxidase
antibodies (a-TPO >10).
d) White blood cell count <2500 cells/mm3; neutrophil count <1500 cells/mm3
(<1000 cells/mm3 if considered a physiological variant in a participant of
African
descent).
e) Glomerular filtration rate (GFR; using Modification of Diet in Renal Disease
[MDRD]) * 60 mL/min.
f) Positive test for drugs of abuse (including recreational drugs) and/or
positive alcohol
test at screening. For positive cannabinoids test, the eligibility is at the
Investigator*s
discretion.
Prior/Concurrent Clinical
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoint<br /><br>* % participants with HBsAg loss at 24 weeks post-EOT.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary Endpoint<br /><br>* % participants with HBsAg loss<br /><br>* % participants with HBsAg seroconversion.<br /><br>* % participants with HBeAg loss (baseline HBeAg-positive participants).<br /><br>* % participants with HBeAg seroconversion (baseline HBeAg-positive<br /><br>participants).<br /><br>* % participants with HBV DNA < lower limit of quantification (LLOQ), <200<br /><br>IU/mL and <2,000 IU/mL.<br /><br>* Including but not limited to: change from baseline in quantitative HBsAg,<br /><br>anti-HBs, HBeAg, anti-HBe, anti-HBc, HBcrAg, HBV RNA, and HBV DNA levels over<br /><br>time.<br /><br>* Estimated PK parameters from sparse sampling and population PK models.<br /><br>* Incidence, nature, and severity of AEs and laboratory abnormalities.<br /><br>* Analyses of PK/PD data.<br /><br>* Relationship between ADA status, PK, safety, PD, and efficacy</p><br>