Evaluation of Virological Efficacy of Entecavir, Selgantolimod, and Tenofovir Disoproxil in HBeAg-Negative Chronic Hepatitis B Patients
- Trial ID
- 2024-515739-32-00
- Protocol
- ANRS HB07 IP-Cure-B
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **virological** efficacy, defined as a decline of at least 1 log10 IU/mL in HBsAg at 76 weeks, of both stopping nucleos(t)ide analogues (NUC) and stopping NUC after treatment with selgantolimod, compared to a control arm where NUC is taken continuously for 76 weeks. This is clinically relevant as it aims to determine the effectiveness of a novel treatment strategy for chronic hepatitis B (CHB) in HBeAg-negative patients, potentially offering an alternative to the current standard of care.
Secondary objectives include:
- Assessing and comparing virological responses at each time point, including HBsAg decline, reduction in HBsAg levels below specific thresholds, and loss of HBsAg.
- Evaluating changes in serum HBsAg, HBcrAg, HBV RNA, and HBV DNA from baseline throughout the study period.
- Assessing the time to HBsAg loss and rates and time to HBsAb seroconversion.
- Describing ALT flares at each time point and assessing all grade adverse events (AEs).
- Evaluating the re-treatment rate with NUC therapy and comparing health-related quality of life using the EuroQol five-dimensions questionnaire (EQ-5D-5L) at baseline, week 28, and week 76.
Participants
The clinical trial involves participants diagnosed with **chronic hepatitis B** (CHB), specifically those who are HBeAg negative. The study population includes both male and female subjects aged between 18 to 70 years. Participants are required to have been on nucleos(t)ide analogues (NUC) therapy for at least three years, with documented HBV DNA levels below 20 IU/mL. The trial does not include a vulnerable population. Participants must have no evidence of advanced fibrosis or cirrhosis, as confirmed by elastography and ultrasonography, and must not have hepatocellular carcinoma. The study requires participants to maintain a stable health status, with ALT levels at or below 1.5 times the upper limit of normal. Women of childbearing potential and men with partners of childbearing potential must adhere to highly effective contraception methods throughout the study. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **virological efficacy** of treatment strategies in patients with **chronic hepatitis B** (CHB) who are HBeAg negative. The study employs a randomized, double-blind, controlled design to compare the effects of stopping nucleos(t)ide analogues (NUC) alone and stopping NUC after treatment with **selgantolimod** against a control group that continues NUC therapy for 76 weeks. The primary endpoint is the percentage of subjects achieving a ≥ 1.0 log10 IU/mL decline in HBsAg at week 76 compared to baseline. Secondary endpoints include various measures of HBsAg decline, seroconversion, and changes in HBV markers at multiple time points throughout the study.
Participants will be involved in the trial for a maximum of 76 weeks, with the study estimated to conclude by October 2025. The trial begins with a screening visit to confirm eligibility, which includes criteria such as documented NUC therapy for at least three years, specific HBV DNA levels, and absence of advanced liver disease. Following randomization, participants will attend regular follow-up visits at weeks 12, 24, 28, 36, 48, and 76 to monitor efficacy and safety outcomes. The end-of-study visit will occur at week 76, where final assessments will be conducted.
Inclusion criteria require participants to be between 18 and 70 years old, with specific laboratory and imaging results confirming the absence of hepatocellular carcinoma and cirrhosis. Women of childbearing potential and men with partners of childbearing potential must adhere to strict contraception guidelines throughout the study. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide insights into the potential benefits of TLR8 stimulation in the management of CHB.
Treatment
The clinical trial involves the administration of several **experimental medications**. The first medication is **Baraclude 0.05 mg/ml oral solution**, which contains the active substance **entecavir**. This medication is provided in the form of an oral solution and is administered orally. The maximum daily dose is 0.5 mg, with a total treatment period of up to 76 weeks. The solution is manufactured by Bristol-Myers Squibb Pharma EEIG and is chemically derived.
Another experimental medication used in the trial is **Selgantolimod**, also known by its sponsor product code GS-9688. This medication is provided as a film-coated tablet and contains the active substance **selgantolimod**. It is administered orally with a maximum daily dose of 3 mg and a total treatment period of 24 weeks. Selgantolimod is produced by Gilead Sciences Inc. and is chemically synthesized.
The trial also includes the administration of **Viread 245 mg film-coated tablets**, which contain the active substance **tenofovir disoproxil**. These tablets are administered orally with a maximum daily dose of 245 mg, and the treatment period can extend up to 76 weeks. Viread is manufactured by Gilead Sciences Ireland Unlimited Company and is chemically derived.
Additionally, **Vemlidy 25 mg film-coated tablets** are used in the trial, containing the active substance **tenofovir alafenamide**. These tablets are administered orally with a maximum daily dose of 25 mg, and the treatment period is up to 76 weeks. Vemlidy is also produced by Gilead Sciences Ireland Unlimited Company and is chemically synthesized.
In this clinical trial, the standard-of-care therapy for chronic hepatitis B (CHB) treatment in HBeAg negative patients is defined as the continuous administration of nucleos(t)ide analogues (NUC) for 76 weeks. The trial aims to evaluate the virological efficacy of stopping NUC therapy and stopping NUC after treatment with Selgantolimod, compared to the control arm where NUC is taken continuously.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the virological response in patients with chronic hepatitis B (CHB). The primary endpoint for efficacy is defined as the percentage of subjects achieving a decline of ≥ 1.0 log10 IU/mL in **HBsAg** levels at week 76 compared to baseline. Secondary endpoints include the percentage of subjects with various levels of HBsAg decline (≥ 0.3, ≥ 0.5, and ≥ 1.0 log10 IU/mL) at multiple time points (weeks 12, 24, 28, 36, 48, and 76) compared to baseline. Additionally, the trial will assess the percentage of subjects with HBsAg levels below 100 IU/mL and 10 IU/mL, as well as the percentage of subjects achieving HBsAg loss and HBsAb seroconversion at specified weeks. Changes in serum HBsAg, HBcrAg, HBV RNA, and HBV DNA levels from baseline to weeks 12, 24, 28, 36, 48, and 76 will also be measured.
Health-related quality of life will be evaluated using the EQ-5D-5L utility score, collected through a self-completed questionnaire at baseline, weeks 28, and 76. The trial will also monitor the percentage of subjects reporting grade 3 or 4 adverse events (AEs), the percentage of subjects with at least one AE, and the percentage of subjects experiencing ALT flares, defined as ALT levels ≥ 10 times the upper limit of normal (ULN). The need for re-initiation of nucleos(t)ide analog (NUC) treatment will be recorded. Efficacy assessments will be conducted at specified intervals to ensure comprehensive data collection and analysis throughout the trial duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with HBeAg negative CHB on documented NUC for ≥ 3 years with HBV DNA < 20 IU/mL by local assay by polymerase chain reaction (PCR) documented at least 3 times over the last 1.5 year. NUC can include only tenofovir/TDF, tenofovir/TAF or entecavir,
- HBsAg ≥ 100 IU/mL but ≤6,000 IU/mL at screening,
- Male and female subjects aged 18 to 70 years (inclusive) at the day of screening,
- Ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 6 months of screening date with no evidence of hepatocellular carcinoma (HCC),
- No evidence of advanced fibrosis or cirrhosis at screening: Elastography (Fibroscan) value ≤ 9 kPa and ultrasonography without any sign of cirrhosis and platelets ≥ 150x109/L, Note: if the abdominal ultrasound was done as part of the routine care within 6 months prior to the screening date, the result may be used for the validation of the participant's eligibility, without being done again at screening
- No evidence of cirrhosis before the onset of NUC therapy,
- HBV DNA < 20 IU/mL at screening,
- ALT levels ≤ 1.5 ULN at screening,
- Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of IMP. If the urine pregnancy test is positive, a follow-up serum test is required for confirmation,
- Women of childbearing potential must agree to use a highly effective method of contraception from screening throughout the study period and for 7 days after the last dose of study drug. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception from screening throughout the study period and for 7 days after the last dose of study drug. a) Women of childbearing potential are sexually mature women who have not undergone bilateral oophorectomy or hysterectomy; or who have not been postmenopausal (ie, who have not menstruated at all) for at least 1 year. b) Highly effective methods of contraception not using hormonal contraceptives will be intrauterine device, tubal sterilization, Essure microinsert system; male partner sterilization; or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the subject. Note: The double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea method, and spermicide only are not acceptable as highly effective methods of contraception.
- Screening Electrocardiogram (ECG) without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) ≤ 450 msec for males and ≤ 470 msec for females,
- Must be willing and able to comply with all study requirements,
- Must have the ability to understand and sign a written informed consent form (ICF),
- Participant covered by Health Insurance (when requested by local regulations)
Exclusion Criteria
- Any history of decompensation of liver disease including history of ascites, encephalopathy and gastrointestinal bleeding,
- Any sign of oesophageal and/or gastric varices,
- Laboratory parameters not within defined thresholds: White blood cells count < 2,500 cells/μL (< 2.5 ×109/L) and neutrophil count < 1,500 cells/μL (or < 1,000 cells/μL if considered a physiological variant in subjects of African descent); Note: in order to verify this criterion, the ethnicity of the participants will be collected in the eCRF. b) Hemoglobin < 11 g/dL (< 110 g/L) for females, < 13 g/dL (< 130 g/L) for males; c) Platelets < 130,000 per μL (< 130×109/L); d) Albumin < 3.5 g/dL (< 35 g/L); e) International normalized ratio (INR) > 1.5; f) Total bilirubin > 1.2 mg/dL (> 20.52 μmol/L). Note: subjects with an elevated indirect bilirubin and known Gilbert’s disease can be included if direct bilirubin is within normal limits. g) Alpha-fetoprotein (AFP) > 20 ng/mL; h) Creatinine clearance (using the Cockcroft-Gault method) < 60 mL/min; NB: Biological parameters outside of these values should be reviewed by the coordinating investigators who should specify the clinically significance. Results considered non-clinically significant by the coordinating investigators are accepted.
- Co-infection with hepatitis C virus (HCV) (HCV RNA positive and patients cured for less than one year prior to the screening date)*, co-infection with human immunodeficiency virus type 1 (HIV-1) (antibodies anti-HIV positive) or hepatitis D virus (HDV) (antibodies anti-HDV positive), *Note: co-infection HCV The following patients are eligible: . Patients treated HCV PCR negative one year after treatement discontinuation . Non-treated patients: anti HCV positive, HCV PCR negative, profile known and confirmed for at least 1 year
- Evidence or history or suspicion of hepatocellular carcinoma,
- Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Note: subjects under evaluation for possible malignancy are not eligible.
- Significant cardiovascular, pulmonary, or neurological disease,
- Received solid organ or bone marrow transplant,
- Received within 3 months of screening or expected to receive prolonged therapy with immunomodulators (eg, corticosteroids, anti-TNF) or biologics (eg, monoclonal antibody, IFN),
- Subjects currently taking medication(s) that are transported through organic anion transporting polypeptide 1 (OATP1) including, but not limited to: atazanavir, rifampin, cyclosporine, eltrombopag, gemfibrozil, lopinavir/ritonavir, and saquinavir,
- Concomitant treatment with the following medications (if taken within 21 days prior the baseline visit through the end of treatment plus 7 days)/diet: a) Hematologic stimulating agents (eg, erythropoiesis-stimulating agents; granulocyte colony stimulating factor [GCSF]; and thrombopoietin [TPO] mimetics), b) Potent CYP3A4 inhibitors or inducers, including but not limited to antifungals (fluconazole, ketoconazole…), antibiotics (telithromycin, rifabutin, rifampicin…), St. John's Wort, grapefruit juice, anticonvulsants (carbamazepine, phenobarbital, phenytoin…) etc, c) Immunosuppressant (except short term use of prednisone as a steroid burst [≤ 1 week of use]) and cytotoxic medications,
- Known hypersensitivity or resistance to study drugs or formulation excipients,
- Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease, hemoglobinopathy, retinal disease, or immunosuppressed patients,
- Use of another investigational agent within 6 months of screening and during the whole duration of the trial,
- Current alcohol or substance abuse judged by the Investigator to potentially interfere with compliance,
- Females who are breastfeeding, pregnant or may wish to become pregnant during the study,
- Female subjects unwilling to refrain from egg donation and in vitro fertilization during and until at least 7 days after the last study drug dose. Male subjects unwilling to refrain from sperm donation during and until at least 7 days after the last study drug,
- Any medical condition that, in the opinion of the investigator, could interfere with evaluation of the study objectives or safety of the subjects.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Feb 2022 | 24 |
 Germany | Not Recruiting | 01 Feb 2022 | 3 |
 Italy | Not Recruiting | 01 Feb 2022 | 15 |
 Spain | Not Recruiting | 01 Feb 2022 | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Selgantolimod | Test | FILM-COATED TABLET | ORAL | 3 | 24 | PRD7296995 |
Vemlidy 25 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 25 | 76 | PRD4659208 |
Baraclude 0.05 mg/ml oral solution | Test | ORAL SOLUTION | ORAL | 0.5 | 76 | PRD2333401 |
Viread 245 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 245 | 76 | PRD294997 |