Efficacy, Safety, and Pharmacokinetics of RBD1016 and Tenofovir Alafenamide in Chronic Hepatitis D Virus Infection: A Phase 2a Multicentre Trial
- Trial ID
- 2023-509007-33-00
- Protocol
- RC04T001
- Sponsor
- Ribocure Pharmaceuticals AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 2a, multicentre trial is to evaluate the **efficacy** of RBD1016 subcutaneous injections in participants with chronic hepatitis D virus infection. Efficacy is measured by assessing HDV RNA levels, which is clinically relevant as it provides insight into the potential of RBD1016 to reduce viral load and improve patient outcomes in this chronic condition.
Secondary objectives include evaluating the safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of RBD1016 injections in the same patient population. These assessments are crucial for understanding the overall therapeutic profile of RBD1016, including its safety and biological activity, which are essential for determining its suitability for further clinical development.
Participants
The clinical trial involves participants diagnosed with **chronic hepatitis D virus infection**. The study population includes both male and female subjects, aged between 18 and 65 years, with a **body mass index (BMI)** ranging from 18 to 35 kg/m². Participants were selected based on documented evidence of HDV and HBV infections, with a requirement for the absence of liver cirrhosis as confirmed by FibroScan® elastography. The trial does not include a vulnerable population. Lifestyle considerations include the use of effective contraception methods for female participants of childbearing potential and sexual abstinence or condom use for male participants to prevent pregnancy and drug exposure. 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 **efficacy**, safety, and pharmacokinetics of RBD1016 in participants with chronic hepatitis D virus infection. This is a phase 2a, multicentre trial that includes a randomized, single-blinded, placebo-controlled exploratory part. The trial will involve the administration of RBD1016 via subcutaneous injection, with a placebo solution used for control purposes. The trial is expected to last until January 2027, with recruitment starting in April 2024. Participants will be involved for a maximum treatment period of 48 weeks.
The trial will commence with a screening visit to assess eligibility based on inclusion criteria such as age, body mass index, and documented evidence of HDV and HBV infections. Participants must also demonstrate the absence of liver cirrhosis and, for females of childbearing potential, a negative pregnancy test. Following successful screening, participants will be randomized to receive either RBD1016 or placebo. The primary endpoint is the mean reduction in HDV RNA levels in plasma at the end of the trial, while secondary endpoints include the frequency and seriousness of adverse events, changes in vital signs, and the proportion of participants with undetectable HDV RNA.
Study visits will be scheduled at regular intervals to monitor the safety and efficacy of the treatment, including assessments of vital signs, laboratory parameters, and physical examinations. The end-of-study visit will occur at week 60, where final evaluations will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the potential of RBD1016 as a treatment for chronic hepatitis D virus infection.
Treatment
The clinical trial involves the administration of **RBD1016**, an experimental medication developed by Ribocure Pharmaceuticals AB. RBD1016 is formulated as an **injection** and is classified as an oligonucleotide, specifically a small interference RNA. The medication is administered via **subcutaneous injection**. The dosing schedule for RBD1016 is determined based on the study protocol, with a maximum treatment period of 48 weeks. The trial aims to evaluate the efficacy of RBD1016 in reducing HDV RNA levels in participants with chronic hepatitis D virus infection. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.
The study also includes a **placebo** group, which receives a corresponding placebo solution. This solution consists of a 25 nM phosphate buffer with 4 μg of vitamin B2 added solely for coloring purposes. The placebo is used to maintain the single-blinded nature of the trial, allowing for a comparison of the effects of RBD1016 against a non-active treatment. The administration route and frequency for the placebo are matched to those of the experimental medication to ensure consistency in the study design.
Additionally, participants may receive **Vemlidy**, a non-experimental treatment, as part of the standard-of-care therapy. Vemlidy, produced by Gilead Sciences Ireland UC, is available in the form of **film-coated tablets** containing 25 mg of the active substance **tenofovir alafenamide**. This antiviral agent is classified under nucleoside and nucleotide analogues with the ATC code J05AF13. Vemlidy is administered **orally** with a maximum daily dose of 25 mg and a total maximum dose of 10,500 mg over a treatment period of up to 60 weeks. The inclusion of Vemlidy in the trial provides a comparator treatment to assess the relative efficacy of RBD1016.
Efficacy
The efficacy of the investigational product RBD1016 in the clinical trial will be assessed primarily by measuring the **HDV RNA** levels in participants with chronic hepatitis D virus infection. The primary endpoint is defined as the mean reduction in HDV RNA levels, expressed as a log10 value, compared to baseline at the end of the trial, which is scheduled for Week 60. Secondary endpoints include the proportion of participants achieving undetectable HDV RNA levels or a reduction of at least 2 log10 in HDV RNA, as well as the normalization of alanine transaminase (ALT) levels at the end of the trial.
Additional secondary endpoints involve the evaluation of the frequency, intensity, and seriousness of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) throughout the trial. Clinically significant changes in vital signs, 12-lead ECG measurements, clinical laboratory parameters, and physical examination findings will also be monitored. The trial will further assess the mean maximum reduction in HDV RNA levels at any timepoint during the trial, and for participants with baseline HBsAg levels greater than 100 IU/mL, the proportion achieving HBsAg levels of 10 IU/mL or less at the end of the trial. Plasma concentrations of RBD1016 and its metabolites, along with pharmacokinetic parameters such as AUC0-t, AUC0-inf, and Cmax, will be estimated. The presence of anti-drug antibodies (ADAs) will be measured at each evaluation time point up to the end of the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Willing and able to give written informed consent for participation in the trial.
- Female participants of childbearing potential must also be willing to practice abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the participant) or be willing to use a highly effective method of contraception (i.e., with a failure rate of <1%/year) to prevent pregnancy from at least 2 weeks prior to the first administration of IMP to 4 weeks after the last administration of IMP. The following are considered highly effective contraceptive methods: • Combined (oestrogen and progestogen-containing) or progestogen-only hormonal contraception associated with the inhibition of ovulation (oral, transdermal, intravaginal, injectable, or implantable). • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). Female participants of non-childbearing potential are defined as pre-menopausal females who have undergone any of the following surgical procedures; hysterectomy, bilateral salpingectomy or bilateral oophorectomy, or who are post-menopausal defined as 12 months of amenorrhoea (in questionable cases a blood sample with detection of follicle stimulating hormone [FSH] >25 IU/mL will be confirmatory). Male participants must be willing, unless they have undergone vasectomy, to practice sexual abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the participant) or use condoms from the first administration of IMP and until 3 months after the last administration of IMP to prevent pregnancy and drug exposure of a female partner.
- Male or female participant aged 18 to 65 years, inclusive.
- Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2 at the time of the screening visit.
- Documented evidence of HDV infection in medical history, i.e., HDV antibodies (HDVAb) and/or HDV RNA positive test results within at least 6 months prior to screening.
- Documented evidence of HBV infection in medical history, i.e., HBsAg and/or HBV DNA positive test results within at least 6 months prior to screening.
- Documented absence of liver cirrhosis, defined as an LSM ≥ 10 kPa measured on FibroScan® elastography at screening.
- Female participants of childbearing potential only: Negative pregnancy test (urine dip-stick) at screening and upon confirmation of eligibility. If urine pregnancy tests are positive, blood/serum pregnancy test will be confirmatory.
Exclusion Criteria
- Laboratory results at screening as follows, or any clinically significant laboratory parameter outliers that may interfere with the evaluation of efficacy and/or safety in the trial, at the discretion of the Investigator: • α-fetoprotein (AFP) > 50 μg/L. • Albumin concentration < 3.0 g/dL. • International normalized ratio (INR) > 1.5. • Platelet count < 90 × 109/L. • Direct bilirubin > 2 × ULN, Gilbert syndrome excluded. • Creatinine concentration > 1.5 × ULN. • Creatinine clearance < 60 mL/min, according to the Cockcroft-Gault equation. • ALT > 5 × ULN (see inclusion criterion no. 7).
- Positive result at screening for hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) and/or prior diagnosis of syphilis, acute hepatitis A and/or acute hepatitis E.
- Prior diagnosis of other liver diseases of non-HBV or non-HDV aetiology, including autoimmune liver disease (e.g., autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis), inherited metabolic liver disease (e.g., haemochromatosis, Wilson’s disease, familial intrahepatic cholestasis), drug-induced liver disease and/or non-alcoholic steatohepatitis (NASH) assessed as moderate or above, at the discretion of the Investigator.
- Prior or current diagnosis of liver cirrhosis.
- History of or active hepatic decompensation, e.g., ascites, variceal bleeding or hepatic encephalopathy, at the discretion of the Investigator.
- History of organ transplantation, previous or concurrent HCC or imaging finding suggesting malignant liver lesions, at the discretion of the Investigator.
- Signs of liver malignancy in abdominal ultrasound at screening.
- Any malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
- History of immune-associated disease, e.g., idiopathic thrombocytopenic purpura, systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune haemolytic anaemia or severe psoriasis, at the discretion of the Investigator.
- Active clinically significant disease or disorder other than liver disease which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or influence the results or the participant’s ability to participate in the trial, e.g., any uncontrolled renal, cardiovascular, pulmonary, thyroid, neurogenic, digestive, endocrine and/or metabolic disease or disorder, at the discretion of the Investigator.
- Active severe mental illness or uncontrolled mental disorders, e.g., schizophrenia, bipolar disorder or depression, which make the participant unsuited for trial participation in the opinion of the Investigator.
- Major surgery within 6 months prior to screening.
- Clinically significant infection (i.e., that required treatment with antibiotics), trauma and/or medical/surgical procedure within 4 weeks of the (first) administration of IMP.
- Planned surgical procedure(s) during the course of the trial, i.e., from the screening visit to the follow-up/end-of-trial visit.
- Participants who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
- History of or active severe allergy/hypersensitivity (i.e., allergic/hypersensitive to several drug substances, foods and/or other allergens), as judged by the Investigator and/or history of hypersensitivity to drugs with a similar chemical structure or class to RBD1016, NAs, or any of their preparation ingredients.
- History of severe hypersensitivity to subcutaneous injections. History of mild reactions, such as localised swelling or redness, is allowed.
- Use of pegylated interferon alpha (PegIFNα) and/or immunomodulators (e.g., thymosin, interleukin-2, levamisole) and/or systemic corticosteroids and/or cytotoxic drugs, within 6 months prior to screening, or planned treatment with such drugs during the course of the trial, i.e., from the screening visit to the follow-up/end-of-trial visit. See also Section 9.6.2.2.
- Planned treatment or treatment with another investigational drug within 1 month prior to the first IMP administration, or within 5 half-lives of the other investigational drug, whichever is longer. Participants consented and screened but not dosed in previous clinical trials will not be excluded.
- Previous participation in clinical trials of similar anti-HBV siRNA or antisense oligonucleotide drugs within 6 months prior to screening.
- Positive screening result for alcohol during the trial. Positive results that are expected given the participant’s medical history and prescribed medications can be disregarded as judged by the Investigator after conferring with the Sponsor.
- Presence or history of drug abuse within 6 months prior to screening, as judged by the Investigator based on reasonable evidence.
- History of alcohol abuse or excessive intake of alcohol within 6 months prior to screening, i.e., > 14 standard units/week for males and > 9 standard units/week for females. One (1) standard unit of alcohol contains 14 g of alcohol and corresponds to, e.g., 360 mL of beer, 150 mL of wine, or 45 mL of spirits at 40% alcohol content.
- The Investigator considers the participant unlikely to comply with trial procedures, restrictions and requirements, or unsuited for participation in the trial for any other reason.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Sweden | Not Recruiting | 01 Apr 2024 | 15 |
Sites & Investigators
Research sites
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 |
|---|---|---|---|---|---|---|
The corresponding placebo solution consists of the 25 nM phosphate buffer solution with 4 μg of vitamin B2 added for colouring purposes only. | Placebo | N/A | — | — | — | N/A |
RBD1016 | Test | INJECTION | SUBCUTANEOUS INJECTION | 000 | 48 | PRD10987159 |
Vemlidy 25 mg film-coated tablets. | Other | FILM-COATED TABLETS | ORAL | 25 | 60 | PRD4659207 |