A phase 2a, multicentre trial to evaluate the efficacy, safety and pharmacokinetics of RBD1016 in participants with chronic hepatitis D virus infection, including a randomized, single-blinded, placebo-controlled exploratory part

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ribocure Pharmaceuticals AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

21 Aug 2024 → ongoing

Decision date (initial)

2024-03-14

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

To evaluate the efficacy (measured as HDV RNA levels) of RBD1016 subcutaneous injections in participants with chronic HDV infection.

Secondary objectives 1

1. To evaluate the safety, pharmacodynamics (PD), PK and immunogenicity of RBD1016 injections in participants with chronic HDV infection.

Conditions and MedDRA coding

Chronic hepatitis D virus infection

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Willing and able to give written informed consent for participation in the trial.
2. 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.
3. Male or female participant aged 18 to 65 years, inclusive.
4. Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2 at the time of the screening visit.
5. 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.
6. 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.
7. Documented absence of liver cirrhosis, defined as an LSM ≥ 10 kPa measured on FibroScan® elastography at screening.
8. 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 24

1. 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).
2. 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.
3. 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.
4. Prior or current diagnosis of liver cirrhosis.
5. History of or active hepatic decompensation, e.g., ascites, variceal bleeding or hepatic encephalopathy, at the discretion of the Investigator.
6. History of organ transplantation, previous or concurrent HCC or imaging finding suggesting malignant liver lesions, at the discretion of the Investigator.
7. Signs of liver malignancy in abdominal ultrasound at screening.
8. Any malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
9. 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.
10. 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.
11. 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.
12. Major surgery within 6 months prior to screening.
13. 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.
14. Planned surgical procedure(s) during the course of the trial, i.e., from the screening visit to the follow-up/end-of-trial visit.
15. Participants who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
16. 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.
17. History of severe hypersensitivity to subcutaneous injections. History of mild reactions, such as localised swelling or redness, is allowed.
18. 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.
19. 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.
20. Previous participation in clinical trials of similar anti-HBV siRNA or antisense oligonucleotide drugs within 6 months prior to screening.
21. 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.
22. Presence or history of drug abuse within 6 months prior to screening, as judged by the Investigator based on reasonable evidence.
23. 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.
24. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean reduction (log10 value) vs. baseline in HDV RNA levels at end of trial (Week 60).

Secondary endpoints 10

1. Frequency, intensity and seriousness of reported AEs, SAEs and AEs of special interest (AESIs) during the trial.
2. Clinically significant changes in vital signs (systolic/diastolic blood pressure, pulse rate) and 12-lead safety ECG measurements, clinical laboratory parameters and physical examination findings.
3. Proportion of participants with undetectable HDV RNA (i.e., < the limit of detection) or ≥ 2 log10 decrease in HDV RNA at end of trial (Week 60).
4. Proportion of participants with undetectable HDV RNA (i.e., < the limit of detection), or ≥ 2 log10 decrease in HDV RNA and alanine transaminase (ALT) normalisation, at end of trial (Week 60).
5. Mean maximum reduction (log10 value) in HDV RNA levels vs. baseline, at any timepoint during the trial.
6. For participants with HBsAg levels > 100 IU/mL at baseline: Proportion of participants with HBsAg levels ≤ 10 IU/mL at end of trial (Week 60).
7. Mean reduction (log10 value) in HBsAg levels vs. baseline, at end of trial (Week 60).
8. Mean maximum reduction (log10 value) in HBsAg levels vs. baseline, at any timepoint during the trial.
9. Plasma concentrations of RBD1016 (and metabolites, as applicable) and estimation of plasma PK parameters, including but not limited to AUC0-t, AUC0-inf and Cmax and/or standard model population PK parameters.
10. Proportion of participants with positive immunogenicity, measured as anti-drug antibodies (ADAs) positive, at each evaluation time point up to end of trial (Week 60).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ribocure Pharmaceuticals AB

Sponsor organisation

Ribocure Pharmaceuticals AB

Address

S Annedal, Medicinaregatan 8a, Goteborgs Annedal Medicinaregatan 8a Goteborgs Annedal

City

Goteborg

Postcode

413 90

Country

Sweden

Scientific contact point

Organisation

Ribocure Pharmaceuticals AB

Contact name

Maria Liljevald

Public contact point

Organisation

Ribocure Pharmaceuticals AB

Contact name

Maria Liljevald

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications