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    Summary
    EudraCT Number:2021-005185-18
    Sponsor's Protocol Code Number:HEPA-CRV431-207
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-05-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2021-005185-18
    A.3Full title of the trial
    ASCEND-NASH: A PHASE 2B, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CRV431 IN ADULT SUBJECTS WITH NONALCOHOLIC STEATOHEPATITIS AND ADVANCED LIVER FIBROSIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ASCEND-NASH: A PHASE 2B, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CRV431 IN ADULT SUBJECTS WITH NONALCOHOLIC STEATOHEPATITIS AND ADVANCED LIVER FIBROSIS
    A.4.1Sponsor's protocol code numberHEPA-CRV431-207
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHepion Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHepion Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHepion Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointCarlos Canizares
    B.5.3 Address:
    B.5.3.1Street Address399 Thornall Street, First Floor
    B.5.3.2Town/ cityEdison
    B.5.3.3Post code NJ 08837
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1732902-4013
    B.5.5Fax number+1732902-4101
    B.5.6E-mailccanizares@hepionpharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRencofilstat
    D.3.2Product code CRV431
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRencofilstat
    D.3.9.1CAS number 1383420-08-3
    D.3.9.2Current sponsor codeCRV431
    D.3.9.4EV Substance CodeSUB245028
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    NONALCOHOLIC STEATOHEPATITIS AND ADVANCED LIVER FIBROSIS
    E.1.1.1Medical condition in easily understood language
    Non-alcoholic fatty liver disease including liver inflammation
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level LLT
    E.1.2Classification code 10086370
    E.1.2Term NASH with fibrosis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy and safety of once daily (QD) 75 mg, 150 mg, and 225 mg doses of Rencofilstat compared to placebo control in subjects with biopsy-proven NASH and stage F2 / F3 liver fibrosis.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female between 18 and 75 years of age (inclusive).
    2. Capable of giving written informed consent and able to effectively communicate with the investigator and study personnel. A signed informed consent form (ICF) must be on file prior to initiating the Screening procedures.
    3. Willing and able to complete all study requirements, restrictions, visits and procedures.
    4. Histologic evidence of NASH based on central readings of the screening biopsy obtained no more than 6 months before Screening defined by presence of all 3 key histological features, Nonalcoholic Fatty Liver Disease Activity Score (NAS) ≥ 4 with at least 1 point each in
    lobular inflammation and hepatocyte ballooning
    a. Historical biopsy may be substituted for Screening biopsy to determine eligibility if the following are met:
    i. Historical biopsy was obtained no more than 180 ± 5 days prior to the first day of Screening.
    ii. Hepatic tissue or slides are available for central histologic evaluation.
    iii. No new therapeutic intervention for NASH was made 90 days prior to screening (e.g., obeticholic acid, vitamin E ≥ 400 IU/day, pioglitazone, incretins [e.g., liraglutide, semaglutide], sodium-glucose cotransporter-2 [SGLT2] inhibitors).
    iv. Subjects must have been metabolically stable since the biopsy (no significant weight loss ≥ 7% of body weight, no major deterioration of glycemic control, and no introduction of new or investigational drugs for the treatment of Type 2 Diabetes
    5. Histologic liver fibrosis stage 2 or 3 as defined by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) scoring of liver fibrosis based on central reading of the Screening biopsy (refer to criteria 4a regarding use of a historical biopsy as a substitute for the Screening biopsy).
    6. Blood pressure up to 160/100 mmHg; potential subjects who meet other eligibility requirements, but who have out of range blood pressure measurements deemed to be not clinically significant by the investigator, may still be considered for study inclusion.
    7. Females of reproductive potential, defined as women who have not been postmenopausal for at least 12 consecutive months (i.e., who have had menses within the preceding 12 months), or women who have not undergone surgical sterilization, specifically, hysterectomy, bilateral
    salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, must have a negative pregnancy test at Screening and prior to dosing at Day 1.
    8. All participants must agree not to participate in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm or egg donation, in vitro fertilization). If participating in sexual activity that could lead to pregnancy, the participant must agree to use 2 reliable methods of contraception simultaneously while receiving study treatment and for 3 months after subject has stopped taking study drug. A combination of TWO of the following methods MUST be used appropriately:
    a. Condoms (male or female) with or without a spermicidal agent.
    b. Diaphragm or cervical cap with spermicide.
    c. Intrauterine device (IUD).
    d. Hormonal-based contraception.
    Note: Participants who are not of reproductive potential (women who have been postmenopausal for at least 12 consecutive months or have undergone hysterectomy, bilateral salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, or men who have documented azoospermia) are eligible without requiring the use of contraceptives. Acceptable documentation of sterilization, menopause or male partner’s azoospermia must be provided; serum follicle stimulating hormone (FSH) measurement can be used to document menopausal status.
    E.4Principal exclusion criteria
    1. Pregnant or breastfeeding or planning to become pregnant during the study period
    2. Known allergy to Rencofilstat, cyclosporine, or any of their inactive ingredients
    3. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus antibodies (HIVAb). If HCVAb test is positive, then an HCVRNA test will be performed. If this test is negative, the subject is allowed to participate in the study, as long as the subject meets all other inclusion criteria and has never been treated for HCV or was treated >2 years ago and achieved a sustained virologic response at that time
    4. Subjects with suspected and symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified prior to first dose
    5. History of or any current medical condition which could compromise the safety of the participant in the study, as determined by the investigator
    6. Clinically significant gastrointestinal, cardiovascular, neurologic, psychiatric, renal, hepatic, respiratory, inflammatory, or infectious disease, as determined by the investigator
    7. Subjects with a history of clinically significant acute cardiac events within 30 days prior to Screening such as stroke, transient ischemic attack, or coronary heart disease
    8. Subjects with uncontrolled or unstable cardiac arrhythmias:
    a. Severe conduction disturbance (e.g., second-degree or third-degree AV block)
    b. History of congenital long QT syndrome, congenital short QT syndrome, Torsades de Pointes, or Wolff Parkinson White syndrome
    9. Safety laboratory abnormalities at Screening which are clinically significant as determined by the investigator
    10. Subjects with transaminases >5 x upper limit of normal (ULN)
    11. Subjects with ALP >2 x ULN
    12. Subjects with total serum bilirubin >1.5 x ULN
    13. Subjects with a platelet count <100,000/mm3
    14. Subjects with an INR ≥ 1.3 in the absence of anticoagulants.
    15. Subjects with albumin <3.5 g/dL.
    16. Model for End-Stage Liver Disease (MELD) score >12, unless due to an alternate etiology such as therapeutic anticoagulation
    17. Current or previous (within the past 6 months) Child-Pugh (CP) score ≥ 7 for F2 or F3 subjects, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation
    18. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2
    19. Subjects with hemoglobin A1c (HbA1c) >9.5%.
    20. Use of systemic immunosuppression therapies within 6 months prior to the first dose of study drug apart from short-term treatment for asthma, inclusive of agents targeting arthritic conditions or chronic skin conditions
    21. Current clinically significant diarrhea or gastric stasis that in the investigator’s opinion could influence drug absorption or bioavailability
    22. Subjects with any history or presence of decompensated cirrhosis including ascites, hepatic encephalopathy or variceal bleeding
    23. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to:
    a. Suspicion of drug-induced liver disease.
    b. Alcoholic liver disease.
    c. Autoimmune hepatitis.
    d. Wilson’s disease.
    e. Primary biliary cholangitis, primary sclerosing cholangitis.
    f. Genetic hemochromatosis (Homozygosity for C282Y or C282Y/H63D compound heterozygote).
    g. Known or suspected hepatocellular carcinoma (HCC).
    h. History or planned liver transplant.
    i. Clinical evidence of portal hypertension such as esophageal varices, ascites, history of hepatic encephalopathy, or splenomegaly.
    24. History of hepatic decompensating events or subjects who develop manifestations of hepatic decompensation between screening and enrollment should not be randomized, inclusive of new or worsening jaundice and ascites, new esophageal varices, etc.
    25. Subjects with Type 2 diabetes who have recent (< 3 months) changes in medication class or dose of the following antidiabetic medications: Glucagon-like-peptide-1 (GLP-1) receptor agonist, dipeptidyl peptidase-4 (DPP-4) inhibitor, sodium/glucose cotransporter 2 (SGLT2) inhibitor, thiazolidinediones (TZD)
    26. Weight loss of more than 7% within 3 months prior to randomization
    27. Current abuse of alcohol or illicit drugs, or history of alcohol or illicit drug abuse within the preceding 2 years, as determined by the investigator.
    28. Judgement by the investigator that the subject should not participate in the study if the subject is unsuitable for the study or unlikely to comply with all study procedures and treatment
    29. Received an investigational drug or investigational vaccine or used an investigational medical device within 60 days prior to first dose of study drug
    30. Received any investigation products being evaluated for the treatment of liver fibrosis or NASH in the 6 months prior to the Screening liver biopsy.

    Please refer to the protocol for the remaining exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    Superiority of Rencofilstat (75mg, 150 mg, 225 mg) compared to placebo on liver histology at Day 365 relative to the screening biopsy, by assessing the proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system) OR NASH resolution without worsening of fibrosis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 365
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    Superiority of Rencofilstat (75 mg, 150 mg, 225 mg) compared to placebo on liver histology at Day 365 relative to the screening biopsy, by assessing the following endpoints:
    - Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system), regardless of effect on NASH.
    - Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN system), regardless of effect on NASH.
    - Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN system) AND no worsening of NASH.
    - Change from baseline in noninvasive assessment of liver fibrosis (including noninvasive hepatic fibrosis index such as ALT, AST, Pro-C3, ELF, CK-18, NFS, FIB-4 score, and liver stiffness through FibroScan and MRE at Day 180 and Day 365).

    Secondary Safety and PK Endpoints:
    Characterization of the population PK (PopPK) of Rencofilstat and possible metabolites in 16 subjects with F2 or F3 NASH in each active treatment cohort and the matching placebo cohort.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 180
    Day 365
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Mexico
    United States
    France
    Spain
    Germany
    Italy
    Hungary
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days6
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 235
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 101
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 94
    F.4.2.2In the whole clinical trial 336
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will return to routine medical care under the guidance of their personal healthcare team upon completion of the trial.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-05-24
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