Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness MedDRA version: 21.0 Level: PT Classification code 10080429 Term: Primary biliary cholangitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Sponsors
Calliditas Therapeutics Suisse SA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patient aged =18 years, inclusive at the time of informed consent. 2. Willing and able to give written informed consent and to comply with the requirements of the study. 3. Definite or probable PBC diagnosis as demonstrated by the presence of =2 of the following 3 diagnostic factors: a. Documented history of elevated ALP levels =1.67×ULN of the local reference range b. Documented history of positive AMA titer or positive PBC specific antibodies (anti-GP210 and/or anti-SP100 or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]). c. Historical liver biopsy consistent with PBC. 4. Serum ALP =1.67×ULN at Screening. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for patients who do not meet this inclusion criterion at Screening Visit 1. If this inclusion criterion is then met at Screening Visit 2, the patient may be eligible for the study. 5. Liver stiffness measured by transient elastography (FibroScan®) of = 8.0 kPa and an interquartile range over median ratio (IQR/med) of =30% at Screening, are taken with the results expressed in kilopascals [kPa]). 6. UDCA prescriptional dose use for the past 6 months (at a stable dose for >3 months prior to Screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to Screening). Intolerance to UDCA is defined as patients unable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported gastrointestinal symptoms such as diarrhea and abdominal pain. 7. For patients receiving OCA, fenofibrate, or bezafibrate treatment for at least 6 months and stable dose for >3 months prior to Screening. 8. For patients intolerant to OCA, OCA must have been discontinued >3 months prior to Screening. 9. For patients previously treated with bezafibrate or fenofibrate, and these agents were discontinued prior to Screening, they must have been discontinued >3 months prior to Screening. 10. Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for =4 weeks before Randomization and must agree to continue strict contraception up to 90 days after the last dose of IMP. a. For the purposes of this study, women of childbearing potential are defined as "Fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy." b. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female patients who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state. Confirmation with more than one FSH measurement is required. c. Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods are: (1) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) (2) Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) (3) Intrauterine device (4) Intra
Exclusion criteria
Exclusion criteria: 1. A positive pregnancy test or breastfeeding for female patients. 2. Any historical or current hepatic decompensation event defined as variceal/portal hypertension bleed and/or hepatic encephalopathy, spontaneous bacterial peritonitis, ascites requiring treatment, or liver transplantation list inclusion. 3. History of liver transplantation, current placement on a liver transplant list or current MELD score of =12 unless the patient is on anticoagulant therapy, or a Child Pugh Score of =6. 4. Cirrhosis with complications, including history or presence of hepatocellular carcinoma. 5. Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screening serum albumin must be within the reference range. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for patients who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the patient may be eligible for the study. 6. Plasma ALT >3×ULN and/or AST >3×ULN. 7. INR >1.2 unless patient is on anticoagulant therapy. 8. Estimated glomerular filtration rate (eGFR) ULN at Screening. 10. Competing etiology for liver disease (eg, hepatitis C, as defined by positive hepatitis C virus antibody and positive hepatitis C RNA [unless effectively cured of hepatitis C (HCV antibody positive and negative HCV RNA) with a sustained virologic response for at least 6 months prior to Screening], active hepatitis B [HBsAg positive], NASH, alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis PBC overlap syndrome, primary sclerosing cholangitis, Gilbert's Syndrome). 11. Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's disease). 12. Known history of HIV infection. If the anti-HIV antibody test is positive, HIV RNA negativity has to be confirmed by the central laboratory. 13. Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator). 14. Positive urine drug screen (if not due to prescriptional use of a concomitant medication, as confirmed by the Investigator) at Screening. Patients on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not allowed. 15. Patients receiving prohibited medications within 3 months of Screening Visit 1 as specified in Section 6.6 and 6.7. 16. Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an interventional clinical study. 17. Evidence of any of the following cardiac conduction abnormalities: A QTc Fridericia interval >450 milliseconds for males or >470 milliseconds for females, as calculated by the central reader. Patients with a second or third degree atrioventricular block are to be excluded. 18. History of a malignancy within 5 years of Screening with the following exceptions: a. Adequately treated carcinoma in situ of the cervix b. Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin cancer. 19. The occurrence of any acute infection requiring systemic antibiotic therapy with
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of setanaxib on ALP at week 24 in patients with PBC and with elevated liver stiffness and intolerance or inadequate response to UDCA;Secondary Objective: - To evaluate the effect of setanaxib on fatigue at Week 24 - To evaluate the effect of setanaxib on liver stiffness at Week 24 - To evaluate the effect of setanaxib on ALP, fatigue, and liver stiffness at Week 24, where setanaxib doses are combined - To evaluate the effect of setanaxib on pruritus at Week 24 - To evaluate the effect of setanaxib on markers of cholestasis at Week 24 - To evaluate the safety and tolerability of setanaxib over a 24-week Treatment Period;Primary end point(s): Change in Alkaline phosphatase (ALP) at Week 24 compared to Baseline;Timepoint(s) of evaluation of this end point: Week-24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Change in fatigue at Week 24 compared to Baseline, as assessed by ?? the Patient-Reported Outcomes Measurement Information System (PROMIS) short form-Fatigue 7b Daily ?? the Patient's Global Impression of Severity (PGIS) fatigue ?? the Patient's Global Impression of Change (PGIC) fatigue ?? the PBC-40 questionnaire (PBC 40) fatigue domain - Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®) - Change in ALP at Week 24 compared to Baseline, where setanaxib doses are combined - Change in fatigue at Week 24 compared to Baseline, as assessed by the PROMIS short form-Fatigue 7b Daily, the PGIS fatigue, the PGIC fatigue, and the PBC-40 fatigue domain, where setanaxib doses are combined - Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®), where setanaxib doses are combined - Change in pruritus at Week 24 compared to Baseline, as assessed by the Worst Itch Numerical Rating Scale (WI-NRS), the PBC 40 itch domain, and the PGIS and the PGIC pruritus -Changes in markers of cholestasis as assessed by proportion of patients at Week 24 with: ?? ALP reduction to <1.67xupper limit of normal (ULN) and total bilirubin =1×ULN and a =15% or =30% or =40% or =70% ALP reduction from Baseline, respectively ?? ALP reduction to <1.5×ULN and total bilirubin =1×ULN and with a =40% ALP reduction from Baseline ?? ALP <1×ULN and total bilirubin =1×ULN ?? Total bilirubin <0.6×ULN - Adverse events (AEs). Monitoring for AEs at all visits. - AEs of special interest (AESIs): ?? Drug induced liver injury (DILI) ?? Anemia ?? Hypothyroidism - Laboratory tests: ?? Hematology ?? Biochemistry ?? Urinalysis ?? Thyroid function - Vital signs - 12-lead electrocardiograms (ECGs): clinically significant abnormalities ;Timepoint(s) of evaluation of this end point: Week-24 | — |
Countries
Australia, Austria, Belgium, Canada, Czechia, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, New Zealand, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Contacts
Public ContactNelly Ekaterinaki
PRA Health Sciences
Outcome results
None listed