| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness |
|
| E.1.1.1 | Medical condition in easily understood language |
| Liver disease caused by autoimmune attack on the small to medium bile ducts |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080429 |
| E.1.2 | Term | Primary biliary cholangitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
- 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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) Intrauterine hormone-releasing system
(5) Bilateral tubal occlusion
(6) Vasectomized partner
(7) Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception).
Female condom and male condom should not be used together.
11. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization/Baseline before dosing.
12. Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method (as defined in the list in item 10c). This requirement begins at the time of informed consent and ends 90 days after receiving the last dose of IMP.
13. Male patients must be willing not to donate sperm, and female study patients must be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP.
|
|
| E.4 | Principal 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) <30 mL/min/1.73 m2, as calculated by the central laboratory using the chronic kidney disease epidemiology collaboration (CKDEPI) equation.
9. TSH >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 within the 2 weeks prior to Screening Visit 1.
20. A history of bone marrow disorder including aplastic anemia, or any current marked anemia defined as hemoglobin <10.0 g/dL.
21. Prior treatment with setanaxib or participation in a previous setanaxib clinical study.
22. Unstable cardiovascular disease as defined by any of the following:
a. Unstable angina within 6 months prior to Screening
b. Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6 months prior to Screening
c. Cerebrovascular accident within 6 months prior to Screening
d. New York Heart Association Class III or IV heart failure
23. Presence of any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a patient’s treatment, assessment, or compliance with the protocol and/or study procedures.
24. Any other condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the patient in the study, or that could interfere with the study objectives, conduct, or evaluation.
25. Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebo compounds. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in Alkaline phosphatase (ALP) at Week 24 compared to Baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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 PGIC pruritus
- Changes in markers of cholestasis as assessed by proportion of patients at Week 24 with:
○ ALP reduction to <1.67×upper 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 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
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Switzerland |
| Australia |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Sweden |
|
| E.8.7 | Trial 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
|
| The end of the study is defined as the date of the last visit or last procedure of the last patient in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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