| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary biliary cholangitis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034176 |
| E.1.2 | Term | PBC |
| E.1.2 | System Organ Class | 100000004871 |
|
| 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 efficacy of elafibranor 80 and 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
To assess the following end-points at week 12
• the response to treatment based on composite endpoints:
o ALP < 1.67 × upper limit of normal (ULN) and total bilirubin within normal limit and > 15% decrease in ALP
o ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease in ALP
• response according to Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score
• ALP response rates of 10%, 20% and 40% decrease
• response based on the percent of patients who normalized ALP and patients who normalized bilirubin and patients who normalized albumin
• the change from baseline in ALT, AST, GGT, 5’nucleotidase, total bilirubin, conjugated bilirubin and albumin
• the change from baseline in:
o lipid parameters
o bile acids :
o C4, FGF19
o IgM
o inflammatory and liver fibrosis markers
• the change from baseline in:
o 5D-itch scale, PBC 40 QOL, VAS
• the tolerability and safety of elafibranor 80 and 120 mg in patients with PBC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must have provided written informed consent (IC)
2. Males or females 18 to 75 years of age
3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 diagnostic factors:
o History of elevated ALP levels for at least 6 months
o Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies
o Liver biopsy consistent with PBC
4. ALP ≥ 1.67x upper limit of normal (ULN) (‘inadequate response to UDCA’)
5. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit
6. Contraception: Females participating in this study must be of non-childbearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below:
a) Cessation of menses for at least 12 months due to ovarian failure
b) Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure
c) Using a highly effective non-hormonal method of contraception (bilateral tubal occlusion, vasectomised partner or intra-uterine device)
d) Double contraception with barrier and highly effective hormonal method of contraception (oral, intravaginal or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation or intrauterine hormone-releasing system). The hormonal contraception must be started at least one month prior to randomization.
7. Must agree to comply with the trial protocol. |
|
| E.4 | Principal exclusion criteria |
1. History or presence of other concomitant liver diseases including:
• Positive hepatitis B surface antigen (HBsAg) at Screening
• Positive HCV RNA (tested for in case of known cured HCV infection, or positive HCV Ab at screening)
• Alcoholic liver disease
• Primary sclerosing cholangitis (PSC)
• Definite autoimmune hepatitis (AIH), or ‘AIH-PBC overlap syndrome’; the existence of AIH is defined as continuing use of budesonide or other systemic corticosteroid therapy, and/or azathioprine, and/or other immunosuppressive therapy following an historical AIH diagnosis (EASL 2015). ‘AIH-PBC overlap syndrome’ is based upon fulfilment of the ‘Paris criteria’ (Chazouillères 1998) for both AIH (ALT ≥5x ULN; IgG ≥2x ULN or smooth muscle antibody; interface hepatitis), and PBC(ALP ≥2x ULN; AMA, and non-suppurative bile duct injury/destruction), requiring corticosteroid therapy for disease management, either currently or in the past.
• Biopsy confirmed Nonalcoholic Steatohepatitis (NASH)
• Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of chronic liver disease
• Gilbert's Syndrome (due to interpretability of bilirubin levels)
2. Screening CPK > ULN
3. Screening ALT or AST > 5 ULN
4. Screening total bilirubin > 2 ULN
5. Screening serum creatinine > 1.5 mg/dl and eGFR < 60 mL/min/1.73 m2, at screening
6. Significant renal disease, including nephritic syndrome, chronic kidney disease
7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh class B, C)
8. Platelet count <150 X 10 3/microliter
9. Albumin <3.5 g/dL
10. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
• Current Model for End Stage Liver Disease (MELD) score ≥ 15; current placement on a liver transplant
list, or history of undergoing liver transplantation
• Any record of complications of cirrhosis and/or portal hypertension such as:
o Gastroesophageal variceal bleeding and endoscopic therapy and/or transjugular intrahepatic portosystemic shunt [TIPS] insertion
o Ascites formation requiring intervention, e.g. diuretic therapy
o Spontaneous bacterial peritonitis
o Hepatic encephalopathy
o Confirmed or suspected hepatocellular carcinoma
11. Hepatorenal syndrome (type I or II) Administration of the following medications is prohibited as specified below:
• From pre-randomization to EOT or V5 visit : indomethacin
• 2 months preceding screening and throughout the trial (up to the last study visit): fibrates or obeticholic acid, thiazoledinediones, glitazones
• 3 months prior to screening and throughout the trial (up to the last study visit): azathioprine, colchicine,
cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other chronic
systemic corticosteroids; and potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
• 12 months prior to inclusion visit and throughout the trial (up to the last study visit): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
• NOTE : Anti-pruritus treatment, including rifamycin, is allowed if prescribed for at least 6 months prior
to screening, and on stable dose at least 3 months prior to screening. and continues at the same dose throughout the study
12. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy
test), or lactating
13. Known history of human immunodeficiency virus (HIV) infection
14. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)
15. Other clinically significant medical conditions that are not well controlled or for which medication needs are
anticipated to change during the trial
16. Anticipated changes to current medications (that will be continued) during the course of the trial
17. History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for men, and more
than 20 g pure alcohol per day for women, or other substance abuse within 1 year prior to Day 0 (randomization visit)
18. Participation in another trial with an investigational drug, biologic, or medical device using active substance
within 30 days prior to screening, or within 5 half lives of the active substance, whichever is longer.
19. History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable
20. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is
uncertain
21. Known hypersensitivity to the investigational product or any of its formulation excipients
22. Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological,
gastrointestinal, neurological, neoplastic, or psychiatric disease. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is to evaluate the efficacy of elafibranor 80 mg or 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 1.67 times ULN and total bilirubin within normal limits and ALP reduction > 15%.
• Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 2 times ULN and total bilirubin within normal limits and ALP reduction > 40%
• Response rate according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score
• Alkaline phosphatase response rates of 10%, 20% and 40% decrease
• Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized ALP at the end of treatment
• Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized bilirubin at the end of treatment
• Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized albumin at the end of treatment
• Changes from baseline in:
o Gamma-glutamyl transferase (GGT)
o Alanine aminotransferase (ALT)
o Aspartate aminotransferase (AST)
o 5’nucleotidase
o Bilirubin (total and conjugated)
o Albumin
o total cholesterol, LDL-chol, HDL-Chol, Triglycerides
o Bile acids : CDCA, cholic acid, litocholic acid, DCA
o C4, FG19
o IgM
o Quality of Life: PBC 40 QOL
o Pruritus: 5-D Pruritus Questionnaire and Visual Analogue Score (VAS)
o Biomarkers of inflammation and liver fibrosis: TNF-α, TGF-β, IL-6, CK-18 and lysophosphatidic acid
• Plasma concentrations of elafibranor and its main metabolite and exposure-response relationship
• Adverse Events (AEs)
• Cardiovascular parameters (12-lead ECG, heart rate, blood pressure)
• Hematology and safety parameters
• Liver Markers
• Other biochemical safety markers |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| France |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| End of Trial is deemed as last patient last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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