| 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 |
| Primary Biliary Cholangitis |
|
| 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 | 21.0 |
| 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 effect of elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint over 52 weeks of the treatment compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP) over 52 weeks of the treatment compared to placebo
To evaluate the effect of Elafibranor (80 mg/day) on pruritus over 52 weeks of the treatment compared to placebo
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Must have provided written informed consent and agree to comply with the study protocol
2)Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)
3)Definite or probable PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic criteria:
a.History of elevated ALP levels for ≥ 6 months prior to randomization (V1)
b.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 (ANA)
c.Liver biopsy consistent with PBC
4)Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
a.1 liver biopsy during the Screening Period (if no historical biopsy within 12 months before screening is available)
b.1 liver biopsy after 52-weeks of treatment
5)ALP ≥ 1.67x upper limit of normal (ULN)
6)Total bilirubin (TB) ≤ 2x ULN
To ensure adequate representation of moderately advanced disease or patients at risk of progression to clinical outcomes, at least 10% of randomized patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < lower limit of normal [LLN]) and at least 20% will have a TB > 0.6 x ULN (patients at risk of progression)
7)Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS) during each of the 7 day intervals in the 14 days prior to randomization (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to randomization (V1)
8)UDCA for at least 12 months (stable dose ≥ 3 months) prior to randomization, or unable to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to randomization (per country standard-of-care dosing)
9)If on colchicine must be on a stable dose for ≥ 3 months prior to randomization
10)Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3 months prior to randomization
11)Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to randomization
12)Females participating in this study must be of non-child bearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the last drug intake:
•Non-child bearing potential: cessation of menses for at least 12 months due to ovarian failure or surgical sterilization such as bilateral oophorectomy, hysterectomy, or medically documented ovarian failure for > 6 months prior to randomization
•If required by local Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and/or national regulations, sexual abstinence may be considered adequate (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)
•Using a highly effective non-hormonal medical contraception (bilateral tubal occlusion, vasectomized partner or intra-uterine device) for ≥ 3 months prior to screening
•Highly effective contraception with barrier or 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 screening
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|
| E.4 | Principal exclusion criteria |
1)History or presence of other concomitant liver disease including:
a)Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or positive hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus (HCV) ribonucleic acid (RNA) (tested for in case of known cured HCV infection or positive HCV Ab at screening)
b)Primary sclerosing cholangitis (PSC)
c)Alcoholic liver disease (ALD)
d)Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence of overlap AIH features, that cannot be explained alone by insufficient response to UDCA
e)Nonalcoholic steatohepatitis (NASH)
f)Gilbert’s Syndrome (exclusion due to interpretability of bilirubin levels)
g)Known history of alpha-1 antitrypsin deficiency
2)Clinically significant hepatic decompensation, including:
a)History of liver transplantation, current placement on a liver transplant list, current Model for End-Stage Liver Disease-Sodium (MELD-Na) score ≥ 12 linked to hepatic impairment
b)Patients with cirrhosis/portal hypertension complications, including known esophageal varices, ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), and hepatic encephalopathy, history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma
c)Hepatorenal syndrome (type I or II)
3)Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease) or which may diminish life expectancy to < 2 years, including known cancers
4)Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2 at screening, or patient is known to have tested positive for HIV
5)Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator
6)Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
7)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 screening visit (SV1)
8)For female patients: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
9)Administration of the following medications are prohibited as specified below:
a)2 months prior to randomization and throughout the study (up to the last study visit): fibrates and glitazones
b)3 months prior to randomization and throughout the study (up to the last study visit): Obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
c)12 months prior to randomization and throughout the study (up to the last study visit): antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or chemokines
10)Patients who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or five half-lives, whichever is longer, prior to screening; patients with previous exposure to seladelpar are excluded.
11)Patients with previous exposure to elafibranor
12)SV value of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5x ULN
13)SV value of albumin < 3.0 g/dL
14)Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < LLN)
15)SV value of international normalized ratio (INR) > 1.3 due to altered hepatic function
16)SV value of creatine phosphokinase CPK > 2X ULN
17)Screening serum creatinine > 1.5 mg/dL
18)Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney failure damage or estimated glomerular filtration rate [eGFR] < 60 mL/min/1,73 m2) calculated by modification of diet in renal disease (MDRD)
19)Platelet count < 150 X 103/µL
20)Alfa-fetoprotein (AFP) > 20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) suggesting presence of liver cancer
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
Response to treatment based on ALP normalization at week 52.
Change in pruritus from baseline through week 52 on PBC Worst Itch NRS score.
Other Secondary Endpoints:
1)Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
2)ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
3)Response to treatment at week 52 according to:
a)ALP < 1.5x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b)ALP < 3x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
c)ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris II)
d)TB response rate of 15% change
e)Normalization of abnormal TB and/or albumin (Rotterdam)
f)TB ≤ 0.6 x ULN
g)ALP ≤ 1.67x ULN and TB ≤ 1 mg/dL [1]
h)No worsening of TB defined as level of TB≤ ULN at week 52 or no increase from baseline of more than 0.1XULN at week 52
4)PBC risk scores at week 52: United Kingdom (UK) PBC score [2] and GLOBE score [3]
5)Response based on bilirubin normalization (TB ≤ ULN) at week 52
6)Response based on albumin normalization at week 52
7)Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, ALT, gamma-glutamyl transferase (GGT), 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
8)Change from baseline to week 52 in biomarkers of inflammation as measured by high-sensitivity C-Reactive Protein (hsCRP), fibrinogen, haptoglobin and tumor necrosis factor-alpha (TNF-alfa)
9)Change from baseline to week 52 in immune response as measured by immunoglobulin G (IgG) and IgM
10)Change from baseline to week 52 in biomarkers, non-invasive and invasive measures of hepatic fibrosis as measured by enhanced liver fibrosis (ELF)(HA, PIINP, TIMP-1), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor beta (TGF-β), cytokeratin-18 (CK-18) (M65 and M30), Pro-C3 and liver stiffness measured by Transient Elastography (TE) (continuous)
11)Change from baseline to week 52 in lipid parameters as measured by total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), calculated VLDL-C and TG
12)Change from baseline to week 52 in fasting plasma glucose (FPG)
13)Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF-19)
14)Proportion of patients with no worsening of pruritus from baseline to week 52 as measured by the PBC Worst Itch NRS
15)Response in PBC Worst Itch NRS defined as at least 30% reduction from baseline of NRS at week 52 in patients with a baseline NRS ≥ 4
16)Change from baseline to week 52 in 5D-Itch
17)Change from baseline to week 52 in Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a
18)Change from baseline to week 52 in the Epworth Sleepiness Scale (ESS)
19)Change from baseline to week 52 in PBC-40
20)Change from baseline to week 52 in health utility as measured by the EQ-5D-5L
21)Onset of clinical outcomes described as a composite endpoint composed of:
a)Progression to histological cirrhosis for non cirrhotic patients at baseline
b)MELD-Na > 14 for patients with baseline MELD-Na ≤12
c)Liver transplant
d)Uncontrolled ascites requiring treatment
e)Hospitalization for new onset or recurrence of any of the following:
i)variceal bleed
ii)hepatic encephalopathy defined as West-Haven/Conn score of 2 or more
iii)spontaneous bacterial peritonitis
f)Death
22)Change from baseline in the histological scores
a)Fibrosis stage according to Nakanuma scoring
b)Bile duct scores
c)Cholangitis activity
d)Interface Hepatitis activity
e)Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct score)
f)Other exploratory scores (Fibrosis according to mdodifeid Ishak scoring, portal inflammation, ductular reaction, cholestasis, concentric periductal fibrosis)
23)Safety and tolerability as assessed by
a)Serious adverse events (SAEs), adverse events (AEs), adverse events of special interest (AESIs), physical examination, vital signs, medical history, electrocardiogram (ECG)
b)Chemistry and hematology
c)Liver markers
d)Renal biomarkers (including urinalysis)
e)Other biochemical safety markers
f)Histology
24)PK assessed by GFT505 and GF1007 concentrations measurement in plasma |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All of the secondary endpoints have defined timepoints included above. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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 | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| Chile |
| France |
| Germany |
| Italy |
| Mexico |
| South Africa |
| Spain |
| Switzerland |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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