| 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 | 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 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 in patients with baseline PBC Worst Itch NRS score ≥4
To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 24 weeks of the treatment compared to placebo in patients with baseline PBC Worst Itch NRS score ≥4
|
|
| 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)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)ALP ≥ 1.67x upper limit of normal (ULN)
5)TB ≤ 2x ULN
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes or moderate disease stage, approximately 10% of randomized patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < lower limit of normal [LLN]) and approximately 20% will have a TB > 0.6 x ULN (patients at risk of progression)
6)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)
7)UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country standard-of-care dosing)
8)If on colchicine must be on a stable dose for ≥ 3 months prior to screening
9)Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3 months prior to screening
10)Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to screening
11)Females participating in this study must be of non-child bearing potential or must be using highly effective 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, or hysterectomy
•Highly effective contraception methods include:
a.Combined (estrogen and progrestogen containing) hormaonal
contraception associated with inhibition of ovulation, oral, intravaginal or transdermal
b.Progestogen-only hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable
c.Intrauterine device (IUD)
d.Intrauterine hormoine release system (IUS)
e.Bilateral tubal occlusion
f.Vasectomized partner
g.Sexual abstinence, if required by local IRB/IEC regulations and/or
considered adequate by National laws (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)
12)For patients who consent to have liver biopsy samples collected,
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 6 months before screening is available)
b.1 liver biopsy after 52-weeks of treatment |
|
| 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; other clinically significant medical conditions that are not well controlled
6)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)
7)For female patients: known pregnancy, or has a positive serum
pregnancy test, or lactating
8)Administration of the following medications are prohibited as specified below:
a)2 months prior to screening: fibrates and glitazones
b)3 months prior to screening: azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
c)12 months prior to screening: antibodies or immunotherapy directed against ILs or other cytokines or chemokines
d)For patients with previous exposure to OCA, OCA should be
discontinued 3 months prior to screening
9)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; for patients with previous
exposure to seladelpar, seladelpar should be discontinued 3 months
prior to screening
10)Patients with previous exposure to elafibranor
11)SV value ALT and/or AST > 5 x ULN
12)For patients with AT or TB>ULN at SV1, variability of AT or TB > 40%
13)SV value albumin<3.0 g/dl
14)Severely advanced patients according to Rotterdam criteria (TB >
ULN and albumin < LLN)
15)SV value INR > 1.3 due to altered hepatic function
16)SV value CPK > 2 x 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 eGFR < 60 mL/min/1,73 m2) calculated by MDRD
19)Platelet count < 150 x 103/μL
20)AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting
presence of liver cancer
21)Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet
22)Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain |
|
| 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:
1) Response to treatment based on ALP normalization at week 52.
2) Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4.
3) Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4
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 ≤ ULN (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
i) Complete biochemical response defined as normal ALP; TB; AST; ALT; albumin; and INR
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, and non-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), highdensity 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 responders in PBC Worst Itch NRS according to clinically meaningful change; at least 30% reduction; and one point, two points or three points decrease in score
from baseline through week 52 and through week 24 in patients with a baseline NRS score ≥ 4
15)Proportion of patients with no worsening of pruritus from baseline through week 52 and through week 24 as measured by the PBC Worst Itch NRS
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)Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density (hip and lumbar) assessed by DEXA scanning
22)Onset of clinical outcomes described as a composite endpoint
composed of:
a)MELD-Na >14 for patients with baseline MELD-Na <12
b)Liver transplant
c)Uncontrolled ascites requiring treatment
d)Hospitalization for new onset or recurrence of any of the following:
i)variceal bleed
ii)hepatic encephalopathy defined as West-Haven score of 2 or more
iii)spontaneous bacterial peritonitis
e)Death
23)Safety and tolerability as assessed by:
a)SAE, AE, AESI, physical examination, vital signs, medical history, ECG
b)Chemistry and hematology
c)Liver markers
d)Renal biomarkers (including urinalysis)
e)Other biochemical safety markers
24)PK assessments 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 | Yes |
| 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Chile |
| Brazil |
| Canada |
| South Africa |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| Türkiye |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| 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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