| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults patients with Primary Sclerosing Cholangitis (PSC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary Sclerosing Cholangitis (PSC) is a progressive liver disease characterised by inflammation and fibrosis of the bile ducts with risk of liver failure. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036732 |
| E.1.2 | Term | Primary sclerosing cholangitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Objectives for the Double-Blind Period (DBP):
Primary Objectives:
To assess the safety and tolerability of daily oral administration of elafibranor 80 mg and 120 mg as compared to placebo in adult participants with PSC after 12 weeks of treatment
Objectives for the Open-Label Extension Period (OLE):
Primary Objective:
To assess the long-term safety and tolerability of daily oral administration of elafibranor up to 120 mg during the OLE |
|
| E.2.2 | Secondary objectives of the trial |
For the DBP:
To evaluate the effect of daily oral administration of elafibranor 80 mg and 120 mg on markers of cholestasis and hepatobiliary injury as compared to placebo in adult participants with PSC after 12 weeks of treatment
To evaluate the effect of daily oral administration of elafibranor 80 mg and 120 mg as compared to placebo in non-invasive markers of hepatic fibrosis as assessed by liver stiffness measurement by transient elastography (FibroScan®) and serum-based biomarkers of fibrosis and of disease activity in adult participants with PSC after 12 weeks of treatment
Secondary PK:
To characterise the PK of elafibranor and its metabolite GFT1007 in adult participants with PSC using a Population PK approach, including identification of covariates impacting PK variability
For the OLE:
To evaluate the maintenance of efficacy and the long-term effect of daily oral administration of elafibranor up to 120 mg during the OLE on markers of cholestasis and hepatobiliary injury |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
2. Participants with a diagnosis of PSC as demonstrated by the presence of the following, and in the absence of apparent causes of secondary sclerosing cholangitis:
i) Historical evidence of an elevated ALP >ULN since at least 6 months prior to SV1.
ii) Cholangiogram (e.g. magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) with features compatible with large duct PSC.
3. ALP ≥1.5x ULN during screening (with variability ≤40% based on two consecutive values). The interval between the two measurements should be of at least 2 weeks (and up to 4 weeks). The baseline value will be the average of all values obtained during screening plus the baseline visit measurement (obtained prior to treatment initiation).
• If the mean value of both ALP values is ≥1.5x ULN and the variability between values is ≤40%, the participant is eligible (even if one of the two values is <1.5x ULN).
• In cases where one of the two values is >1.5x ULN, but the mean value is <1.5x ULN, or if the variability between values is >40%, an additional value during screening may be obtained at least 2 weeks (and up to 4 weeks) after the previous measurement during screening.
• In cases where an additional value is checked, the participant will be eligible if the variability between the second and the third value is ≤40%, and the mean value of all ALP values during screening is ≥1.5x ULN.
• In cases of ineligibility, the candidate may be subsequently re-screened once at investigator’s discretion, and enrolled if stable qualifying values are demonstrated.
• All ALP values during screening should be analysed via the central laboratory.
4. Total bilirubin ≤2.0x ULN at SV1.
5. If taking UDCA, the participant should have:
i) Total daily dose ≤23 mg/kg/day.
ii) Minimum of 6 months of stable treatment prior to screening period and expected to remain on stable dose through the 12-week DBP.
iii) Minimum of 3 months off treatment prior to screening period if UDCA was recently discontinued.
6. For participants with IBD:
i) Participants with Crohn’s disease must be in remission based on the investigator’s clinical assessment and should be on stable treatment prior to randomisation and during screening.
ii) Participants with ulcerative colitis must be in remission or have low activity disease as per the judgement of the investigator and should be on stable treatment prior to randomisation and during screening.
iii) Current treatment for IBD is permitted, if the participant has been well controlled for ≥3 months prior to the screening period and is anticipated to remain on a stable dose of drugs for IBD treatment, including biologics, immunosuppressants, immunomodulators, or systemic corticosteroids. This provision regarding stability of IBD treatment applies to the following, among others:
• 5-aminosalicylic acid drugs.
• Azathioprine; 6-mercaptopurine; methotrexate.
• Budesonide (within recommended doses for management of IBD). In addition to oral formulation, topical application of budesonide (rectal foam or enema) is allowed.
• Other systemic corticosteroids.
• Biologics (e.g. anti-tumour necrosis factor or anti-integrin therapies).
• Other immunosuppressants or immunomodulators used for IBD treatment.
iv) Participants with IBD should have a colonoscopy performed within two years prior to the screening period showing no evidence of dysplasia or cancer.
7. Medications for management of pruritus (e.g. cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥3 months prior to the screening period.
8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Refer to section 5.1 of the protocol for the rest. |
|
| E.4 | Principal exclusion criteria |
1. History or presence of other concomitant chronic liver disease including:
i) ImmunoglobulinG 4 (IgG4) related sclerosing cholangitis, or IgG4 ≥4x ULN at SV1.
ii) Small duct PSC.
iii) Documented history of secondary sclerosing cholangitis.
iv) Presence of hepatitis B surface antigen (HBsAg) at screening.
v) Hepatitis C virus (HCV) infection defined by positive anti-HCV antibody and positive HCV ribonucleic acid (RNA) (Note: Participants with positive anti-HCV antibody due to previously treated HCV infection, may be enrolled if a confirmatory HCV RNA is undetectable and sustained viral response has been documented).
vi) PBC or history of positive anti-mitochondrial antibody.
vii) Alcoholic liver disease.
viii) Autoimmune hepatitis (AIH): Simplified Diagnostic Criteria of the IAIHG ≥6.
ix) Presence of history of PSC-PBC or PSC-AIH overlap syndrome.
x) NASH.
xi) Known history of alpha-1 antitrypsin deficiency.
2. Presence of percutaneous drain or bile duct stent at screening or within three months prior to screening.
3. History of bacterial cholangitis within 60 days prior to the screening period, or participant on ongoing or planned long-term (a year or more) antibiotics for prophylaxis of recurrent cholangitis.
4. History or any current suspicion of cholangiocarcinoma or elevated value of carbohydrate antigen 19-9 (CA19-9) >129 U/mL at SV1.
5. Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) suggesting presence of liver cancer.
6. Participants with cirrhosis who are also classified as Child-Pugh B or C based on the Child-Pugh score. Participants with cirrhosis with Child-Pugh A score are allowed.
7. History of clinically significant hepatic decompensation, including:
i) History of liver transplantation, current placement on a liver transplant list, current model for end-stage liver disease (MELD)-Na score ≥12 due to hepatic impairment (MELD-Na will be calculated only when MELD >11).
ii) Evidence of complications of cirrhosis, including hepatic decompensation or evidence of significant portal hypertension complications including presence of ascites requiring treatment; history or presence of spontaneous bacterial peritonitis; presence of hepatic encephalopathy grade 2 or higher per West-Haven criteria; history of oesophageal variceal bleeding or related interventions (e.g. oesophageal variceal banding, or transjugular intrahepatic portosystemic shunt placement). Note: Participants with grade 1 varices may be eligible to enrol.
iii) Hepatorenal syndrome (type I or II).
8. Presence or history of hepatocellular carcinoma.
9. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease).
10. Medical conditions that may diminish life expectancy to <2 years, including known cancers.
11. Participant has a positive test for human immunodeficiency virus (HIV) type 1 or 2 at SV1, or participant is known to have tested positive for HIV.
12. Evidence of any other unstable or untreated clinically significant immunological, endocrine, neurological, gastrointestinal, haematologic, psychiatric diseases as evaluated by the investigator; other clinically significant conditions that are not well controlled.
13. Known malignancy or history of malignancy within the last 5 years, with the exception of local, successfully treated basal cell carcinoma or in-situ carcinoma of the uterine cervix.
Prior/concomitant therapy:
14. Administration of the following medications are prohibited as specified below:
i) 3 months prior to the screening period: fibrates and glitazones.
ii) 3 months prior to the screening period: cyclosporine, mycophenolate, pentoxifylline, and chronic systemic corticosteroids (except as specified in inclusion criteria 6 as part of management of IBD at an ongoing stable dose) (NOTE: Short courses ≤21 days of tapered oral steroids in the previous 3 months for a non-hepatic and non-IBD related indication would not be exclusionary if tapering was completed at least 6 weeks prior to screening); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin).
iii) Obeticholic acid.
iv) 2 months prior to the screening period: systemic antibiotics (e.g. minocycline, vancomycin, metronidazole) specifically for prophylaxis of recurrent cholangitis or for treatment of PSC. Note: Short (up to 30 days) antibiotic courses for other indications are permitted during the study if medically necessary.
Refer to section 5.2 of the protocol for the rest. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
During the 12-week DBP:
• Number and percentage of participants who experience TEAEs, treatment-related TEAEs, SAEs, and AESIs
• Number and percentage of participants who develop clinically significant changes from baseline in physical examination findings, vital signs, and ECG
During the OLE period:
• Number and percentage of participants who develop clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures
During the OLE period:
• Number and percentage of participants who experience TEAEs, treatment-related TEAEs, SAEs, and AESIs
• Number and percentage of participants who develop
clinically significant changes from baseline in physical
examination findings, vital signs and ECG
• Number and percentage of participants who develop
clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the DBP: After 12 weeks of treatment
For the OLE: After the last dose of study intervention |
|
| E.5.2 | Secondary end point(s) |
Endpoints for the DBP:
Secondary end point 1 for secondary objective 1:
• Relative change from baseline in ALP at Week 12
• Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 12
• Absolute change from baseline in ALP at Week 12
• Number and percentage of participants with ALP: <1.3x ULN and <1.5x ULN at Week 12
• Number and percentage of participants who normalised ALP at Week 12
• Change from baseline in ALT, AST, GGT, 5’ nucleotidase, total bilirubin, conjugated bilirubin, albumin and fractionated ALP at Week 12
Secondary end point 2 for secondary objective 2:
• Change from baseline in ELF test at Week 12
• Change from baseline in LSM assessed by FibroScan® at Week 12
• Change from baseline in other non-invasive hepatic fibrosis serum markers as measured by PAI-1, TGF-β, marker of type V collagen formation (Pro-C5), and marker of type III collagen formation (Pro-C3) at Week 12
• Change from baseline in FIB-4 and APRI at Week 12
• Change from baseline in CK-18 (M65 and M30) at Week 12
For secondary PK:
Individual PK parameters (during a dosing period of 24 hours) after single administration and at steady state:
- AUC0-24 (area under the plasma concentration-time
curve from time 0 to 24 hours)
- Cmax (maximum (peak) plasma drug concentration)
- Tmax (time to maximum plasma concentration)
• Population PK parameters:
- CL (apparent clearance of drug from plasma)
- VZ (apparent volume of distribution)
Endpoints for the OLE:
• Relative change from baseline in ALP at Week 52 and
Week 96 of treatment in OLE
• Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 52 and Week 96 of treatment in OLE
• Absolute change from baseline in ALP at Week 52 and Week 96 of treatment in OLE |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the DBP: At week 12
For the OLE: At week 52 and week 96
|
|
| 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 | 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) | 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 | 22 |
| 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 |
| Canada |
| United Kingdom |
| United States |
| Germany |
| Italy |
| Portugal |
| Spain |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 13 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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