ELAFIBRANOR for Primary biliary cholangitis

Inclusion criteria

• {"criterion_text":"- Must have provided written informed consent and agree to comply with the study protocol"}
• {"criterion_text":"- Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to screening"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- ALP ≥ 1.67x upper limit of normal (ULN)"}
• {"criterion_text":"- Total bilirubin (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)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- If on colchicine must be on a stable dose for ≥ 3 months prior to screening"}
• {"criterion_text":"- Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3 months prior to screening"}

Exclusion criteria

• {"criterion_text":"- 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"}
• {"criterion_text":"- Patients with previous exposure to elafibranor"}
• {"criterion_text":"- SV value ALT and/or AST > 5 x ULN"}
• {"criterion_text":"- For patients with AT or TB>ULN at SV1, variability of AT or TB > 40%"}
• {"criterion_text":"- SV value albumin<3.0 g/dl"}
• {"criterion_text":"- Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < LLN)"}
• {"criterion_text":"- SV value INR > 1.3 due to altered hepatic function"}
• {"criterion_text":"- SV value CPK > 2 x ULN"}
• {"criterion_text":"- Screening serum creatinine > 1.5 mg/dl"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Platelet count < 150 x 103/μL"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer"}
• {"criterion_text":"- Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet"}
• {"criterion_text":"- Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- For female patients: known pregnancy, or has a positive serum pregnancy test, or lactating"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}

Primary endpoints

• {"endpoint_text":"- Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ULN and ALP decrease ≥ 15%.","definition_or_measurement_approach":"Laboratory measurement of alkaline phosphatase (ALP) and total bilirubin (TB) at Week 52; response defined as ALP <1.67 x ULN AND TB ≤ ULN AND ≥15% reduction in ALP from baseline."}

Secondary endpoints

• {"endpoint_text":"- Response to treatment based on ALP normalization at week 52.","definition_or_measurement_approach":"ALP laboratory value at Week 52; endpoint assesses normalization of ALP."}
• {"endpoint_text":"- Change in pruritus from baseline through week 52 based on PBC Worst Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4.","definition_or_measurement_approach":"Patient-reported PBC Worst Itch Numeric Rating Scale (NRS) change from baseline to Week 52 in subgroup with baseline NRS ≥4."}
• {"endpoint_text":"- Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4","definition_or_measurement_approach":"PBC Worst Itch NRS change from baseline to Week 24 in patients with baseline NRS ≥4."}
• {"endpoint_text":"- Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks","definition_or_measurement_approach":"Serial laboratory ALP measurements at Weeks 4, 13, 26, 39 and 52 compared to baseline."}
• {"endpoint_text":"- ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52","definition_or_measurement_approach":"Proportion of subjects achieving ≥10%, ≥20% and ≥40% ALP reduction from baseline at Week 52 using laboratory ALP."}
• {"endpoint_text":"- Response to treatment at week 52 according to: a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN b) ALP < 3 x ULN, AST <2x ULN and TB < 1 mg/dL (Paris I) c) ALP ≤ 1.5 x 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","definition_or_measurement_approach":"Composite biochemical response definitions at Week 52 using laboratory measures (ALP, AST, TB, albumin) as specified (Paris I/II, Rotterdam criteria)."}
• {"endpoint_text":"- Response to treatment at week 52 according to: g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1] h) No worsening of TB defined as level of TB at week 52 < ULN 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","definition_or_measurement_approach":"Laboratory-based composite endpoints at Week 52 assessing ALP, TB, AST, ALT, albumin and INR."}
• {"endpoint_text":"- PBC risk scores at week 52: UK PBC score [2] and GLOBE score [3]","definition_or_measurement_approach":"Calculated UK-PBC and GLOBE risk scores at Week 52 using specified formulae and laboratory inputs."}
• {"endpoint_text":"- Response based on the normalization of bilirubin at week 52","definition_or_measurement_approach":"Normalization of total bilirubin (TB ≤ ULN) at Week 52 by laboratory measurement."}
• {"endpoint_text":"- Response based on the normalization of albumin at week 52","definition_or_measurement_approach":"Normalization of serum albumin at Week 52 by laboratory measurement."}
• {"endpoint_text":"- Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, ALT, GGT, 5' NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)","definition_or_measurement_approach":"Serial laboratory measurements of listed liver function and injury markers from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, fibrinogen, haptoglobin and TNF-α","definition_or_measurement_approach":"Laboratory measurement of hsCRP, fibrinogen, haptoglobin and TNF-α comparing baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in immune response as measured by IgG and IgM","definition_or_measurement_approach":"Serologic measurement of IgG and IgM at baseline and Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver stiffness measured by TE (continuous)","definition_or_measurement_approach":"Measured biomarkers (ELF panel, PAI-1, TGF-β, CK-18, Pro-C3) and transient elastography liver stiffness at baseline and Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated VLDL-C and triglycerides (TG)","definition_or_measurement_approach":"Laboratory lipid panel changes from baseline to Week 52 (TC, LDL-C, HDL-C, VLDL-C, TG)."}
• {"endpoint_text":"- Change from baseline to week 52 in FPG","definition_or_measurement_approach":"Fasting plasma glucose measured at baseline and Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile acids, C4 and FGF-19","definition_or_measurement_approach":"Laboratory measurement of bile acids, serum C4 and FGF-19 at baseline and Week 52."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Responder rates on PBC Worst Itch NRS (≥30% reduction and absolute point decreases) through Weeks 24 and 52 in patients with baseline NRS ≥4."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportion with no worsening on PBC Worst Itch NRS at Weeks 24 and 52 compared to baseline."}
• {"endpoint_text":"- Change from baseline to week 52 in 5D-Itch","definition_or_measurement_approach":"Change in 5D-Itch patient-reported instrument score from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in PROMIS Fatigue Short Form 7a","definition_or_measurement_approach":"PROMIS Fatigue Short Form 7a patient-reported outcome change from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in ESS","definition_or_measurement_approach":"Change in Epworth Sleepiness Scale (ESS) score from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in PBC-40","definition_or_measurement_approach":"Change in PBC-40 health-related quality of life questionnaire score from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in health utility as measured by the EQ-5D-5L","definition_or_measurement_approach":"Change in EQ-5D-5L health utility index from baseline to Week 52."}
• {"endpoint_text":"- Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density (hip and lumbar) assessed by DEXA scanning","definition_or_measurement_approach":"Serum bone turnover markers and DEXA-assessed BMD (hip and lumbar) changes from baseline to Week 52."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Composite clinical outcomes captured during follow-up including MELD-Na changes, liver transplant, ascites, hospitalizations for listed hepatic events, and death."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Standard safety assessments: reported AEs/SAEs/AESIs, physical exams, vitals, ECGs, clinical laboratory chemistry and hematology, liver and renal markers, urinalysis."}
• {"endpoint_text":"- PK assessments by GFT505 and GF1007 concentrations measurement in plasma","definition_or_measurement_approach":"Plasma pharmacokinetic concentration measurements of GFT505 (elafibranor) and metabolite GF1007."}

Belgium

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

07-10-2025

Processing Time Days

434

Number Of Sites

2

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

07-10-2025

Processing Time Days

434

Number Of Sites

7

Number Of Participants

21

Germany

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

07-10-2025

Processing Time Days

434

Number Of Sites

5

Number Of Participants

10

Italy

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

30-01-2026

Processing Time Days

549

Number Of Sites

3

Number Of Participants

4

France

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

30-03-2026

Processing Time Days

608

Number Of Sites

5

Number Of Participants

20

Primary sponsor

Full Name

Ipsen Pharma

Organisation Type

Pharmaceutical company

Country Of Registered Address

France

Contract research organisations

Name

Cytel

Responsibilities

Sponsor duties codes: 6, 7 (statistical/operational duties indicated)

Name

Pharmetheus AB

Responsibilities

PK assessments

Name

Eresearchtechnology Inc.

Responsibilities

ePro

Name

Eurofins Adme Bioanalyses

Responsibilities

Bioanalysis

Name

Cerba Research

Responsibilities

Medical image analysis/review - X-ray, MRI, ultrasound

Name

Suvoda LLC

Responsibilities

Operational duties (sponsor duties code 3)

Name

Almac Clinical Services Limited

Responsibilities

Study drug supplier

Name

Cognizant Worldwide Limited

Responsibilities

Pharmacovigilance

Name

Fortrea France S.A.R.L.

Responsibilities

Operational support (sponsor duties code 5)

Third parties

• {"country":"Switzerland","full_name":"Cytel","duties_or_roles":"Sponsor duties codes: 6, 7","organisation_type":"Industry"}
• {"country":"Sweden","full_name":"Pharmetheus AB","duties_or_roles":"PK assessments","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"ePro","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"Bioanalysis","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Cognizant Worldwide Limited","duties_or_roles":"Pharmacovigilance","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"Sponsor duties code: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Belgium","full_name":"Cerba Research","duties_or_roles":"Medical image analysis/review - X-ray, MRI, ultrasound; other duties","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Fortrea France S.A.R.L.","duties_or_roles":"Sponsor duties code: 5","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Study drug supplier","organisation_type":"Pharmaceutical company"}