A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response or Intolerance to Ursodeoxycholic Acid

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ipsen Pharma

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

18 Jan 2021 → ongoing

Decision date (initial)

2024-09-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ipsen Pharma

External identifiers

EU CT number

2024-512232-30-00

EudraCT number

2019-004941-34

ClinicalTrials.gov

NCT04526665

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

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.

Secondary objectives 3

1. To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP) over 52 weeks of the treatment compared to placebo.
2. To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 52 weeks of the treatment compared to placebo in patients with baseline PBC Worst Itch NRS score =4.
3. 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.

Conditions and MedDRA coding

Primary Biliary Cholangitis

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants. Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board. Supporting Information Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later. Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available at https://vivli.org/members/ourmembers/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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. 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)
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

Exclusion criteria 22

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ULN and ALP decrease ≥ 15%.

Secondary endpoints 28

1. Response to treatment based on ALP normalization at week 52.
2. Change in pruritus from baseline through week 52 based 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
4. Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
5. ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
6. 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
7. 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
8. PBC risk scores at week 52: UK PBC score [2] and GLOBE score [3]
9. Response based on the normalization of bilirubin at week 52
10. Response based on the normalization of albumin at week 52
11. 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)
12. Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, fibrinogen, haptoglobin and TNF-α
13. Change from baseline to week 52 in immune response as measured by IgG and IgM
14. 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)
15. Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated VLDL-C and triglycerides (TG)
16. Change from baseline to week 52 in FPG
17. Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile acids, C4 and FGF-19
18. 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
19. 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
20. Change from baseline to week 52 in 5D-Itch
21. Change from baseline to week 52 in PROMIS Fatigue Short Form 7a
22. Change from baseline to week 52 in ESS
23. Change from baseline to week 52 in PBC-40
24. Change from baseline to week 52 in health utility as measured by the EQ-5D-5L
25. Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density (hip and lumbar) assessed by DEXA scanning
26. 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
27. 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
28. PK assessments by GFT505 and GF1007 concentrations measurement in plasma

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ipsen Pharma

Sponsor organisation

Ipsen Pharma

Address

70 Rue Balard

City

Paris

Postcode

75015

Country

France

Scientific contact point

Organisation

Ipsen Pharma

Contact name

Medical Development Director

Public contact point

Organisation

Ipsen Pharma

Contact name

Ipsen Clinical Study Enquiries

Third parties 9

Locations

5 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 100 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications