A Study of Elafibranor in Adults with Primary Biliary Cholangitis and Inadequate Response or Intolerance to Ursodeoxycholic Acid

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ipsen Bioscience Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

15 Oct 2024 → ongoing

Decision date (initial)

2024-10-01

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ipsen Biosciences, Inc.

External identifiers

EU CT number

2024-510695-20-00

ClinicalTrials.gov

NCT06383403

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC on normalisation of ALP

Secondary objectives 8

1. To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC on biochemical markers of response
2. To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC on patient-reported outcomes
3. To evaluate the safety and tolerability of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC
4. To evaluate the effect of elafibranor 80 mg daily as compared to placebo on biomarkers: - Liver Tests - Non-invasive markers of fibrosis - Biomarkers of Pruritus - Lipid parameters - PBC prognosis score - Biomarkers of inflammation and immune response - Biomarkers of bile acid synthesis - Bone mineral density
5. To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC on clinical outcome events of interest
6. To evaluate the PK of elafibranor and its metabolite GFT1007 in the participant population using a population PK approach
7. To evaluate the association of biomarkers with clinical data on selected efficacy and safety endpoints, if applicable
8. To assess the relationship between PK and PD (efficacy and safety if applicable) endpoints

Conditions and MedDRA coding

Primary Biliary Cholangitis (PBC)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male or female participants age ≥18 years of age.
2. Participants with a historical diagnosis of PBC as demonstrated by the presence of ≥2 of the following three historical diagnostic criteria: i. History of elevated ALP levels for ≥6 months prior to SV1. ii. Positive (Antimitochondrial antibody ) AMA titres (≥1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay) or positive PBC-specific antinuclear antibodies. iii. Liver biopsy consistent with PBC.
3. ALP >1 × ULN and <1.67 × ULN.
4. (a) Participants taking UDCA should have been on this medication for at least 12 months and at a stable dose for ≥ 6 months prior to SV1. Participants who are intolerant to UDCA may participate and should have taken the last dose of UDCA ≥3 months prior.
5. (a) Participants taking medications for management of pruritus (e.g cholestyramine, naltrexone, sertraline or colchicine) must be on a stable dose for ≥3 months prior to screening.
6. (b) Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (Appendix 10.4). Male participants: • Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 30 days after the last dose of study intervention: • Refrain from donating sperm. PLUS either: - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR - Must agree to use contraception / barrier as detailed below:  Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak as there remains when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Female participants • Female participants are eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: • Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 10.4. OR • Is a WOCBP abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) or using a systemic hormonal contraceptive method that is highly effective (with a failure of <1% per year) along with a barrier method (e.g. condom) or using a non-hormonal contraceptive method that is highly effective (with a failure rate of <1% per year) preferably with low user dependency, as described in Appendix 10.4 during the study intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g. noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.4.6). • If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are specified within the protocol. • The investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
7. Capable of giving signed informed consent as described in Appendix 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria 28

1. History or presence of other concomitant liver diseases
2. History of hepatocellular carcinoma
3. Alpha-foetoprotein (AFP) >20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting presence of liver cancer
4. (12) Administration of the following medications is prohibited during the study, and prior to the study as per the timelines specified below: i.Systemic (oral or parenteral) use within 3 months prior to SV1 of: fibrates, seladelpar, glitazones, obeticholic acid, azathioprine, cyclosporine, methotrexate, mycophenolate, or long-term systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyl-dopa, valproic acid, isoniazid or nitrofurantoin) ii) Breat Cancer Resistance Protein (BRCP) inhibitors within 1 month prior to SV 1
5. Participants with previous exposure to elafibranor
6. Participants 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 5 half-lives, whichever is longer
7. Total bilirubin (TB) >2 × ULN. Participants with Gilbert’s syndrome are eligible with a TB above 2 × ULN if direct bilirubin is <30% of TB
8. (Alanine aminotransferase) ALT and/or (aspartate aminotransferase) AST >5 × ULN
9. (Creatine phosphokinase) CPK >2 × ULN
10. (18) Platelet count <75,000/µL
11. International normalised ratio >1.3 in the absence of anticoagulant therapy
12. Participants with known cirrhosis who have a Child-Pugh B or C score. Participants with cirrhosis with Child-Pugh A score are allowed.
13. 20 (a) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 per the Modification of Diet in Renal Disease (MDRD)-6 formula or on dialysis at SV1.
14. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).
15. For female participants: known pregnancy, or has a positive serum pregnancy test, or is breastfeeding
16. Regular alcohol intake in excess of the recommended limit of 2 standard drinks per day for men or 1 standard drink per day for women
17. History of alcohol abuse, or other substance abuse within 1 year prior
18. Known hypersensitivity to the investigational product or to any of the excipients of elafibranor
19. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
20. Any other condition that, in the opinion of the investigator, would interfere with study participation or completion, or would put the participant at risk, including a potential participant assessed as being at high risk of noncompliance with the study
21. History of liver transplantation
22. History or presence of clinically significant hepatic decompensation
23. Known history of human immunodeficiency virus (HIV) infection
24. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease)
25. Evidence of any other unstable or untreated clinically significant conditions that are not well controlled
26. Medical condition with a life expectancy <2 years
27. Known malignancy or history of malignancy within the last 2 years, except for successfully treated localised basal cell carcinoma or squamous cell carcinoma of the skin; or in-situ carcinoma of the uterine cervix
28. Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of participants with normalisation of ALP at Week 52

Secondary endpoints 22

1. Percentage of participants with normalisation of ALP Levels [Time Frame: From baseline to Week 4, Week 12, Week 24 and Week 36]
2. Change from baseline in ALP levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]
3. Percentage of participants with normalisation of ALP Levels and ≥15% decrease from Baseline [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]
4. Percentage of participants with ≥40% decrease from Baseline in ALP Levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]
5. Percentage of participants with ALP <0.5 × Upper Limit of Normal (ULN) [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]
6. Changes from baseline in Total Bilirubin (TB) Levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]
7. Percentage of participants with TB <0.7 × ULN [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]
8. Percentage of participants with normalisation of ALP and TB <0.7 × ULN [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]
9. Percentage of participants with normalisation of TB and ALP Levels [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]
10. Percentage of participants with complete biochemical response [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]
11. Change from baseline in PBC Worst Itch Numeric Rating Scale (NRS) score [Time Frame: From baseline through Week 52]
12. Percentage of participants with moderate to severe pruritus at baseline (i.e. score ≥4) with a clinically meaningful response in PBC Worst Itch NRS [Time Frame: From baseline through Week 52]
13. Change from baseline in 5-D itch score [Time Frame: From baseline to Week 4, Week 24, and Week 52]
14. Change from baseline in Patient Global Impression of Severity (PGI-S) scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]
15. Patient Global Impression of Change (PGI-C) scores [Time Frame: At Week 4, Week 24, and Week 52]
16. Change from baseline in PBC-40 Quality of Life (QoL) scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]
17. Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]
18. Percentage of participants experiencing Treatment- Emergent Adverse Events (TEAEs), treatment- related TEAEs, Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs). [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]
19. Percentage of participants developing clinically significant changes in physical examination [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]
20. Percentage of participants developing clinically significant changes in vital signs [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]
21. Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) Readings [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]
22. Percentage of participants developing clinically significant changes in laboratory parameters [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ipsen Bioscience Inc.

Sponsor organisation

Ipsen Bioscience Inc.

Address

1 Main Street Ste 7

City

Cambridge

Postcode

02142-1599

Country

United States

Scientific contact point

Organisation

Ipsen Bioscience Inc.

Contact name

Ipsen Clinical Study Enquiries

Public contact point

Organisation

Ipsen Bioscience Inc.

Contact name

Ipsen Clinical Study Enquiries

Third parties 9

Locations

7 EU/EEA countries · 34 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 174 files

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

Application history

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