Effects of NNC0194-0499, cagrilintide, and semaglutide alone or in combinations on liver damage and alcohol use in people with alcohol-related liver disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novo Nordisk A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

7 Aug 2024 → 13 Jan 2026

Decision date (initial)

2024-06-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508170-28-00

WHO UTN

U1111-1295-6713

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on liver damage and function in people with alcohol-related liver disease.

Secondary objectives 3

1. To investigate the safety and tolerability of NNC0194-0499, cagrilintide, and semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo in people with alcohol-related liver disease.
2. To investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on alcohol intake and dependency in people with alcohol-related liver disease.
3. To investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on cardio-metabolic factors in people with alcohol-related liver disease.

Conditions and MedDRA coding

alcohol-related liver disease

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board, Danish Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Participants are eligible to be included in the study only if all the following criteria apply:
2. 1.     Informed consent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
3. 2. Male or female.
4. 3.     Age 18 years or above, and at the legal drinking age according to local requirements (Section 10.16) at the time of signing the informed consent.
5. 4.     Patient-reported history of alcohol overuse for ≥5 years with an alcohol history of a mean of ≥50 grams (male)/40 grams (female) pr day for the last year leading up to the time of signing informed consent.
6. 5.     ELF ≥ 9.0 units.

Exclusion criteria 44

1. Liver-related exclusion criteria:
2. a)     ALT > 5 x ULN at V1. AST > 5 x ULN at V1.
3. b)    Total bilirubin > 1.5 mg/dL at V1. Total bilirubin level > 1.5 mg/dL is allowed if conjugated bilirubin is within normal range.
4. c)     Alkaline phosphatase levels > 2 x ULN at V1.
5. d)    INR of prothrombin time ≥ 1.35 at V1.
6. e)     MELD score > 12 points at V1.
7. f)     eGFR < 60 mL/min/1.73 m2 as defined according to the CKD-EPI creatinine equation (CKD-EPI, 2021) at V1. HbA1c > 80 mmol/mol (9.5%) at V1. Platelet count < 100,000 per µL of blood at V1.
8. Diabetes-related exclusion criteria:
9. 9. For participants with type 2 diabetes: Uncontrolled and potentially unstable diabetic retinopathy or maculopathy verified by a fundus examination performed within 90 days prior to V1 or in the period between V1 and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examinations.
10. 10. Treatment with GLP-1 RAs within 90 days prior to V1.
11. 11. Presence of acute pancreatitis within 180 days prior to V1.
12. 1.Documented causes of chronic liver disease other than Alcohol-related liver disease (ALD).
13. 12. History or presence of type 1 diabetes at V1.
14. 13.Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
15. Alcohol-related exclusion criteria:
16. 14.History of seizure disorder (except childhood febrile seizures)
17. 15.  CIWA-Ar score ≥ 10
18. Mental health related exclusion criteria:
19. 16. Active or unstable depression or other active or unstable psychiatric conditions[1] which in the investigator’s opinion can jeopardise the participant’s safety or compliance with the protocol.
20. 17. A history of a suicidal attempt within 5 years before screening
21. 18. Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at V2.
22. 19. Baseline screening using Montgomery–Åsberg Depression Rating Scale (MADRS) at V2, score corresponding to ≥ 34 (severe depression).
23. 2.Positive HBsAg, positive HIV-1 or HIV-2 Ab, positive HCV RNA at screening (V1) or any known presence of HCV RNA or HBsAg within 2 years of screening (V1).
24. General safety-related exclusion criteria:
25. 20. BMI ≤ 25 kg/m2.
26. 21.Known or suspected hypersensitivity to study intervention(s) or related products. (incl. excipients).
27. 22. Previous participation (i.e., signed informed consent) in this study. If exclusion criteria 5, 15, 24, or 33 is met, a single rescreening is possible at the investigator’s discretion. Re-screening is also allowed if a participant has previously screen-failed on the exclusion criterion for blood pressure (criterion 33 in protocol version 1-4). Re-screening is also allowed once if a participant has previously screen failed on the inclusion criterion 5 (ELF score ≥9.8 in protocol version 1-5), if ELF score was previously ≥9.0 and <9.8.
28. 23. Participation (i.e., signed informed consent) in any other interventional clinical study within 180 days before visit (V1), including any post-treatment follow-up period.
29. 24. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using highly effective contraceptive method with low user-dependence
30. 25. Presence or history of malignant neoplasms other than hepatocellular carcinoma within 5 years prior to V1. Basal and squamous cell skin cancer and any carcinoma in situ are allowed.
31. 26. History or presence of chronic pancreatitis at V1.
32. 27. Uncontrolled thyroid disease, as assessed by the investigator.
33. 28. Any of the following: myocardial infarction, stroke, classification of heart failure NYHA Class IV, hospitalisation for unstable angina pectoris or transient ischaemic attack within 90 days prior to V1.
34. 3.Presence or history of ascites more than grade 1, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or liver transplantation at screening (V1).
35. 29. Any participant for whom substantial weight loss might, in the investigator’s opinion, jeopardise the safety of the participant.
36. 30. Known or suspected drug (including opioids) or chemical substance abuse (excluding alcohol) within 1 year before screening.
37. 31.Any condition which might, in the investigator’s opinion, jeopardise the safety of the participant or compliance with the protocol.This includes incapacitated subjects, subjects deprived of liberty or subjects committed to an institution.‎
38. 32. Treatment with medications approved for AUD within 90 days prior to V1 (i.e., naltrexone, acamprosate, disulfiram, topiramate, varenicline, or baclofen). Benzodiazepines are allowed for up to 2 weeks as rescue medication for alcohol withdrawal symptoms."
39. 33 Pulse outside the range of 50-89 beats/minute at screening.
40. 4. Alcohol hepatitis at randomisation (as defined by NIAAA75)
41. 5. Vibration Controlled Transient Elastography LSM ≥ 25 kPa at V2. If participants meet this criterion, rescreening is allowed once.
42. 6. Presence or history of gastro-oesophageal varices ≥ grade 2* at V2. For participants with LSM ≥ 20 kPa as well as blood platelets count < 150,000 per µL of blood an oesophagogastroduodenoscopy performed no more than 52 weeks prior to V2 must be available at V2. *Grade 2: varices projecting by one-third of the luminal diameter that cannot be compressed with air insufflation4
43. 7.Presence or history of hepatocellular carcinoma at V1
44. 8. Any laboratory safety parameters at screening outside the below laboratory ranges, see designated reference range documents for specific values:

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in Enhanced Liver Fibrosis (ELF)

Secondary endpoints 11

1. Supportive secondary endpoints:
2. Change in Pro-peptide of Collagen 3 (Pro-C3)
3. Change in liver stiffness assessed by Vibration Controlled Transient Elastography (VCTE)
4. Change in liver steatosis assessed by Controlled Attenuated Parameter (CAP)
5. Change in Alanine Aminotransferase (ALT)
6. Change in Aspartate Aminotransferase (AST)
7. Supportive secondary endpoints to secondary objectives:
8. Number of treatment-emergent adverse events
9. Change in Phosphatidylethanol (PEth)
10. Change in alcohol amount measured by timeline follow-back (TLFB)
11. Change in total cholesterol

Investigational products

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

Test 12

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novo Nordisk A/S

Sponsor organisation

Novo Nordisk A/S

Address

Novo Alle 1

City

Bagsvaerd

Postcode

2880

Country

Denmark

Scientific contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Public contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Third parties 11

Locations

10 EU/EEA countries · 46 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 117 files

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

Application history

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