Research study on whether a combination of 2 medicines (NNC0194-0499 and Semaglutide) works in people with non-alcoholic steatohepatitis (NASH)

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] - Digestive System Diseases [C06]

Trial duration

31 Aug 2021 → 14 Mar 2025

Decision date (initial)

2024-05-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novo Nordisk A/S

External identifiers

EU CT number

2023-506961-74-00

EudraCT number

2020-003566-39

WHO UTN

U1111-1255-5551

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To confirm the effect of NNC0194-0499 30 mg once weekly in combination with semaglutide 2.4 mg once weekly versus placebo once weekly on fibrosis in subjects with NASH and fibrosis stage 2−4 (F2−F4).

Secondary objectives 8

1. To confirm the effect of NNC0194-0499 7.5 mg and 15 mg once weekly in combination with semaglutide 2.4 mg once weekly versus placebo once weekly on fibrosis.
2. To confirm the effect of NNC0194-0499 30 mg once weekly versus placebo once weekly on fibrosis.
3. To confirm that NNC0194-0499 7.5 mg, 15 mg and 30 mg once weekly contributes to the effect of the corresponding combination of NNC0194-0499 7.5 mg, 15 mg and 30 mg once weekly with semaglutide 2.4 mg once weekly on fibrosis.
4. To confirm that semaglutide 2.4 mg once weekly contributes to the effect of the combination of NNC0194-0499 7.5 mg, 15 mg and 30 mg once weekly with semaglutide 2.4 mg once weekly on NASH resolution.
5. To investigate the dose-response relationship of NNC0194-0499 (7.5 mg, 15 mg and 30 mg) once weekly in combination with semaglutide 2.4 mg once weekly on liver histology and tolerability.
6. To investigate the safety and tolerability of NNC0194-0499 30 mg once weekly alone, NNC0194-0499 7.5 mg, 15 mg and 30 mg once weekly in combination with semaglutide 2.4 mg once weekly and NNC0174-0833 2.4 mg once weekly in combination with semaglutide 2.4 mg once weekly.
7. To compare and investigate the effects versus placebo once weekly of NNC0194-0499 30 mg once weekly alone, NNC0194-0499 7.5 mg, 15 mg and 30 mg once weekly in combination with semaglutide 2.4 mg once weekly and NNC0174-0833 2.4 mg once weekly in combination with semaglutide 2.4 mg once weekly on 1) fibrosis and NASH resolution (for the treatment group comparisons not already described in the primary and confirmatory objectives), 2) cardiovascular disease and cardio-metabolic factors, 3) body weight, 4) NASH biomarkers, and 5) patient-reported outcomes.
8. To compare and investigate the effects versus semaglutide 2.4 mg once weekly of NNC0174-0833 2.4 mg once weekly in combination with semaglutide 2.4 mg once weekly on 1) fibrosis and NASH resolution, 2) cardiovascular disease and cardio-metabolic factors, 3) body weight, and 4) NASH biomarkers, and 5) patient-reported outcomes.

Conditions and MedDRA coding

Non-alcoholic steatohepatitis (NASH)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency, Pharmaceuticals And Medical Devices Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Aged ≥ 18 years at the time of signing informed consent. In Republic of Korea, subjects must be aged ≥ 19 years. In Japan, subjects must be aged ≥ 20 years. In Singapore, subjects must be aged ≥ 21 years.
2. Histological evidence of NASH based on a central pathologist evaluation of the baseline liver biopsy. The baseline liver biopsy can be a historical biopsy obtained within 180 days prior to Visit 1.
3. Histological evidence of fibrosis stage 2, 3 or 4 according to the NASH CRN classification based on a central pathologist evaluation of the baseline liver biopsy.
4. Histological non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥ 4 for subjects with F2/F3 or ≥ 3 for subjects with F4 based on a central pathologist evaluation of the baseline liver biopsy. All subjects must have a score of 1 or more in steatosis, lobular inflammation and hepatocyte ballooning.

Exclusion criteria 8

1. Documented causes of chronic liver disease other than NAFLD.
2. Positive HBsAg, positive anti-HIV, positive HCV RNA at screening (V2A) or any known presence of HCV RNA or HBsAg within 2 years of screening (V2A).
3. Presence or history of ascites more than grade 1, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at V2A.
4. For subjects with F4, presence or history of gastro-oesophageal varices ≥ grade 2 at V3. An oesophagogastroduodenoscopy performed no more than 52 weeks prior to V3 must be available at V3.
5. Known or suspected excessive consumption of alcohol (>20 g/day for women or > 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)).
6. Treatment with vitamin E (at doses ≥ 800 IU/day) or pioglitazone or medications approved for the treatment of NASH which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.
7. Treatment with GLP-1 RAs within 90 days prior to V2A. Subjects with a historical liver biopsy taken more than 90 days prior to V2A are excluded if they receive treatment with GLP-1 RAs from time of biopsy until V2A.
8. Treatment with glucose-lowering agent(s) (other than GLP-1 RAs), lipid-lowering medication or weight loss medication not stable in the opinion of the investigator in the period from 90 days prior to V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Improvement in liver fibrosis and no worsening of NASH (Yes/No) from baseline (week 0) to week 52

Secondary endpoints 24

1. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) from baseline (week 0) to week 52.
2. Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) from baseline (week 0) to week 52.
3. Change in histology-assessed liver collagen proportionate area from baseline (week 0) to week 52.
4. Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) from baseline (week 0) to week 52.
5. Improvement in liver fibrosis (Yes/No) from baseline (week 0) to week 52.
6. Progression of liver fibrosis (Yes/No) from baseline (week 0) to week 52. For subjects with fibrosis stage 2 or 3 at baseline.
7. Worsening in steatohepatitis (Yes/No) from baseline (week 0) to week 52.
8. Improvement in ballooning (Yes/No) from baseline (week 0) to week 52.
9. Improvement in inflammation (Yes/No) from baseline (week 0) to week 52.
10. Improvement in steatosis (Yes/No) from baseline (week 0) to week 52.
11. Change in ALT from baseline (week 0) to week 52.
12. Change in AST from baseline (week 0) to week 52.
13. Change in inflammation assessed by HsCRP from baseline (week 0) to week 52.
14. Change in ELF score from baseline (week 0) to week 52.
15. Change in HbA1c from baseline (week 0) to week 52. For subjects with type 2 diabetes.
16. Change in triglycerides from baseline (week 0) to week 52.
17. Change in free fatty acids from baseline (week 0) to week 52.
18. Change in LDL cholesterol from baseline (week 0) to week 52.
19. Change in HDL cholesterol from baseline (week 0) to week 52.
20. Relative change in body weight from baseline (week 0) to week 52.
21. Change in SF-36 bodily pain from baseline (week 0) to week 52.
22. Change in NASH-CHECK pain from baseline (week 0) to week 52.
23. Change in PROMIS Fatigue score from baseline (week 0) to week 52.
24. Number of treatment emergent adverse events (TEAEs) from baseline (week 0) to week 59.

Investigational products

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

Test 3

Placebo 3

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 9

Locations

11 EU/EEA countries · 50 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 97 files

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

Application history

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