A study to investigate the safety and efficacy of GSK4532990 compared with placebo in adult participants aged 18 to 70 years with alcohol-related liver disease.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

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

26 Dec 2024 → ongoing

Decision date (initial)

2024-10-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety

To evaluate the efficacy of GSK4532990 on the reduction from baseline in LSM / MELD in participants with ALD.

Secondary objectives 2

1. To evaluate the efficacy of GSK4532990 in participants with ALD.
2. To evaluate GSK4532990 exposure parameters in participants with ALD

Conditions and MedDRA coding

Liver Diseases, Alcoholic

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

o IPD Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: Sharing Clinical Trial Data’ on the GSK Study Register (www.gsk-studyregister.com). o IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months. o IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Main Study Period A female participant is eligible to participate, if she is not pregnant or breastfeeding and one of the following conditions applies: INC#5 − Is a woman of nonchildbearing potential (WONCBP) as defined in Section 10.4 (Appendix 4: Contraceptive and barrier guidance). OR – Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4. Contraceptive measures must start at least 28 days prior to the first dose of study intervention and should continue during the study intervention period, for a minimum of 18 weeks 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 (serum or urine as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.3.5 Pregnancy testing).
2. Main Study Period Participants using any of the specified medications listed below can be included, but only if all these requirements are met: INC#6 − the dose has been stable for ≥3 months prior to D1, and − the participant is expected to continue the same dosing regimen throughout study participation. The specified medications are: incretin analogues such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), or glucagon receptor agonist, alone or in combination; PPAR agonists (e.g., pioglitazone, saroglitazar), sodium glucose cotransporter 2 (SGLT2) inhibitors; thyroid hormone receptor beta agonists; farnesoid X receptor (FXR) agonists; fatty acid synthase inhibitors; fibroblast growth factor 21 (FGF21) agonists; or Vitamin E (at doses greater than 400 IU/day). NOTE: If a switch to another medication within the same class is required, this will only be permitted if the new medication dose is equivalent to the prior medication dose. Switches to a different medication class are not permitted during the study.
3. Main Study Period Participant must be 18 to 70 years of age inclusive, at the time of screening. (Participants in South Korea must be ≥19 years of age.) INC#1
4. Main Study Period Capable of giving signed informed consent prior to the performance of any study-specific procedures, as described in Section 10.1.3. INC#2
5. Participant has advanced chronic liver disease. INC#7

Exclusion criteria 33

1. Main Study Period Presence of hepatitis B surface antigen (HBsAg) at Screening 1 or within 3 months prior to first dose of study intervention (Based on local or central laboratory measurements; 1 repeat test is allowed). EXC#14
2. Main Study Period Positive hepatitis C antibody test result at Screening 1 or within 3 months prior to first dose of study intervention. Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained and provided treatment for HCV infection occurred 2 years or more prior to screening (Based on central laboratory measurements; 1 repeat test is allowed). EXC#15
3. Main Study Period Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. (Based on central laboratory measurements; 1 repeat test is allowed) Note: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. EXC#16
4. Main Study Period Other primary causes of liver disease (including but not limited to primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, hemochromatosis, and alpha-1-antitryspin deficiency), based on medical history, blood tests including autoantibody serology and serum immunoglobulins, and/or the liver histology. ALD or MetALD must be the primary cause of liver disease. EXC#17
5. Main Study Period Current, or history of known hepatocellular carcinoma (HCC). EXC#18
6. Main Study Period All organ transplant recipients, except for history of corneal transplants, or current listing or active consideration for listing for liver transplant during the screening period. EXC#19
7. Main Study Period Chronic or acute, including partial, known portal vein thrombosis. EXC#20
8. Main Study Period Prior transjugular intrahepatic portosystemic shunt (TIPSS) insertion. EXC#21
9. Main Study Period Positive HIV antibody test at Screening 1 (central laboratory measurements; 1 repeat test is allowed). EXC#22
10. Main Study Period Any acute cardiovascular event including myocardial infarction, unstable angina, symptomatic heart failure, or cerebrovascular accident in the 6 months prior to Screening 1. EXC#23
11. Main Study Period Poorly controlled hypertension defined as systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg at both Screening 1 and Screening 2 despite standard medical management EXC#24
12. Main Study Period BMI >35 kg/m2. EXC#25
13. Main Study Period HbA1≥9.5% (80.3 mmol/mol or 12.5 mmol/L) at screening visits 1 and 2. EXC#26
14. Main Study Period Any history of anaphylaxis or hypersensitivity to GSK4532990 or any of the constituents of the injection. EXC#27
15. Main Study Period Current use of other GalNAc conjugated siRNA therapy. EXC#28
16. Main Study Period Previous use of other investigational therapies targeting HSD17B13 and/or PNPLA3. EXC#29
17. Main Study Period Prior investigational therapies unless beyond washout period of at least 5 half-lives or 6 weeks (whichever is longer) from Screening 1. EXC#30
18. Main Study Period Use of therapies known to induce steatohepatitis (e.g., methotrexate, tamoxifen, amiodarone, 5-fluorouracil) for more than 2 weeks in the year prior to D1. EXC#31
19. Main Study Period Recent major surgery within previous 6 weeks prior to D1. EXC#32
20. Main Study Period Current or ongoing malignancy (except for basal cell carcinoma or uterine carcinoma-in-situ) at Screening 1. Participants under evaluation for possible malignancy at Screening 1 are not eligible. EXC#33
21. Main Study Period Any symptomatic infection including COVID-19 during Screening. Participants may be eligible 2 weeks after resolution of symptoms. EXC#34
22. Main Study Period Current or planned participation in any clinical trial of investigational therapies or medical devices. Participation in clinical trial of investigational software applications for the treatment of Alcohol Use Disorder is permitted. EXC#35
23. Main Study Period Clinical suspicion of rhabdomyolysis during the screening period. EXC#36
24. Main Study Period Clinical suspicion of a bleeding episode during the screening period related to either portal hypertension or low blood fibrinogen level (
25. Main Study Period Any abnormality on a 12-lead ECG during the screening period that, in the opinion of the Investigator, compromises the participant’s safety in this study. EXC#38
26. Main Study Period ALP ≥250 U/L at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#8
27. Main Study Period ALT or AST ≥250 U/L at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#9
28. Main Study Period Average of triplicate QTc >450 msec for males or QTc >470 msec for females or QTc >480 msec in participants with bundle branch block (1 repeat test is allowed). EXC#52
29. Main Study Period Platelets <50,000/μL, INR >2.3, or albumin <2.5 g/dL at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#10
30. Main Study Period Evidence of Wernicke-Korsakoff syndrome or alcohol-related dementia in the opinion of investigator. EXC#41
31. Main Study Period Current use of anticoagulants that increase prothrombin time (PT) and INR. EXC#11
32. Main Study Period Urinary albumin to creatinine ratio ≥300 mg/g creatinine (≥33.9 mg/mmol creatinine) at Screening 1 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#13
33. Main Study Period Meeting any definition of organ system failure as defined by the North American Consortium for Study of End-stage Liver Disease (NACSELD) (see Section 10.10.5). EXC#2

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from baseline in LSM using FibroScan® at Week 52, considering death, liver-related hospitalization, liver transplantation and HCC to be poor outcomes
2. Change from baseline in MELD score at Week 52, considering death, liver-related hospitalization, liver transplantation and HCC to be poor outcomes

Secondary endpoints 3

1. Change from baseline in serum AST at Week 52, considering death, liver-related hospitalization, liver transplantation and HCC to be poor outcomes
2. Plasma exposure parameters of GSK4532990 including: • Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) • Maximum observed concentration (Cmax)
3. Change from baseline in ELF at Week 52, considering death, liver-related hospitalization, liver transplantation and HCC to be poor outcomes

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 41

Locations

8 EU/EEA countries · 47 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 173 files

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

Application history

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