A Phase 2, Multicenter, Placebo-Controlled, Randomized, Double-Blind, 48-Week Study to Evaluate the Efficacy and Safety of Combination Therapy of K-877-ER and CSG452 in Patients with Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Kowa Research Institute Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

16 Feb 2023 → ongoing

Decision date (initial)

2024-07-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Kowa Research Institute, Inc.

External identifiers

EU CT number

2023-508104-38-00

EudraCT number

2021-003901-23

ClinicalTrials.gov

NCT05327127

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to evaluate the superiority of K-001 QD (combination therapy of K-877-ER 0.4 mg QD and CSG452 20 mg QD) compared with placebo in histological primary efficacy endpoint at Week 48 when K-001 or placebo are administered for 48 weeks in subjects with noncirrhotic NASH with liver fibrosis.

Secondary objectives 8

1. To explore the superiority of K-001 QD compared with K-877-ER 0.4 mg QD alone in the primary efficacy endpoint at Week 48
2. To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the primary efficacy endpoint at Week 48
3. To explore the superiority of K-001 QD, K-877-ER 0.4 mg QD alone, or CSG452 20 mg QD alone compared with placebo in the key secondary efficacy endpoints at Week 48
4. To explore the superiority of K-001 QD compared with K-877-ER 0.4 mg QD alone in the key secondary efficacy endpoints at Week 48
5. To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the key secondary efficacy endpoints at Week 48
6. To explore the superiority of K-877-ER 0.4 mg QD or CSG452 20 mg QD compared with placebo in histological efficacy at Week 48 when K-877-ER 0.4 mg QD, CSG452 20 mg QD, or placebo are administered for 48 weeks in subjects with noncirrhotic NASH with liver fibrosis.
7. To explore the efficacy of K-001 QD, K-877-ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo in the other secondary efficacy endpoints
8. To evaluate the safety and tolerability of K-001 QD, K-877-ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo

Conditions and MedDRA coding

Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Able to understand and comply with study procedures and give written informed consent
2. Age ≥18 years
3. NAS ≥4 with a score of at least 1 in each component of the NAS (steatosis, lobular inflammation, and ballooning) at the baseline biopsy, or a historical liver biopsy performed within 24 weeks of randomization
4. Fibrosis stage of 1 or greater and below 4 on NASH CRN fibrosis staging system at the baseline biopsy, or a historical liver biopsy performed within 24 weeks of randomization
5. Subject can be with or without T2DM, but T2DM subjects must be well controlled on a stable dose of antidiabetic medication for at least 8 weeks prior to Visit 1 or without medication. Subjects without T2DM must have fasting plasma glucose ≥90 mg/dL at Visit 1. A single repeat measurement is permitted, excluding those caused by invalid measurements such as, but not limited to, hemolysis, lost samples, sample contamination, or non-fasting blood draw, which are deemed outside of the single repeat.
6. Female subjects must not be breastfeeding and must have a negative serum pregnancy test at Visit 1 if they are women of childbearing potential.

Exclusion criteria 40

1. Participation in another clinical trial involving an investigational agent within 30 days prior to signing the ICF for this study.
2. Ongoing or recent consumption of greater than moderate amounts of alcohol, or Alcohol Use Disorders Identification Test – Concise (AUDIT-C) score ≥3 in females or ≥4 in males during the Screening Period. Greater than moderate alcohol consumption is defined as on average >1 standard drink per day in women and on average >2 standard drinks per day in men over a 1-year period prior randomization. A standard alcoholic drink is any drink that contains about 14 g of pure alcohol.
3. Evidence of other forms of chronic liver disease as follows: a. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) b. History of hepatitis C treatment within 5 years of Screening, or active Hepatitis C as defined by presence of hepatitis C virus RNA c. Ongoing autoimmune liver disease based on historical evidence of diagnosis d. Primary biliary cirrhosis e. Primary sclerosing cholangitis f. Wilson’s disease based on historical evidence of diagnosis g. Alpha-1-antitrypsin deficiency based on historical evidence of diagnosis h. Hemochromatosis based on historical evidence of diagnosis or historical evidence of iron overload as defined by the presence of 3+ or 4+ stainable iron on liver biopsy i. Drug-induced liver disease as defined by typical exposure and history j. Known condition that involves bile duct obstruction k. Suspected or proven liver cancer l. Any type of liver disease other than NASH
4. Subjects listed for liver transplantation, or a history of liver transplantation
5. Initiation of, or change in, current doses of thiazolidinediones, agents with GLP-1 receptor agonist activity, or vitamin E within 26 weeks of randomization
6. Current or planned use of fibrates, agents with potent selective peroxisome proliferator-activated receptor alpha (PPARα) agonist activity, or sodium glucose co transporter 2 (SGLT2) inhibitors, or subjects who have previously received K-877 or CSG452 within 26 weeks of randomization
7. Subjects with type 1 diabetes mellitus
8. Subjects with poorly controlled T2DM as defined by HbA1c >9% at Visit 1
9. Subjects with a prior history of VTE, including PE and DVT, or a confirmed diagnosis of a hypercoagulable state
10. Initiation of, or change in, current TG-lowering therapy within 8 weeks before Visit 1, or if a historical liver biopsy performed more than 8 weeks before Visit 1 is used, from the date of the liver biopsy until Visit 1. TG-lowering therapy is defined as niacin >100 mg/day, or dietary supplements or prescription of omega-3 fatty acids >1000 mg/day
11. Initiation of, or change in, current doses of orlistat, phentermine, topiramate, naltrexone, or bupropion or any other medication that could promote weight loss in the opinion of the investigator within 8 weeks before Visit 1, or if a historical liver biopsy performed more than 8 weeks before Visit 1 is used, from the date of the liver biopsy until Visit 1
12. Subjects with severe infections, during a perioperative period, or with serious injuries
13. Subjects with urinary tract infection or genital infection
14. Subjects with active current symptomatic gallstone disease
15. Subjects with severe renal impairment at Visit 1, who are receiving dialysis at Visit 1, or who have had a kidney transplant, regardless of level of renal function
16. Subjects with weight change of 5% or more: 1) between Visit 1 to Visit 2 and or 2) between Visit 2 to Visit 3 (randomization)
17. Subjects who performed significant attempt to change diet and exercise, at the investigator’s opinion, within 12 weeks of Screening
18. Model for End-stage Liver Disease (MELD) score >12 at Visit 1
19. Presence of clinical or histological evidence of compensated cirrhosis, or biochemical evidence of compensated cirrhosis
20. Inability to safely obtain a liver biopsy
21. History or evidence of major and clinically significant, cardiovascular, pulmonary, renal, hematologic, gastrointestinal (including clinically significant malabsorption), endocrine (other than T2DM), immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic (including drug allergies but excluding untreated or treated seasonal allergies at the time of dosing) disease that would interfere with the conduct of the study, subject’s safety, or interpretation of the data
22. Ongoing or history of malignancy within the past 5 years, except for basal or squamous cell skin carcinoma or any other carcinoma in situ, that has undergone curative therapy, and prostate cancer that has been managed through active surveillance or watchful waiting
23. Any past history of HCC and/or HCC treatment
24. History of bariatric surgery within 5 years of Screening
25. Uncontrolled hypertension at Visit 1 (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg after 5 minutes of sitting)
26. Subjects with evidence of portal hypertension (eg, low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly)
27. Known infection with human immunodeficiency virus (HIV) 1 or HIV 2
28. Known hypersensitivity or intolerance to fibrates, PPARα agonists, or SGLT2 inhibitors
29. Anticipation of major surgery during the study
30. Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of OATP1B1, or OATP1B3
31. Thyroid diseases such as active hyperthyroidism, clinical evidence of untreated hypothyroidism with thyroid-stimulating hormone values >7 IU/L with hypothyroid symptoms or >10 × IU/L without symptoms, or thyroid hormone therapy that is not stable for at least 6 weeks prior to Screening
32. ALT and/or AST >200 IU/L at Visit 1
33. ALT instability during the Screening Period, defined as a substantial change in ALT from Visit 1 to Visit 2 (Visit 2 ALT is both >50% AND >50 IU/L different from Visit 1 ALT). In such cases, Visit 2.1 must be scheduled by the Investigator at least 2 weeks after Visit 2 to re-test ALT once, unless the subject failed Screening due to meeting other exclusion criteria. If ALT level at Visit 2.1 is not substantially different from Visit 1 or Visit 2 values and does not suggest clinically significant ALT instability and/or clinically unfavorable trend in the opinion of the Investigator, the subject will be allowed to participate in the study
34. ALP ≥2 × ULN at Visit 1
35. Unexplained CK concentration >5 × ULN or CK elevation due to known muscle disease (eg, polymyositis, mitochondrial dysfunction) at Visit 1
36. Subjects who have previously received K-877 or CSG452 within 26 weeks of randomization
37. Current or past history of illicit drug use within 1 year of Visit 1
38. Any condition or therapy, which, in the opinion of the Investigator, might pose a risk to the subject or make participation in the study not in the best interest of the subject
39. Special or vulnerable status (eg institutionalized, or person related to or an employee of the sponsor, or investigator)
40. Unlikely to have noncirrhotic NASH with liver fibrosis based on Visit 1 or historical (performed within 12 weeks prior to Visit 1) FibroScan and Visit 1 AST. FibroScan assessment at Visit 1 can be repeated once if the first attempt failed due to technical reasons.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is improvement from Baseline (defined by central reading of a liver biopsy sample obtained at the Baseline Biopsy Visit, or historical biopsy obtained within 24 weeks of randomization) in disease activity and no worsening of liver fibrosis on the NASH Clinical Research Network (CRN) fibrosis score at Week 48. The improvement in disease activity is defined as improvement in NAFLD Activity Score (NAS) >=2 points.

Secondary endpoints 6

1. Resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis on the NASH CRN fibrosis score at Week 48. Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis.
2. Improvement from Baseline in liver fibrosis score ≥1 and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 48
3. Both resolution of steatohepatitis and improvement in liver fibrosis score ≥1 from Baseline at Week 48
4. Resolution of steatohepatitis on overall histopathological reading at Week 48.
5. Improvement from Baseline in liver fibrosis score ≥1 at Week 48
6. Improvement from Baseline in each of the NAS components (inflammation, ballooning, and steatosis) ≥1 point at Week 48

Investigational products

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

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Kowa Research Institute Inc.

Sponsor organisation

Kowa Research Institute Inc.

Address

430 Davis Drive Suite 200

City

Morrisville

Postcode

27560-6802

Country

United States

Scientific contact point

Organisation

Kowa Research Institute Inc.

Contact name

Kelsey Behrens

Public contact point

Organisation

Kowa Research Institute Inc.

Contact name

Kelsey Behrens

Third parties 5

Locations

2 EU/EEA countries · 10 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 27 files

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

Application history

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