Efficacy and Safety Evaluation of Pemafibrate and Tofogliflozin Combination in Noncirrhotic NASH with Liver Fibrosis: A Phase 2 Randomized, Double-Blind Study
- Trial ID
- 2023-508104-38-00
- Protocol
- K-001-201
- Sponsor
- Kowa Research Institute Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **superiority** of K-001 QD, a combination therapy of K-877-ER 0.4 mg QD and CSG452 20 mg QD, compared with placebo in the histological primary efficacy endpoint at Week 48. This is conducted in subjects with noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis. The clinical relevance of this objective lies in its potential to provide a more effective treatment option for patients with NASH, a condition characterized by liver inflammation and damage due to fat accumulation, which can progress to more severe liver diseases.
Secondary objectives include:
- Exploring the superiority of K-001 QD compared with K-877-ER 0.4 mg QD alone and CSG452 20 mg QD alone in the primary efficacy endpoint at Week 48.
- Assessing the superiority of K-001 QD, K-877-ER 0.4 mg QD alone, or CSG452 20 mg QD alone compared with placebo in key secondary efficacy endpoints at Week 48.
- Evaluating the superiority of K-001 QD compared with K-877-ER 0.4 mg QD alone and CSG452 20 mg QD alone in key secondary efficacy endpoints at Week 48.
- Investigating the superiority of K-877-ER 0.4 mg QD or CSG452 20 mg QD compared with placebo in histological efficacy at Week 48 in subjects with noncirrhotic NASH with liver fibrosis.
- Exploring the efficacy of K-001 QD, K-877-ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo in other secondary efficacy endpoints.
- Evaluating the safety and tolerability of K-001 QD, K-877-ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo.
Participants
The clinical trial involves a total of **194 participants** diagnosed with **Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a NAS score of 4 or higher with a score of at least 1 in each component of the NAS, and a fibrosis stage between 1 and 3 on the NASH CRN fibrosis staging system. The trial includes individuals with or without Type 2 Diabetes Mellitus (T2DM), provided that T2DM subjects have well-controlled blood glucose levels. Female participants of childbearing potential must not be breastfeeding and are required to have a negative serum pregnancy test at the initial visit. The trial population is characterized by a diverse range of health statuses, and the selection process ensures the inclusion of a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of combination therapy with K-877-ER and CSG452 in patients diagnosed with noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis. The trial is set to last for 48 weeks, with the primary objective being to assess the superiority of the combination therapy over placebo in improving histological endpoints at Week 48. Participants will be randomly assigned to receive either the active combination therapy or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.
The study will involve several key visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, liver biopsy results, and control of type 2 diabetes mellitus (T2DM) if applicable. Following successful screening, participants will be enrolled and randomized into the study. Throughout the trial, participants will attend regular follow-up visits to monitor safety, adherence, and efficacy outcomes. These visits will include assessments such as liver biopsies, blood tests, and other relevant clinical evaluations. The end-of-study visit will occur at Week 48, where final assessments will be conducted to evaluate the primary and secondary endpoints.
Participant involvement is expected to last for the entire 48-week duration of the trial. However, conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The primary efficacy endpoint is defined as an improvement from baseline in disease activity and no worsening of liver fibrosis, as measured by the NASH Clinical Research Network (CRN) fibrosis score. Secondary endpoints include resolution of steatohepatitis and improvement in liver fibrosis score, among others. The trial is anticipated to conclude by July 31, 2026, with recruitment having commenced on February 16, 2023.
Treatment
The clinical trial involves the administration of **Tofogliflozin**, a potent and selective inhibitor of SGLT2, which is provided in the form of a film-coated tablet. The dosage for Tofogliflozin is 20 mg, administered orally once daily. The maximum treatment period for this medication is 48 weeks. Tofogliflozin is produced by Kowa Research Institute Inc. and is identified by the sponsor product code CSG452. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to Tofogliflozin, the trial also includes the administration of **Pemafibrate**, a potent and selective SPPARM, also provided in the form of a film-coated tablet. The dosage for Pemafibrate is 0.4 mg, administered orally once daily, with a maximum treatment period of 48 weeks. Pemafibrate is also produced by Kowa Research Institute Inc. and is identified by the sponsor product code K-877-ER. Compliance with the dosing schedule for Pemafibrate will be similarly monitored.
The study includes the use of placebo treatments for both Tofogliflozin and Pemafibrate. The placebo for Tofogliflozin is referred to as CSG452 (Tofogliflozin) placebo, and the placebo for Pemafibrate is referred to as K-877 ER (Pemafibrate) placebo. These placebos are used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the efficacy and safety of the active treatments. The placebos are administered in the same manner as their respective active treatments, with oral administration once daily for a period of 48 weeks.
Efficacy
The efficacy of the combination therapy of K-877-ER and CSG452 in patients with noncirrhotic Nonalcoholic Steatohepatitis (NASH) with liver fibrosis will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the improvement from baseline in disease activity, as determined by a central reading of a liver biopsy sample, with no worsening of liver fibrosis on the NASH Clinical Research Network (CRN) fibrosis score at Week 48. Improvement in disease activity is defined as an increase in the NAFLD Activity Score (NAS) by at least 2 points.
Secondary efficacy endpoints include the resolution of steatohepatitis, defined as the absence of fatty liver disease or isolated/simple steatosis without steatohepatitis, and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis, with no worsening of liver fibrosis on the NASH CRN fibrosis score at Week 48. Additional secondary endpoints involve improvement from baseline in liver fibrosis score by at least 1 point, with no worsening of steatohepatitis, and the resolution of steatohepatitis alongside improvement in liver fibrosis score by at least 1 point from baseline at Week 48. Furthermore, improvement from baseline in each NAS component (inflammation, ballooning, and steatosis) by at least 1 point at Week 48 will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand and comply with study procedures and give written informed consent
- Age ≥18 years
- 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
- 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
- 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.
- 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
- Participation in another clinical trial involving an investigational agent within 30 days prior to signing the ICF for this study.
- 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.
- 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
- Subjects listed for liver transplantation, or a history of liver transplantation
- Initiation of, or change in, current doses of thiazolidinediones, agents with GLP-1 receptor agonist activity, or vitamin E within 26 weeks of randomization
- 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
- Subjects with type 1 diabetes mellitus
- Subjects with poorly controlled T2DM as defined by HbA1c >9% at Visit 1
- Subjects with a prior history of VTE, including PE and DVT, or a confirmed diagnosis of a hypercoagulable state
- 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
- 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
- Subjects with severe infections, during a perioperative period, or with serious injuries
- Subjects with urinary tract infection or genital infection
- Subjects with active current symptomatic gallstone disease
- 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
- 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)
- Subjects who performed significant attempt to change diet and exercise, at the investigator’s opinion, within 12 weeks of Screening
- Model for End-stage Liver Disease (MELD) score >12 at Visit 1
- Presence of clinical or histological evidence of compensated cirrhosis, or biochemical evidence of compensated cirrhosis
- Inability to safely obtain a liver biopsy
- 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
- 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
- Any past history of HCC and/or HCC treatment
- History of bariatric surgery within 5 years of Screening
- Uncontrolled hypertension at Visit 1 (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg after 5 minutes of sitting)
- Subjects with evidence of portal hypertension (eg, low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly)
- Known infection with human immunodeficiency virus (HIV) 1 or HIV 2
- Known hypersensitivity or intolerance to fibrates, PPARα agonists, or SGLT2 inhibitors
- Anticipation of major surgery during the study
- Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of OATP1B1, or OATP1B3
- 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
- ALT and/or AST >200 IU/L at Visit 1
- 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
- ALP ≥2 × ULN at Visit 1
- Unexplained CK concentration >5 × ULN or CK elevation due to known muscle disease (eg, polymyositis, mitochondrial dysfunction) at Visit 1
- Subjects who have previously received K-877 or CSG452 within 26 weeks of randomization
- Current or past history of illicit drug use within 1 year of Visit 1
- 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
- Special or vulnerable status (eg institutionalized, or person related to or an employee of the sponsor, or investigator)
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 16 Feb 2023 | 6 |
 Spain | Not Recruiting | 16 Feb 2023 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CSG452 (Tofogliflozin) placebo | Placebo | N/A | — | — | — | N/A |
pemafibrate | Test | FILM COATED TABLET | ORAL USE | 0.4 | 48 | PRD11336562 |
K-877 ER (Pemafibrate) placebo | Placebo | N/A | — | — | — | N/A |
TOFOGLIFLOZIN | Test | FILM COATED TABLET | ORAL USE | 20 | 48 | PRD11336538 |