| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10086370 |
| E.1.2 | Term | NASH with fibrosis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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), K-877-ER 0.4 mg QD, or CSG452 20 mg QD compared with placebo in histological primary efficacy endpoint at Week 48 when K-001, 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. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are the following:
• 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
• To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the primary efficacy endpoint at Week 48
• 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
• 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
• To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the key secondary efficacy endpoints at Week 48
• 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
• 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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Criteria for Inclusion:
Subjects are eligible for the study if all of the following criteria are met:
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 12 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 12 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 3 months prior to randomization. Subjects without T2DM must have fasting plasma glucose ≥ 100 mg/dL at Visit 1
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. Female subjects of childbearing potential must use one of the following acceptable birth control methods as specified before enrollment and throughout the study:
a. Surgical sterilization (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 6 months before the first dose of study drug
b. Intrauterine device in place for at least 3 months before the first dose of study drug and throughout the study
c. Barrier method (condom or diaphragm) with spermicide for at least 30 days before the first dose of study drug and throughout the study
d. Surgical sterilization of the male partner (vasectomy at least 6 months before the first dose of study drug)
e. Hormonal contraceptives with a barrier method for at least 3 months before the first dose of study drug and throughout the study
Female subjects are not considered to be of childbearing potential if they meet at least one of the following two criteria as documented by the Investigator:
- They have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at minimum 1 menstrual cycle prior to signing the Informed Consent Form
-They are postmenopausal, defined as 1 year since the last menstrual period without an alternative medical cause or have a follicle-stimulating hormone (FSH) level in menopausal range (defined as >20 miU/mL and <122 miU/mL) in women who are not using hormonal contraception or hormonal replacement therapy and are ≥50 years of age.
− For women ≤50 years old, ≥2 years since her last menstrual period without an alternative medical cause, and documented FSH level in the postmenopausal range |
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| E.4 | Principal exclusion criteria |
-Participation in another clinical trial involving an investigational agent within 30 days prior to signing the Informed Consent Form for this study.
-Ongoing or recent consumption of significant amounts of alcohol, or Alcohol Use Disorders Identification Test - Concise (AUDIT-C) score ≥3 in females or ≥4 in males during the Screening Period. Significant alcohol consumption is defined as >21 standard drinks per week in men and >14 standard drinks per week in women over a 2-year period prior to randomization. A standard alcoholic drink is any drink that contains about 14 g of pure alcohol.-Evidence of other forms of chronic liver disease -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 6 months 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 within 6 months of randomization -Subjects with type 1 diabetes mellitus -Subjects with poorly controlled T2DM as defined by HbA1c >10% at Visit 1 -Subjects with a prior history of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), or a confirmed diagnosis of a hypercoagulable state -Initiation of, or change in, current TG-lowering therapy within 3 months of randomization -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, lorcaserin, phentermine, topiramate, naltrexone, or bupropion or any other medication that could promote weight loss in the opinion of the investigator within 3 months of randomization -Subjects with severe infections, during a perioperative period, or with serious injuries -Subjects with urinary tract infection or genital infection -History of 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 between Visit 2 and randomization -Subjects who performed significant attempt to change diet and exercise, at the investigator’s opinion, within 6 months 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 -Inability to safely obtain an MRI (US sites) -History or evidence of major and clinically significant, cardiovascular, pulmonary, renal, hematologic, gastrointestinal endocrine, immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic disease that would interfere with the conduct of the study or interpretation of the data
-History of malignancy within the past 5 years, except for basal or squamous cell skin carcinoma that has undergone curative therapy -Any past history of hepatocellular carcinoma (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 -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-stimulating hormone >1.5 × upper limit of normal (ULN), clinical evidence of hypothyroidism, 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 IL/U 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 creatinine kinase (CK) concentration >5 × ULN or CK elevation due to known muscle disease at Visit 1 -Subjects who have previously received K-877 or CSG452 within 1 year of Visit 1 -Current or past history of illicit drug use or alcohol abuse within 1 year of Visit 1 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is improvement from Baseline (liver biopsy at the Baseline Biopsy Visit, or a historical liver biopsy obtained within 12 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. The worsening of fibrosis is defined as any numerical increase in the stage. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary efficacy endpoints
• 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.
• 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
• Both resolution of steatohepatitis and improvement in liver fibrosis score ≥ 1 from Baseline at Week 48
• Resolution of steatohepatitis on overall histopathological reading at Week 48.
• Improvement from Baseline in liver fibrosis score ≥1 at Week 48
• Improvement from Baseline in each of the NAS components (inflammation, ballooning, and steatosis) ≥1 point at Week 48
Other secondary efficacy endpoints
• Improvement from Baseline in liver fat content measured by magnetic resonance imaging-derived proton density fat fraction (MRI PDFF) (defined as a ≥30% reduction) at Week 48
• Improvement from Baseline in alanine aminotransferase (ALT) (defined as an ALT ≤40 U/L with a ≥30% decrease from baseline) at Week 48
• Change and percent change from baseline to Week 48 in NAS, each score of NAS components (inflammation, ballooning, and steatosis), NASH CRN fibrosis score, liver fat content by MRI-PDFF, ALT, alkaline phosphatase (ALP), AST, γ-glutamyl transferase (γ GTP), Cytokeratin18, bile acid, ProC3, hyaluronic acid, type IV collagen 7S domain, Mac-2 binding protein glycan isomer (M2BPGi), nonalcoholic fatty liver disease (NAFLD) fibrosis score, NAFIC score, enhanced liver fibrosis (ELF) test, fibrosis-4 (FIB 4) score, TG, total cholesterol (TC), LDL C, high-density lipoprotein cholesterol (HDL C), free fatty acids (FFA), fasting plasma glucose (FPG), fasting insulin, hemoglobin A1C (HbA1c), homeostasis model assessment of insulin resistance (HOMA IR), homeostasis model assessment of β-cell function (HOMA β), body weight, body mass index (BMI), and waist circumference |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| United States |
| Bulgaria |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient last visit or last contact, whichever occurs last. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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