| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-alcoholic steatohepatitis with fibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| non-alcoholic fatty liver disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019668 |
| E.1.2 | Term | Hepatic fibrosis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 |
| To evaluate the effects of VK2809 compared to placebo on liver fat content (assessed by MRI-PDFF, Magnetic Resonance Imaging- Proton Density Fat Fraction). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effects of VK2809 compared to placebo on histologic changes assessed by hepatic biopsy.
2. To assess the safety and tolerability of VK2809 administered for 52 weeks. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study and is willing and able to participate;
2. Have a histologically-confirmed diagnosis of NASH on a liver biopsy performed during screening or within 6 months before screening; for this study, confirmation requires: (a) NASH Clinical Research Network (CRN) fibrosis stage 1 to stage 3 and (b) NASH activity score (NAS) of ≥4 with at least a score of 1 in each of the following NAS components: ballooning degeneration (score = 0-2), lobular inflammation (score = 0-3) and steatosis (score = 0-3); (c) F1 subjects must have at least one of these risk factors: type 2 diabetes, body mass index of ≥ 30 mg/ m2, and/ or alanine aminotransferase > 1.5 x ULN
3. Have a screening MRI-PDFF with ≥ 8% liver fat fraction;
4. Male and females be 18 to 75 years of age, inclusive, at screening;
5. Be able to comply with contraception restrictions:
Female subjects of non-childbearing potential must: (a) have documentation of surgical intervention (i.e., bilateral oophorectomy, hysterectomy, or tubal ligation) or (b) be naturally sterile (i.e., reliable history of >12 consecutive months without menses). Female subjects of childbearing potential must: (c) have a negative serum pregnancy (beta human chorionic gonadotropin) test at screening, (d) have a negative urine pregnancy test documented within the 24-hour period prior to the first dose of investigational product, (e) agree to use two effective methods of contraception from the date of screening until 28 days after the last dose of investigational product; acceptable effective methods of contraception include hormonal contraception intrauterine devices including hormone-containing devices and barrier methods, (f) abstinence is allowed if documented in medical record to be reliable and ongoing for at least 12 months or more and considered appropriate by the investigator. For purposes of the trial, abstinence is defined as a long-term habitual practice if it has been practiced for twelve months or more. Abstinence should be verified by being included in the medical history and the subject must continue abstinence until 28 days after study completion, (g) not be breastfeeding, and (h) not plan to become pregnant during the study; Male subjects who are sexually active with female partners of reproductive potential must: (i) use barrier contraception and their female partners must use a second effective birth control method (see Inclusion Criteria 5 (e) for acceptable, effective contraception methods) during the study and for at least 28 days after the last dose of investigational product; OR (j) have had a vasectomy and use barrier contraception (e.g. condom with spermicide) or their female partners must use an effective birth control method during the study and for at least 28 days after the last dose of investigational product;
6. Subjects with type 2 diabetes must have stable glycemic control defined as screening Hemoglobin A1C < 9%. The following oral agents are permitted as long as treatment has been stable for at least 3 months prior to the qualifying liver biopsy until randomization: (a) biguanides (example: metformin) (b) sulfonylureas (c) DPP4 inhibitors (d) meglitinides (e) α-Glucosidase inhibitors (example: acarbose) (f) bromocriptine (g) SLGT2 inhibitors are permitted as long as treatment has been stable for at least 6 months prior to the qualifying liver biopsy until randomization NOTE 1: Insulin is permitted as long as stable treatment (day to day dose variability of no more than 25% is acceptable) has been established and not discontinued from at least 6 months prior to the baseline liver biopsy until randomization;
7. Must be willing and able to undergo an MRI procedure;
8. Agree to refrain from exercise and heavy physical activity for at least 24 hours prior to each clinic visit;
9. Agree to refrain from drinking caffeinated beverages for at least 30 minutes prior to clinic visit;
10. Be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol.
11. Must be willing to maintain and establish therapeutic lifestyle without introduction of major changes from 3 months prior to screening until the end of the study. |
|
| E.4 | Principal exclusion criteria |
Please refer to the protocol for the full exclusion criteria
1. Are unwilling to undergo the required liver biopsy procedures or have any condition that would prevent obtaining a liver biopsy as part of this clinical protocol;
2. Have evidence of current or history of excessive alcohol consumption of more than 20 g per day for women and 30 g per day for men, on average, within 6 months before the qualifying liver biopsy and up to randomization, or are unable to provide a reliable estimate of alcohol consumption during this period;
3. Have evidence (positive drug and alcohol test) of or acknowledge use of illicit drugs and excessive alcohol consumption within 6 months prior to screening with the exception of: (a) use of medical marijuana (b) recreational use of marijuana, if in the opinion of the Investigator it will have no adverse impact on the compliance and safety of the subject in the study;
4. Have had weight change > 5% within 6 months prior to the qualifying liver biopsy and up to randomization;
5. Treatment with medications for the purpose of weight loss within 6 months prior to qualifying liver biopsy, unless approved after consultation with the medical monitor. These include drugs approved for weight loss (e.g. orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as drugs used off-label, herbal preparations and dietary supplements marketed for control of body weight or appetite;
6. History of eating disorders;
7. Active involvement in a structured weight loss program (including programs such as Weight Watchers, Jenny Craig, etc.) within 6 months prior to qualifying liver biopsy, unless approved after consultation with the medical monitor;
8. Have a history of: (a) Type 1 diabetes or Latent autoimmune diabetes in adults (LADA) (b) uncontrolled Type 2 diabetes (Hemoglobin A1c ≥9% at Screening);
9. Have a history of: (a) solid organ or bone marrow transplantation, (b) active thyroid disease including hyperthyroidism, (c) hepatic decompensation (example: including history of esophageal varices, ascites, hepatic encephalopathy, etc.) (d) immunologically-mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis), or (e) osteoporosis;
10. Have a history of effective bariatric surgery prior to qualifying for the study (subjects with ineffective surgery may be able to participate after consultation with the medical monitor),
11. Have a diagnosis (or current evidence) of other chronic liver diseases, including: (a) Hepatitis B (HBV) infection, as defined by presence of hepatitis B surface antigen (HBsAg) (b) HCV, as defined by positive antibody and detectable HCV RNA NOTE: Hep C RNA testing instead of initial screening for HCV antibody positivity must be done in all subjects with prior history of Hep C infection. Subjects with detectable HCV RNA levels within 6 months prior to the qualifying liver biopsy and up to screening will not be eligible to participate; (c) Hepatitis E (HEV) infection NOTE: Hep E testing instead of initial screening for HEV infection positivity must be done in all subjects with prior history of Hep E infection. Subjects with detectable HEV RNA levels within 6 months prior to the qualifying liver biopsy and up to screening will not be eligible to participate; (d) Acute Hepatitis A HAV IgM antibodies in serum (e) cirrhosis (f) hepatic malignancy (primary or metastatic) within 5 years of screening (g) hepatic transplantation (prior or planned) (h) signs and symptoms of portal hypertension (example: varices, chronic loss from portal gastropathy, variceal bleed, etc.) (i) drug-induced liver disease (j) autoimmune hepatitis (k) primary biliary cholangitis (PBC) (l) primary sclerosing cholangitis (PSC) (m) Wilson disease (n) alpha-1-antitrypsin deficiency (o) hemochromatosis (p) bile duct obstruction;
12. Have a history of human immunodeficiency virus (HIV) infection or HIV positive test at screening;
13. Have any active serious medical disease with likely life expectancy ≤5 years;
14. Have any major cardiovascular events (MI, unstable angina, coronary revascularization, stroke, TIA) within 6 months prior to screening; |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Relative change in liver fat content (assessed by MRI-PDFF) from baseline to Week 12 in subjects treated with VK2809 compared to the change in subjects treated with placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Absolute change in liver fat content (assessed by MRI-PDFF) from baseline to Week 52 in subjects treated with VK2809 compared to the change in subjects treated with placebo.
2. Relative change in liver fat content (assessed by MRI-PDFF) from baseline to Week 52 in subjects treated with VK2809 compared to the change in subjects treated with placebo.
3. Proportion of subjects with a relative percent decrease in liver fat content ≥ 30% (assessed by MRI-PDFF) from baseline to Week 12 and Week 52 in subjects treated with VK2809 compared to the change in subjects treated with placebo.
4. Proportion of subjects with normalization of liver fat (assessed by MRI-PDFF and defined as a fat fraction of < 5%) from baseline to Week 12 and Week 52 in subjects treated with VK2809 compared to the change in subjects treated with placebo.
5. Proportion of subjects with an absolute change >5% in liver fat content (assessed by MRI-PDFF) from baseline to Week 12 and Week 52 in subjects treated with VK2809 compared to the change in subjects treated with placebo.
The following secondary endpoints compare central reader scored histopathologic assessments (liver biopsies) from baseline to Week 52 for subjects treated with VK2809 to responses for subjects treated with placebo.
6. Proportion of subjects with resolution of steatohepatitis on overall histpathological reading and no worsening of liver fibrosis on NASH CRN fibrosis score. 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.
7. Proportion of subjects with improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis).
8. Proportion of subjects with ≥ 2-point improvement in NAS (with at least 1-point improvement in ballooning or inflammation) with no worsening of fibrosis stage.
9. Proportion of subjects with resolution of steatohepatitis and improvement in fibrosis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| baseline to Week 12 and/or Week 52 [#6-9: are only baseline and W52] |
|
| 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 | No |
| 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 | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Belgium |
| France |
| Mexico |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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