| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Noncirrhotic, Nonalcoholic Steatohepatitis and Fibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Noncirrhotic, Nonalcoholic Steatohepatitis and Fibrosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| 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 |
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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 |
Cohort A (Adults)
• To assess the effect of treatment with AXA1125 compared with placebo on steatohepatitis, using liver biopsy and the Clinical Research Network (CRN) histologic scoring system, in subjects with nonalcoholic steatohepatitis (NASH).
Cohort B (Adolescents)
• To assess the safety and tolerability of AXA1125 in adolescent subjects with NASH. |
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| E.2.2 | Secondary objectives of the trial |
Cohort A (Adults)
• Assess safety and tolerability of AXA1125 in subjects with NASH;
• Assess changes in liver fat content, biomarkers of fibro-inflammation, and biomarkers of metabolism following treatment with AXA1125 compared with placebo in subjects with NASH;
• Assess changes in liver stiffness using vibration controlled transient elastography (VCTE) delivered by the FibroScan®, following treatment with AXA1125 compared with placebo, in subjects with NASH;
•Assess the dose-response relationship of AXA1125 in subjects with NASH.
Cohort B (Adolescents)
• Assess changes in liver fat content, biomarkers of fibro-inflammation, and biomarkers of metabolism following treatment with AXA1125 compared with placebo in subjects with NASH;
• Assess changes in liver stiffness using VCTE delivered by the FibroScan®, following treatment with AXA1125 compared with placebo, in subjects with NASH;
• Assess dose-response relationship of AXA1125 in subjects with NASH.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort A (Adults)
1. Male / female subjects 18 years of age (inclusive) or older.
2. Able to provide written informed consent, understand, and comply with protocol requirements.
3. Must have NASH and fibrosis on a liver biopsy sample confirmed by using the NASH CRN histologic scoring system: Total NAS above/equal 4 with a score of at least 1 in each component (steatosis, lobular inflammation, and ballooning); and Fibrosis stage 2 or 3;
Note: Requirements for historical liver biopsy are given in Protocol Section 4.1.1. Excursions from the criteria may apply, if supported by documented rationale and approval from the Medical Monitor prior to the biopsy.
4. Subjects may have a diagnosis of T2DM, dyslipidemia, hypertension, hypothyroidism, and/or impaired glucose tolerance. If treated for these conditions, subjects must be well controlled on a stable regimen for at least 3 months prior to and during Screening, and anticipate no significant alterations to these regimens for the duration of the study. Doses of medications used to treat stable chronic conditions may be modified during the study for safety or tolerability issues.
5. Subjects must have a negative urine screen for drugs of abuse or legal substance abuse, during Screening. If the subject’s urine ethyl glucuronide is positive during the study, it will lead to the subject’s withdrawal from the study.
6. Female subjects must: Be surgically sterile or postmenopausal with at least 12 months of amenorrhea without an alternate medical cause; have follicle-stimulating hormone level consistent with postmenopausal state if amenorrhoeic for <12 months or if <55 years of age; to be of childbearing potential with a negative serum pregnancy test during Screening, not lactating, and to agree to abstain from sexual activity or use a highly effective birth control during the study and for at least 30 days after the last dose of study drug;
7. Male subjects with a partner who is a FCBP must agree to abstain from sexual activity or use a highly effective form of birth control during the study and for at least 90 days after last dose of study drug; Male subjects capable of fathering a child must agree to refrain from sperm donation during the study and for at least 90 days after the last dose of study drug.
Cohort B (Adolescents)
1. Male or female subjects 14 to 17 years of age (both inclusive).
2. Parent(s) / legal representative(s)/guardian must provide signed informed consent.
3. Subjects able to provide informed assent, and to understand and comply with protocol requirements.
4. Subjects must have a diagnosis of NASH and fibrosis for at least 6 months prior to Screening, per standard of care.
5. Subjects must meet 1 of the following:
a. Historical liver biopsy up to 12 months prior to Screening, with a total NAS above/equal 4 and a score of at least 1 in each component (steatosis, lobular inflammation, and ballooning). The historical biopsy must have been obtained with no medications that can cause steatosis or NASH , and no agents /procedures for the treatment of NAFLD or NASH within 3 months (or 5 half-lives from last dose of prior IP). Subjects should not have a weight loss of >5% from the time of the qualifying liver biopsy until Screening.
b. Screening AST above/equal 20 IU/L AND a FibroScan done within 3 months prior to Screening or at Screening with CAP score above/equal 280 dB/m and liver stiffness measure above/equal 8.5 kPa.
c. FibroScan-AST score ≥0.35, based on a FibroScan within 3 months prior to or during Screening.
6. Same as Inclusion criterion#4 of Cohort A.
7. Same as Inclusion criterion#5 of Cohort A.
8. All female subjects must have a negative serum pregnancy test during Screening, must not be lactating, and must agree to abstain from sexual activity or to use a highly effective form of birth control for the duration of the study and for at least 30 days after the last dose of study drug.
9. Same as Inclusion criterion#7 of Cohort A.
10. Fasting ALT >44 IU/L (females) and >50 IU/L (males).
11. BMI ≥95th percentile for age and sex.
12. Tanner Stage 5.
13. MRI-PDFF >10%.
14. Subjects may have either prediabetes or T2DM. Prediabetes is established by 1 of the following: a. Fasting blood glucose of ≥100 mg/dL (≥5.5 mmol/L) but <126 mg/dL (<7.0 mmol/L) or HbA1c ≥5.7% but <6.4% based on the Screening visit laboratory results; b. Historical evidence of impaired fasting glucose or glucose intolerance per the standard of care
of the study center; c. Subject is already on a stable regimen for approximately 120 days prior to the Screening Visit for the treatment of prediabetes (eg, diet or lifestyle).
15. Subjects with Investigator-confirmed T2DM should have HbA1c <9.5% at Screening and must be stable on their usual diabetic medications for approximately 120 days prior to the Screening and should not be anticipating clinically significant dose adjustments of the T2DM medications for the anticipated duration of the study. |
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| E.4 | Principal exclusion criteria |
Cohort A (Adults)
1. Have taken medication to treat NASH for >2 weeks within 3 months prior to Screening;
2. Have taken any of the following prohibited medications for >2 weeks in the 3 months prior to or at Screening: a. Drugs causing hepatic steatosis (ie, systemic corticosteroids, amiodarone, tamoxifen, valproic acid); b. Glucagon-like peptide-1 (GLP-1) receptor agonists (ie, liraglutide, semaglutide, dulaglutide) or peroxisome proliferator-activated receptor agonists (ie, thiazolidinediones); c. drugs associated with high risk for hepatotoxicity (ie, phenytoin).
3. Are not on a stable dose of vitamin E for at least 6 months prior to the qualifying liver Biopsy.
4. Are unable to stop the use of AA or protein supplements, carnitine, creatine, or Nac between Screening and end of study.
5. History or presence of liver disease (other than NAFLD, NASH, or resolved hepatitis A), such as alcoholic liver disease, Wilson’s disease, hemochromatosis, primary biliary cholangitis, noncirrhotic portal, hypertension, primary sclerosing cholangitis, history of bile duct obstruction/biliary diversion, autoimmune hepatitis, α-1 antitrypsin deficiency, hepatocellular carcinoma, liver transplant, or any condition causing portal hypertension.
6. Screening Alcohol Use Disorders Identification Test (AUDIT) score above/equal 8, history of significant alcohol consumption (>30 g/day for males and >20 g/day for females), and/or inability to reliably quantify alcohol consumption within 6 months prior to Screening.
7. History or presence of cirrhosis including: any liver biopsy finding indicative of cirrhosis; Hepatic decompensation (ie, ascites); Model for End-Stage Liver Disease (MELD) score >12; at least one of the following lab abnormalities unless explained by other causes: Platelet count <150000/µL; Serum albumin <3.5 g/dL; International normalized ratio >1.3.
8. Have a total bilirubin >1.3 mg/dL.
9. Have an AST or ALT >5 ULN.
10. Have a serum alkaline phosphatase >2 ULN.
11. Have an HbA1c >9.5%. Note: For subjects with prior diagnosis of T2DM, with fasting plasma glucose (FPG) above /equal 126 mg/dL, and HbA1c above/equal 6.5% and <9.5% at Screening, and for subjects with no documented diagnosis of T2DM, with FPG above/equal 126 mg/dL and/or HbA1c above/equal 6.5% and <9.5% at Screening, a consultation with treating physician or endocrinologist is recommended at Screening to check diabetic status and antidiabetic medication .
12. Have an eGFR <60 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.
13. Are positive for HIV antibody, hepatitis C virus (HCV), or hepatitis B during Screening.
14. Are positive for SARS-CoV-2 RNA by RT-PCR) test.
15. Have a planned or prior organ transplant.
16. Have a history of type 1 diabetes mellitus.
17. Have a history of inborn errors of metabolism that may impact AA metabolism such as urea cycle disorders;
18. Have a history of significant neurological disorders, which may interfere with the ability to properly assess safety and tolerability.
19. Have a history or presence of malignancy, within the past 2 years.
20. Have had a weight gain or loss >5% or used medications for weight loss, such as anti-obesity medications and/or dietary supplements 3 months prior to Screening or between the qualifying liver biopsy and Screening, whichever is longer.
21. Have a significant or uncontrolled concomitant medical illness, that would jeopardize the objectives of the study.
22. Have a history of a surgical or a medical condition that may interfere with absorption of the study drug (ie, resection of any part of the gastrointestinal tract, gastric or intestinal bypass, etc).
23. Have used an investigational drug, product, or device within 30 days or 5 half-lives (whichever is longer) before Screening.
24. Have a contraindication, sensitivity, or allergy to any ingredient of the study drug
25. Are considered to be a poor attendee, or not able to comply with the study procedures.
Cohort B (Adolescents)
1-5. Same as exclusion criteria#1 to #5 of Cohort A.
6. Have a Screening AUDIT score >2, a history of significant alcohol consumption (>30 g/day for males and >20 g/day for females), and/or inability to reliably quantify alcohol consumption within 6 months prior to Screening.
7 – 9 . Same as exclusion criteria# 7 – 9 of Cohort A.
10. Have a serum alkaline phosphatase >400 U/L unless determined to be of bone origin.
11. Have an impaired renal function (ie, eGFR <60 mL/min/1.73 m2 calculated using the Schwartz equation.
12-18. Same as exclusion criteria#13-19 of Cohort A.
19. Have experienced a weight gain or loss >7% or have used medications intended to produce weight loss such as anti-obesity medications and/or dietary supplements for weight loss 3 months prior to Screening.
20-24. Same as exclusion criteria# 21 – 25 of Cohort A.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohort A (Adults)
The primary efficacy endpoint is:
•The proportion of subjects with at least a 2-point improvement from baseline to Week 48 in the non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS).
Note: The reduction in NAS must include at least a 1-point reduction in either ballooning or inflammation.
The full list of the study endpoints can be found in the protocol
Cohort B (Adolescents)
The primary endpoint is the safety and tolerability of AXA1125, which will be assessed throughout the study. The safety and tolerability endpoints are:
• AEs and SAEs;
• Vital signs and body weight;
• Clinical laboratory assessments (chemistry, hematology, coagulation, and urinalysis);
• 12-lead ECGs; and
• PROMIS (4a, 5a, and 6a) assessment of gastrointestinal symptoms.
The full list of the study endpoints can be found in the protocol
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort A (Adults)
From baseline to Week 48
Cohort B (Adolescents)
Will be assessed throughout the study
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| E.5.2 | Secondary end point(s) |
Cohort A (Adults)
The secondary efficacy endpoints are:
• Other liver histologic assessments from baseline to Week 48, including the following:
oThe proportion of subjects with resolution of NASH with no worsening of fibrosis; Note: Resolution of NASH is defined as a post-treatment ballooning score of 0 and an inflammation score of 0 or 1 on liver biopsy.
oThe proportion of subjects with no worsening of fibrosis, defined as no increase in CRN fibrosis score;
oThe mean change in fibrosis score;
oThe proportion of subjects who have at least a 1-stage improvement in fibrosis and no worsening of NASH;
oThe mean change in NAS and each of its components (steatosis, lobular inflammation, and ballooning);
• The mean change in liver stiffness and controlled attenuation parameter (CAP) score on FibroScan® from baseline to Weeks 12, 24, and 48;
• The mean change (absolute and relative) in liver fat content assessed by MRI-PDFF from baseline to Weeks 12, 24, and 48;.
• The mean change in biomarkers of metabolism at predefined time points from baseline, including the following:
− Lipid panel, free fatty acids, adiponectin
− Markers of glucose homeostasis, such as HbA1c, fasting insulin, fasting C-peptide, fasting glucose, and HOMA-IR
• The mean change in biomarkers of fibro-inflammation at predefined time points from baseline, including the following:
− Serum tests of liver injury, including ALT, AST, and gamma-glutamyl transferase (GGT);
− High-sensitivity C-reactive protein (hsCRP), Pro-C3, and fibrosis-4 index (FIB-4).)
The full list of endpoints can be found in the study protocol.
Cohort B (Adolescents)
The secondary efficacy endpoints are as follows:
• The mean change in liver stiffness and CAP score on FibroScan® from baseline to Weeks 12, 24, and 48.
• The mean change (absolute and relative) in liver fat content assessed by MRI-PDFF from baseline to Weeks 12, 24, and 48.
• The mean change in biomarkers of metabolism at predefined time points from baseline, including the following:
− Lipid panel, free fatty acids, and adiponectin
− Markers of glucose homeostasis, such as HbA1c, fasting insulin, fasting C-peptide, fasting glucose, and HOMA-IR
• The mean change in biomarkers of fibro-inflammation at predefined time points from baseline, including the following:
− Serum tests of liver injury, including ALT, AST, and GGT
− hsCRP, Pro-C3, and FIB-4
The full list of endpoints can be found in the study protocol.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort A (Adults)
• Other Liver Histologic assessments : From baseline to Week 48
• The mean change in liver stiffness and CAP score on FibroScan®, and the mean change (absolute and relative) in liver fat content assessed by MRI-PDFF: From baseline to Weeks 12, 24, and 48;
•The mean change in biomarkers of metabolism and the mean change in biomarkers of fibro-inflammation : At predefined time points from baseline.
Cohort B (Adolescents)
•The mean change in liver stiffness and CAP score on FibroScan®,and the mean change (absolute and relative) in liver fat content assessed by MRI-PDFF: From baseline to Weeks 12, 24, and 48;
•The mean change in biomarkers of metabolism and the mean change in biomarkers of fibro-inflammation : At predefined time points from baseline.
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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 | Yes |
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Australia |
| Canada |
| Puerto Rico |
| United States |
| France |
| Poland |
| United Kingdom |
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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
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
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