Non-Alcoholic Steatohepatitis (NASH)
Conditions
Keywords
Non-Alcoholic Steatohepatitis, NASH, peroxisome proliferator-activated receptor (PPAR), Liver Diseases, Fibrosis, Fatty Liver, Non-alcoholic Fatty Liver Disease, Digestive System Diseases, IVA337
Brief summary
Non-alcoholic steatohepatitis, abbreviated as NASH, is a chronic liver disease that may progress to cirrhosis. The disease is mostly associated with obesity and type 2 diabetes mellitus, or insulin resistance and is very common. However, Treatment of NASH is a significant unmet clinical need. IVA337 (lanifibranor) is a next generation pan-PPAR (peroxisome proliferator-activated receptors) agonist addressing the pathophysiology of NASH : metabolic, inflammatory and fibrotic. The purpose of this research is to evaluate the efficacy and the safety of two doses of IVA337 (800mg, 1200 mg) per day for 24 weeks versus placebo in adult NASH patients with liver steatosis and moderate to severe necroinflammation without cirrhosis.
Detailed description
Randomized (stratified on diabetes), placebo-controlled, double-blind, parallel-assignment, dose-range multicenter study There are 3 parallel treatment groups: placebo, IVA337 800mg once a day (Quaque Die, QD) and IVA337 1200mg QD (identical tablets of 400mg IVA337 or placebo). Both, patient and investigator are blinded. For each patient, the study duration will be an overall of 6 to 8 months (with a 10-day to 4-week selection period, a 24-week treatment period and a 4-week follow-up period).
Interventions
DRUGIVA337
1200mg
DRUGPlacebo
Placebo to match
Sponsors
Inventiva Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult subjects, age ≥18 years. * NASH histological diagnosis according to the currently accepted definition of both EASL and AASLD, requiring the combined presence of steatosis (any degree ≥ 5%) + lobular inflammation of any degree + liver cell ballooning of any amount, on a liver biopsy performed ≤ 6 months before screening in the study or at screening and confirmed by central reading during the screening period and * SAF Activity score of 3 or 4 (\>2) * SAF Steatosis score ≥ 1 * SAF Fibrosis score \< 4 * Subject agrees to have a liver biopsy performed after 24 weeks of treatment. * Compensated liver disease * No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, Hepatitis B virus (HBV), hepatitis C virus (HCV), Wilson's, α-1-antitrypsin deficiency, hemochromatosis, etc…). * If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting glycemia \<10 mmol/L, no changes in medication in the previous 6 months, and no new symptoms associated with decompensated diabetes in the previous 3 months. * Have a stable weight since the liver biopsy was performed defined by no more than a 5 % loss of initial body weight. * Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progestogen containing) hormonal/ progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study * Subjects having given her/his written informed consent.
Exclusion criteria
* Evidence of another form of liver disease. * History of sustained excess alcohol ingestion: daily alcohol consumption \> 30 g/day (3 drinks per day) for males and \> 20 g/day (2 drinks per day) for females. * Unstable metabolic condition: Weight change \> 5kg in the last three months, diabetes with poor glycemic control (HbA1c \> 8.5%), introduction of an antidiabetic or of an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening. * History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months. * Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the American Heart Association , AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator, would preclude treatment with IVA337 and/or adequate follow up. * HB antigen \>0, HCV Polymerase chain reaction (PCR) tests \>0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), HIV infection. * Pregnancy/lactation or inability to adhere to adequate contraception in women of child-bearing potential. * Active malignancy except cutaneous basocellular carcinoma. * Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study. * Body mass index (BMI) \>45 kg/m2. * Type 1 diabetes and type 2 diabetic patient on insulin. * Diabetic ketoacidosis * Fasting Triglycerides \> 300 mg/dL. * Hemostasis disorders or current treatment with anticoagulants. * Contra-indication to liver biopsy. * History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease event, including myocardial infarction, except patients with only well controlled hypertension. Any clinically significant ECG abnormality reported by central ECG reading. * Participation in any other clinical study within the previous 3 months. * Have a known hypersensitivity to any of the ingredients or excipients of the Investigational medicinal product (IMP) * Be possibly dependent on the Investigator or the sponsor (e.g., including, but not limited to, affiliated employee). * Creatine phosphokinase (CPK)\>5 x ULN * Osteopenia or any other well documented Bone disease. Patient without well documented osteopenia treated with vitamin D and/or Calcium based supplements for preventive reasons can be included. (The criteria below are applicable only for patients who will undergo a MRI/LMS in selected centers) * Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator. * Metallic implant of any sort that prevents MRI examination including, but not limited to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural stimulator, metallic contraceptive device, tattoo, body piercing that cannot be removed, cochlear implant; or any other contraindication to MRI examination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | 24 weeks | SAF-A is the activity part of the Steatosis Activity Fibrosis \[SAF\] histological score, calculated as the sum of lobular inflamation score and balloning score. No worsening of fibrosis means that the CRN fibrosis score (CRN-F) remains stable or decreases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NASH Resolution and no Worsening of Fibrosis | 24 weeks | Resolution of NASH is defined as a CRN Inflammation score equal to 0 or 1, and a CRN Ballooning score equal to 0. No worsening of fibrosis means that the CRN fibrosis score remains stable or decreases. |
| Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | 24 weeks | Improvement of fibrosis is defined as a decrease of at least one stage in CRN Fibrosis score. No worsening of NASH is defined as no increase of CRN Steatosis score, no increase of CRN Inflammation score ans no increase of CRN Ballooning score. |
| Activity (SAF-A) Improvement | 24 weeks | SAF-A is the activity part of the Steatosis Activity Fibrosis \[SAF\] histological score, calculated as the sum of lobular inflamation score and balloning score. Improvement of SAF-A is defined as a decrease of at least 1 point. |
| Steatosis (CRN-S) Improvement | 24 weeks | Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point. |
| Lobular Inflammation (CRN-I) Improvement | 24 weeks | Improvement of CRN Lobular inflammation score (CRN-I) is defined as a decrease of at least 1 point. |
| Hepatocyte Balooning (CRN-B) Improvement | 24 weeks | Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point. |
| Fibrosis (CRN-F) Improvement | 24 weeks | Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point. |
| Modified ISHAK Fibrosis (ISHAK-F) Improvement | 24 weeks | Improvement of Modified ISHAK Fibrosis (ISHAK-F) is defined as a decrease of at least 1 point. |
| Absolute Change in ALT | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| Absolute Change in AST | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| Absolute Change in GGT | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| Absolute Change in Fibrinogen | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| Absolute Change in Hs-CRP | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| NASH Improvement | 24 weeks | NASH improvement is defined as a decrease of at least 2 points in NAS score (sum of CRN Steatosis, Inflammation and Ballooning scores) without worsening of CRN Fibrosis score. |
| Absolute Change in Haptoglobulin | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
| Absolute Change of Fasting Plasma Glucose | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in Insulin | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in HOMA Index | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in HbA1c | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in Total Cholesterol | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change of HDL-Cholesterol | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change of LDL-Cholesterol | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in Triglycerides | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in Apo A1 | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Absolute Change in Adiponectin | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. |
| Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | From baseline to Week 24. | Resolution of NASH is defined as a CRN Inflammation score equel to 0 or 1, and a CRN ballooning score equal to 0. Improvement of firbosis is defined as a decrease of at least one stage in CRN Fibrosis score. |
| Absolute Change in Alpha2 Macroglobulin | 24 weeks | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, France, Germany, Italy, Mauritius, Poland, Slovenia, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Recruitment of patients started in February 2017, and last patient was recruited on March 2019. A total of 868 patients were screened for the study.
Pre-assignment details
Patients were invited to participate into the study by their referent doctor according to the patient's medical records. Patients had to fulfil all the inclusion and none of the exclusion criteria to be eligible. A total of 247 patients were randomised, and 621 were not randomised.Main reason for non randomization was inclusion/exclusion criteria not met (470 - 76%).
Participants by arm
| Arm | Count |
|---|---|
| IVA337 1200mg IVA337 400mg, once a day (Quaque Die, QD) with food
IVA337: 1200mg | 83 |
| IVA337 800mg IVA337 400mg, once a day (Quaque Die, QD) with food
IVA337: 800mg | 83 |
| Placebo Placebo to match, once a day (Quaque Die, QD) with food
Placebo: Placebo to match | 81 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Non compliance | 0 | 1 | 1 |
| Overall Study | Use of prohibited drug | 0 | 0 | 2 |
| Overall Study | Withdrawal by patient and adverse event non fatal | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | IVA337 1200mg | IVA337 800mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 14 Participants | 18 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 67 Participants | 69 Participants | 63 Participants | 199 Participants |
| Age, Continuous | 52.2 years STANDARD_DEVIATION 13.8 | 55 years STANDARD_DEVIATION 10.4 | 53.4 years STANDARD_DEVIATION 13.1 | 53.6 years STANDARD_DEVIATION 12.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 78 Participants | 80 Participants | 74 Participants | 232 Participants |
| Region of Enrollment Australia | 3 participants | 7 participants | 3 participants | 13 participants |
| Region of Enrollment Austria | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Belgium | 10 participants | 11 participants | 11 participants | 32 participants |
| Region of Enrollment Bulgaria | 17 participants | 16 participants | 22 participants | 55 participants |
| Region of Enrollment Canada | 3 participants | 1 participants | 4 participants | 8 participants |
| Region of Enrollment Czechia | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment France | 15 participants | 15 participants | 9 participants | 39 participants |
| Region of Enrollment Germany | 7 participants | 3 participants | 3 participants | 13 participants |
| Region of Enrollment Italy | 3 participants | 1 participants | 1 participants | 5 participants |
| Region of Enrollment Mauritius | 2 participants | 3 participants | 2 participants | 7 participants |
| Region of Enrollment Poland | 1 participants | 2 participants | 3 participants | 6 participants |
| Region of Enrollment Slovenia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 3 participants | 4 participants | 5 participants | 12 participants |
| Region of Enrollment Switzerland | 0 participants | 3 participants | 1 participants | 4 participants |
| Region of Enrollment United Kingdom | 3 participants | 2 participants | 2 participants | 7 participants |
| Region of Enrollment United States | 13 participants | 11 participants | 12 participants | 36 participants |
| Sex: Female, Male Female | 49 Participants | 54 Participants | 41 Participants | 144 Participants |
| Sex: Female, Male Male | 34 Participants | 29 Participants | 40 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 83 | 0 / 83 | 0 / 81 |
| other Total, other adverse events | 60 / 83 | 48 / 83 | 30 / 81 |
| serious Total, serious adverse events | 7 / 83 | 3 / 83 | 3 / 81 |
Outcome results
Primary
SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F)
SAF-A is the activity part of the Steatosis Activity Fibrosis \[SAF\] histological score, calculated as the sum of lobular inflamation score and balloning score. No worsening of fibrosis means that the CRN fibrosis score (CRN-F) remains stable or decreases.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | Yes | 41 Participants |
| IVA337 1200mg | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | No | 42 Participants |
| IVA337 800mg | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | Yes | 34 Participants |
| IVA337 800mg | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | No | 49 Participants |
| Placebo | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | Yes | 22 Participants |
| Placebo | SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | No | 59 Participants |
Comparison: The primary endpoint was a binary outcome (Yes/No). Responders rates were compared between the placebo and lanifibranor 800 mg at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetic status at baseline (that was the stratified factors in the randomisation).~The CMH risk ratio is used to estimate the effect size. Patients with missing data are considered as non-responders.p-value: =0.06195% CI: [0.98, 2.12]Cochran-Mantel-Haenszel
Comparison: The primary endpoint was a binary outcome (Yes/No). Responders rates were compared between the placebo and lanifibranor 1200 mg at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetic status at baseline (that was the stratified factors in the randomisation).~The CMH risk ratio is used to estimate the effect size. Patients with missing data are considered as non-responders.p-value: =0.00495% CI: [1.24, 2.4]Cochran-Mantel-Haenszel
Secondary
Absolute Change in Adiponectin
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Adiponectin | 17.12 microgram/mL | Standard Error 1.44 |
| IVA337 800mg | Absolute Change in Adiponectin | 11.95 microgram/mL | Standard Error 1.51 |
| Placebo | Absolute Change in Adiponectin | -0.35 microgram/mL | Standard Error 1.44 |
Secondary
Absolute Change in Alpha2 Macroglobulin
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Alpha2 Macroglobulin | 0.13 g/L | Standard Error 0.38 |
| IVA337 800mg | Absolute Change in Alpha2 Macroglobulin | 0.15 g/L | Standard Error 0.4 |
| Placebo | Absolute Change in Alpha2 Macroglobulin | 0.05 g/L | Standard Error 0.35 |
Secondary
Absolute Change in ALT
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in ALT | -24.54 U/L | Standard Error 3.82 |
| IVA337 800mg | Absolute Change in ALT | -26.08 U/L | Standard Error 3.85 |
| Placebo | Absolute Change in ALT | -1.4 U/L | Standard Error 3.88 |
Secondary
Absolute Change in Apo A1
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Apo A1 | -4.39 mg/dL | Standard Error 2.16 |
| IVA337 800mg | Absolute Change in Apo A1 | -0.29 mg/dL | Standard Error 2.19 |
| Placebo | Absolute Change in Apo A1 | 0.03 mg/dL | Standard Error 2.18 |
Secondary
Absolute Change in AST
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in AST | -12.04 U/L | Standard Error 3.17 |
| IVA337 800mg | Absolute Change in AST | -15.11 U/L | Standard Error 3.2 |
| Placebo | Absolute Change in AST | -0.08 U/L | Standard Error 3.22 |
Secondary
Absolute Change in Fibrinogen
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Fibrinogen | -0.14 g/L | Standard Error 0.81 |
| IVA337 800mg | Absolute Change in Fibrinogen | -0.10 g/L | Standard Error 0.61 |
| Placebo | Absolute Change in Fibrinogen | 0.02 g/L | Standard Error 0.67 |
Secondary
Absolute Change in GGT
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in GGT | -27.87 U/L | Standard Error 5.57 |
| IVA337 800mg | Absolute Change in GGT | -43.38 U/L | Standard Error 5.61 |
| Placebo | Absolute Change in GGT | 4.41 U/L | Standard Error 5.65 |
Secondary
Absolute Change in Haptoglobulin
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Haptoglobulin | -0.099 g/L | Standard Error 0.378 |
| IVA337 800mg | Absolute Change in Haptoglobulin | -0.053 g/L | Standard Error 0.256 |
| Placebo | Absolute Change in Haptoglobulin | 0.074 g/L | Standard Error 0.291 |
Secondary
Absolute Change in HbA1c
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in HbA1c | -0.41 percentage | Standard Error 0.05 |
| IVA337 800mg | Absolute Change in HbA1c | -0.38 percentage | Standard Error 0.05 |
| Placebo | Absolute Change in HbA1c | 0.07 percentage | Standard Error 0.05 |
Secondary
Absolute Change in HOMA Index
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in HOMA Index | -5.46 index | Standard Error 0.58 |
| IVA337 800mg | Absolute Change in HOMA Index | -5.79 index | Standard Error 0.58 |
| Placebo | Absolute Change in HOMA Index | -1.47 index | Standard Error 0.57 |
Secondary
Absolute Change in Hs-CRP
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Hs-CRP | -1.37 mg/L | Standard Error 0.46 |
| IVA337 800mg | Absolute Change in Hs-CRP | -2.05 mg/L | Standard Error 0.47 |
| Placebo | Absolute Change in Hs-CRP | 0.11 mg/L | Standard Error 0.47 |
Secondary
Absolute Change in Insulin
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Insulin | -114.91 pmol/L | Standard Error 11.75 |
| IVA337 800mg | Absolute Change in Insulin | -118.66 pmol/L | Standard Error 11.66 |
| Placebo | Absolute Change in Insulin | -35.7 pmol/L | Standard Error 11.6 |
Secondary
Absolute Change in Total Cholesterol
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Total Cholesterol | -0.07 mmol/L | Standard Error 0.07 |
| IVA337 800mg | Absolute Change in Total Cholesterol | -0.02 mmol/L | Standard Error 0.08 |
| Placebo | Absolute Change in Total Cholesterol | 0.01 mmol/L | Standard Error 0.08 |
Secondary
Absolute Change in Triglycerides
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change in Triglycerides | -0.44 mmol/L | Standard Error 0.09 |
| IVA337 800mg | Absolute Change in Triglycerides | -0.49 mmol/L | Standard Error 0.09 |
| Placebo | Absolute Change in Triglycerides | 0.06 mmol/L | Standard Error 0.09 |
Secondary
Absolute Change of Fasting Plasma Glucose
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change of Fasting Plasma Glucose | -0.6 mmol/L | Standard Error 0.12 |
| IVA337 800mg | Absolute Change of Fasting Plasma Glucose | -0.78 mmol/L | Standard Error 0.12 |
| Placebo | Absolute Change of Fasting Plasma Glucose | 0.24 mmol/L | Standard Error 0.12 |
Secondary
Absolute Change of HDL-Cholesterol
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change of HDL-Cholesterol | 0.11 mmol/L | Standard Error 0.02 |
| IVA337 800mg | Absolute Change of HDL-Cholesterol | 0.16 mmol/L | Standard Error 0.02 |
| Placebo | Absolute Change of HDL-Cholesterol | 0.01 mmol/L | Standard Error 0.02 |
Secondary
Absolute Change of LDL-Cholesterol
Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IVA337 1200mg | Absolute Change of LDL-Cholesterol | 0.03 mmol/L | Standard Error 0.07 |
| IVA337 800mg | Absolute Change of LDL-Cholesterol | 0.03 mmol/L | Standard Error 0.07 |
| Placebo | Absolute Change of LDL-Cholesterol | 0.01 mmol/L | Standard Error 0.07 |
Secondary
Activity (SAF-A) Improvement
SAF-A is the activity part of the Steatosis Activity Fibrosis \[SAF\] histological score, calculated as the sum of lobular inflamation score and balloning score. Improvement of SAF-A is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Activity (SAF-A) Improvement | Yes | 62 Participants |
| IVA337 1200mg | Activity (SAF-A) Improvement | No | 21 Participants |
| IVA337 800mg | Activity (SAF-A) Improvement | Yes | 54 Participants |
| IVA337 800mg | Activity (SAF-A) Improvement | No | 29 Participants |
| Placebo | Activity (SAF-A) Improvement | Yes | 40 Participants |
| Placebo | Activity (SAF-A) Improvement | No | 41 Participants |
Secondary
Fibrosis (CRN-F) Improvement
Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Fibrosis (CRN-F) Improvement | Yes | 36 Participants |
| IVA337 1200mg | Fibrosis (CRN-F) Improvement | No | 47 Participants |
| IVA337 800mg | Fibrosis (CRN-F) Improvement | Yes | 28 Participants |
| IVA337 800mg | Fibrosis (CRN-F) Improvement | No | 55 Participants |
| Placebo | Fibrosis (CRN-F) Improvement | Yes | 22 Participants |
| Placebo | Fibrosis (CRN-F) Improvement | No | 59 Participants |
Secondary
Hepatocyte Balooning (CRN-B) Improvement
Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Hepatocyte Balooning (CRN-B) Improvement | Yes | 60 Participants |
| IVA337 1200mg | Hepatocyte Balooning (CRN-B) Improvement | No | 23 Participants |
| IVA337 800mg | Hepatocyte Balooning (CRN-B) Improvement | Yes | 54 Participants |
| IVA337 800mg | Hepatocyte Balooning (CRN-B) Improvement | No | 29 Participants |
| Placebo | Hepatocyte Balooning (CRN-B) Improvement | Yes | 37 Participants |
| Placebo | Hepatocyte Balooning (CRN-B) Improvement | No | 44 Participants |
Secondary
Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH
Improvement of fibrosis is defined as a decrease of at least one stage in CRN Fibrosis score. No worsening of NASH is defined as no increase of CRN Steatosis score, no increase of CRN Inflammation score ans no increase of CRN Ballooning score.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | Yes | 35 Participants |
| IVA337 1200mg | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | No | 48 Participants |
| IVA337 800mg | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | Yes | 23 Participants |
| IVA337 800mg | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | No | 60 Participants |
| Placebo | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | Yes | 19 Participants |
| Placebo | Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | No | 62 Participants |
Secondary
Lobular Inflammation (CRN-I) Improvement
Improvement of CRN Lobular inflammation score (CRN-I) is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Lobular Inflammation (CRN-I) Improvement | Yes | 43 Participants |
| IVA337 1200mg | Lobular Inflammation (CRN-I) Improvement | No | 40 Participants |
| IVA337 800mg | Lobular Inflammation (CRN-I) Improvement | Yes | 34 Participants |
| IVA337 800mg | Lobular Inflammation (CRN-I) Improvement | No | 49 Participants |
| Placebo | Lobular Inflammation (CRN-I) Improvement | Yes | 30 Participants |
| Placebo | Lobular Inflammation (CRN-I) Improvement | No | 51 Participants |
Secondary
Modified ISHAK Fibrosis (ISHAK-F) Improvement
Improvement of Modified ISHAK Fibrosis (ISHAK-F) is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Modified ISHAK Fibrosis (ISHAK-F) Improvement | Yes | 41 Participants |
| IVA337 1200mg | Modified ISHAK Fibrosis (ISHAK-F) Improvement | No | 42 Participants |
| IVA337 800mg | Modified ISHAK Fibrosis (ISHAK-F) Improvement | Yes | 32 Participants |
| IVA337 800mg | Modified ISHAK Fibrosis (ISHAK-F) Improvement | No | 51 Participants |
| Placebo | Modified ISHAK Fibrosis (ISHAK-F) Improvement | Yes | 25 Participants |
| Placebo | Modified ISHAK Fibrosis (ISHAK-F) Improvement | No | 56 Participants |
Secondary
NASH Improvement
NASH improvement is defined as a decrease of at least 2 points in NAS score (sum of CRN Steatosis, Inflammation and Ballooning scores) without worsening of CRN Fibrosis score.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | NASH Improvement | Yes | 53 Participants |
| IVA337 1200mg | NASH Improvement | No | 30 Participants |
| IVA337 800mg | NASH Improvement | Yes | 43 Participants |
| IVA337 800mg | NASH Improvement | No | 40 Participants |
| Placebo | NASH Improvement | Yes | 26 Participants |
| Placebo | NASH Improvement | No | 55 Participants |
Secondary
NASH Resolution and no Worsening of Fibrosis
Resolution of NASH is defined as a CRN Inflammation score equal to 0 or 1, and a CRN Ballooning score equal to 0. No worsening of fibrosis means that the CRN fibrosis score remains stable or decreases.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | NASH Resolution and no Worsening of Fibrosis | Yes | 37 Participants |
| IVA337 1200mg | NASH Resolution and no Worsening of Fibrosis | No | 46 Participants |
| IVA337 800mg | NASH Resolution and no Worsening of Fibrosis | Yes | 27 Participants |
| IVA337 800mg | NASH Resolution and no Worsening of Fibrosis | No | 56 Participants |
| Placebo | NASH Resolution and no Worsening of Fibrosis | Yes | 15 Participants |
| Placebo | NASH Resolution and no Worsening of Fibrosis | No | 66 Participants |
Secondary
Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage
Resolution of NASH is defined as a CRN Inflammation score equel to 0 or 1, and a CRN ballooning score equal to 0. Improvement of firbosis is defined as a decrease of at least one stage in CRN Fibrosis score.
Time frame: From baseline to Week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | Yes | 26 Participants |
| IVA337 1200mg | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | No | 57 Participants |
| IVA337 800mg | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | Yes | 17 Participants |
| IVA337 800mg | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | No | 66 Participants |
| Placebo | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | Yes | 6 Participants |
| Placebo | Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | No | 75 Participants |
Secondary
Steatosis (CRN-S) Improvement
Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IVA337 1200mg | Steatosis (CRN-S) Improvement | Yes | 54 Participants |
| IVA337 1200mg | Steatosis (CRN-S) Improvement | No | 29 Participants |
| IVA337 800mg | Steatosis (CRN-S) Improvement | Yes | 46 Participants |
| IVA337 800mg | Steatosis (CRN-S) Improvement | No | 37 Participants |
| Placebo | Steatosis (CRN-S) Improvement | Yes | 21 Participants |
| Placebo | Steatosis (CRN-S) Improvement | No | 60 Participants |