An Evaluation of the Safety and Efficacy of Nitazoxanide on Collagen Turnover in NASH Patients With Fibrosis

A Monocentric, Open-Label, Proof of Concept Study to Evaluate the Safety and Efficacy of Nitazoxanide at 500mg Twice Daily on Collagen Turnover in Plasma in NASH Patients With Fibrosis Stage 2 or 3

To evaluate the safety and tolerability of Nitazoxanide (NTZ) 500mg Twice Daily (BID) after 24 weeks of treatment in patients with NASH induced Stage 2 or Stage 3 fibrosis

Based on the anti-fibrotic properties demonstrated in the animal models of fibrosis, this proof of concept clinical study aims at evaluating NTZ in patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage 2 and 3. Although NTZ has been evaluated in liver disease populations up to 60 weeks, this is the first study evaluating NTZ treatment in a population with NASH induced stage 2 and 3 fibrosis. The aim of this study is to evaluate the safety and tolerability of NTZ 500 mg BID after 24 weeks of treatment in this population.

This proof of concept study will also evaluate the anti-fibrotic effect of NTZ as a secondary objective.

The methods of evaluation of fibrosis will include an innovative method of metabolic labeling.This approach is based on the concept that liver status can be determined by measuring the ratio of newly synthesized/pre-existing proteins.The turn-over rate of newly synthesized collagen and proteins represents the hepatic fibrogenic disease activity. Patients will be given "heavy water" to drink. Heavy water contains D20, deuterium being a stable isotope of hydrogen. Mass spectrometry is used to identify individual proteins and to quantify the ratio of labeled protein to total protein. The results are expressed as fractional synthesis rate of these proteins (FSR). This method has been previously published (Decaris et al, 2017).

Other non-invasive methods will be used to evaluate the liver stiffness changes after NTZ treatment: Magnetic Resonance Elastography (MRE) and FibroScan®.

Inclusion Criteria:

1. Males or females aged from 18 to 75 years inclusive the Screening Visit.
2. Must provide signed written informed consent and agree to comply with the study protocol.
3. Females participating in this study must be of non-childbearing potential or using highly efficient contraception for the full duration of the study
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
5. Fibrosis stage of 2 or 3, according to the NASH Clinical Research Network fibrosis staging system on a diagnostic liver biopsy (biopsy obtained within 6 months prior to Screening or during the Screening Period).
6. Two assessments of ALT, AST, Total bilirubin, Alkaline phosphatase (ALP), Creatine phosphokinase (CPK) will be collected during screening at least 4 weeks apart. To be eligible the second value cannot be ≥2x the first value.

Exclusion Criteria:

1. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study.

2. Patients with HbA1c >10.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be repeated. A repeated abnormal HbA1c (HbA1c >10.0%) leads to exclusion.

3. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization procedures).

4. Weight loss of more than 10% within 6 months prior to Randomization.

5. Patient with any history or presence of decompensated cirrhosis.

6. Current or recent history (<1 year) of significant alcohol consumption. For men, significant consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically defined as higher than 20 g pure alcohol per day.

7. Current or history of other substance abuse within 1 year prior to screening.

8. Pregnant or lactating females or females planning to become pregnant during the study period.

9. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to:

   1. Positive hepatitis B surface antigen (HBsAg)
   2. Positive Hepatitis C virus (HCV) RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at Screening)
   3. Suspicion of drug-induced liver disease
   4. Alcoholic liver disease
   5. Autoimmune hepatitis
   6. Wilson's disease
   7. Primary biliary cirrhosis, primary sclerosing cholangitis
   8. Genetic homozygous hemochromatosis
   9. Known or suspected Hepatocellular Carcinoma
   10. History or planned liver transplant, or current Model for End-Stage Liver Disease score >15.

10. Patients who cannot be contacted in case of emergency.

11. Known hypersensitivity to the investigation product or any of its formulation excipients.

12. Patients who are taking warfarin or other highly plasma protein-bound drugs with narrow therapeutic indices.

13. Patients who are currently participating in, plan to participate in, or have participated in an investigational drug trial or medical device trial containing active substance within 30 days or five half-lives, whichever is longer, prior to Screening.

14. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease.

15. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.

16. History of noncompliance with medical regimens, or patients who are considered to be unreliable.

17. Positive anti-human immunodeficiency virus (HIV) antibody.

18. AST and/or ALT >10 x upper limit of normal (ULN).

19. Total bilirubin >1.3 mg/dL due to altered hepatic function.

20. Direct bilirubin > ULN Note: Gilbert Disease patients are allowed into the study.

21. International Normalized Ratio >1.2 in the absence of anticoagulant therapy.

22. Platelet count <150,000/mm3 in the context of portal hypertension.

23. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate of less than 60 ml/min/1.73 m2).