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

Phase 2

Completed

Conditions: Fatty Liver
Non-alcoholic Steatohepatitis
Fibrosis, Liver
Compensated Cirrhosis

Interventions: Drug: Nitazoxanide 500mg BID

Registration Number: NCT03656068

Lead Sponsor: Pinnacle Clinical Research, PLLC

Brief Summary: 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

Detailed Description: 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®.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Males or females aged from 18 to 75 years inclusive the Screening Visit.
Must provide signed written informed consent and agree to comply with the study protocol.
Females participating in this study must be of non-childbearing potential or using highly efficient contraception for the full duration of the study
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).
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).
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

History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study.
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.
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).
Weight loss of more than 10% within 6 months prior to Randomization.
Patient with any history or presence of decompensated cirrhosis.
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.
Current or history of other substance abuse within 1 year prior to screening.
Pregnant or lactating females or females planning to become pregnant during the study period.
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.
Patients who cannot be contacted in case of emergency.
Known hypersensitivity to the investigation product or any of its formulation excipients.
Patients who are taking warfarin or other highly plasma protein-bound drugs with narrow therapeutic indices.
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.
Evidence of any other unstable or, untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease.
Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
History of noncompliance with medical regimens, or patients who are considered to be unreliable.
Positive anti-human immunodeficiency virus (HIV) antibody.
AST and/or ALT >10 x upper limit of normal (ULN).
Total bilirubin >1.3 mg/dL due to altered hepatic function.
Direct bilirubin > ULN Note: Gilbert Disease patients are allowed into the study.
International Normalized Ratio >1.2 in the absence of anticoagulant therapy.
Platelet count <150,000/mm3 in the context of portal hypertension.
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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open label NTZ	Nitazoxanide 500mg BID	Open label. All patients will receive study drug

Primary Outcome Measures

Name	Time	Method
Number of NTZ Treated Participants Presenting Any Study Drug Related TEAE	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of study drug-related treatment-emergent adverse events (TEAEs).
Number of NTZ Treated Participants Presenting Any Study Drug-related AE Leading to Withdrawal From Study or Study Drug	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of study drug-related adverse events (AEs) leading to withdrawal from study or study drug
Number of NTZ Treated Participants Presenting at Least One Clinically Significant (CS) Change in Clinical Laboratory Evaluations	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by performing clinical laboratory evaluations. Changes in clinical laboratory evaluations were considered clinically significant or not as per Investigator judgment.
Number of NTZ Treated Participants Presenting Any SAE	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of serious adverse events (SAEs).
Number of NTZ Treated Participants Presenting Any Treatment Emergent Adverse Event (TEAE)	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of treatment-emergent adverse events (TEAEs).
Number of NTZ Treated Participants Presenting Study Drug-Related SAE	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of study drug-related serious adverse events (SAEs).
Deaths Due to AE	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of deaths due to adverse events (AEs).
Number of NTZ Treated Participants Presenting Any AE Leading to Withdrawal From Study or Study Drug	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by assessing the occurrence of adverse events (AEs) leading to withdrawal from study or study drug.
Number of NTZ Treated Participants Presenting at Least One Clinically Significant (CS) Change in Vital Signs	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by measuring vital signs. Changes in vital signs were considered clinically significant or not as per Investigator judgement
Number of NTZ Treated Participants Presenting at Least One Clinically Significant (CS) Change in Electrocardiogram Parameters	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by performing electrocardiograms (ECGs). Changes in ECGs parameters were considered clinically significant or not as per Investigator judgement.
Number of NTZ Treated Participants Presenting at Least One Clinically Significant (CS) Change in Physical Examinations	28 weeks	To assess the safety and tolerability of NTZ after 24 weeks of treatment by conducting physical examinations. Changes in physical examinations were considered clinically significant or not as per Investigator judgement.

Secondary Outcome Measures

Name	Time	Method
Change in Fibroblast Growth Factor 21 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Fibroblast Growth Factor 21 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Human Chitinase 3-like 1 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Hyaluronic Acid From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Hyaluronic Acid From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in M30 Biomarker From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Liver Stiffness From Baseline to End of Treatment as Evaluated by FibroScan®	24 weeks	FibroScan is a specialized ultrasound machine that measures fibrosis (scarring) and steatosis (fatty change) in the liver. It was required that each subject's FibroScan® assessments be done with the same type of probe at each study visit. The fibrosis result is measured in kilopascals (kPa) It's normally between 2 and 6 kPa indicating the abscence of abscence of fibrosis (F0) or a potential fibrosis of stage 1 (F1). The highest possible result is 75 kPa indicating advanced liver fibrosis of stage 4 (F4).
Change in Alpha-2 Macroglobulin From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Alpha-2 Macroglobulin From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Fibroblast Growth Factor 19 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Fibroblast Growth Factor 19 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Fibroblast Growth Factor 19 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Fibroblast Growth Factor 21 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Human Chitinase 3-like 1 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Lumican Fractional Synthesis Rate (FSR) From Baseline to End of Treatment	From baseline to end of treatment (Visit 10, Week 24 or early termination)	Percent Change in Lumican FSR from baseline to end of treatment evaluated through the use of deuterated water. Lumican is a marker indicative of hepatic fibrogenesis with its turnover assessed by Fractional Synthesis Rate (FSR). This innovative method of metabolic labelling is based on the concept that liver status could be determined by measuring the ratio of newly synthesized/pre-existing proteins. The turnover rate of newly synthesized collagen and proteins represents the hepatic fibrogenic disease activity. Patients were given "heavy water" to drink. Heavy water contains D20, deuterium being a stable isotope of hydrogen. Mass spectrometry was used to identify individual proteins and to quantify the ratio of labeled protein to total protein.
Percent Change in Alpha-2 Macroglobulin From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Transforming Growth Factor Beta-induced Protein (TGFBI) FSR From Baseline to End of Treatment	From baseline to end of treatment (Visit 10, Week 24 or early termination)	Change in transforming growth factor beta-induced-protein (TGFBI) Fractional Synthesis Rate (FSR) from baseline to end of treatment evaluated through the use of deuterated water. TGFBI is a marker indicative of hepatic fibrogenesis with its turnover assessed by FSR. This innovative method of metabolic labelling is based on the concept that liver status could be determined by measuring the ratio of newly synthesized/pre-existing proteins. The turnover rate of newly synthesized collagen and proteins represents the hepatic fibrogenic disease activity. Patients were given "heavy water" to drink. Heavy water contains D20, deuterium being a stable isotope of hydrogen. Mass spectrometry was used to identify individual proteins and to quantify the ratio of labeled protein to total protein. The results were expressed as FSR of these proteins.
Percent Change in Transforming Growth Factor Beta-induced Protein (TGFBI) FSR From Baseline to End of Treatment	From baseline to end of treatment (Visit 10, Week 24 or early termination)	Percent Change in transforming growth factor beta-induced protein (TGFBI) FSR from baseline to end of treatment evaluated through the use of deuterated water. TGFBI is a marker indicative of hepatic fibrogenesis with its turnover assessed by Fractional Synthesis Rate (FSR). This innovative method of metabolic labelling is based on the concept that liver status could be determined by measuring the ratio of newly synthesized/pre-existing proteins. The turnover rate of newly synthesized collagen and proteins represents the hepatic fibrogenic disease activity. Patients were given "heavy water" to drink. Heavy water contains D20, deuterium being a stable isotope of hydrogen. Mass spectrometry was used to identify individual proteins and to quantify the ratio of labeled protein to total protein. The results were expressed as FSR of these proteins.
Change in Controlled Attenuation Parameter (CAP) Score From Baseline to End of Treatment as Evaluated by FibroScan®	24 weeks	FibroScan is a specialized ultrasound machine that measures fibrosis (scarring) and steatosis (fatty change) in the liver. It was required that each subject's FibroScan® assessments be done with the same type of probe at each study visit. The CAP score is a measurement of fatty change in the liver, naming the steatosis grade. The CAP score is measured in decibels per meter (dB/m). It ranges from 100 to 400 dB/m. 100 to 237 dB/M indicates no hepatic steatosis, 238 to 260 dB/m indicates mild hepatic steatosis (steatosis S1), 260 to 290 dB/m indicates moderate steatosis (steatosis S2), and a CAP score greater than 290 dB/m indicates severe steatosis (steatosis S3).
Percent Change in Controlled Attenuation Parameter (CAP) Score From Baseline to End of Treatment as Evaluated by FibroScan®	24 weeks	FibroScan is a specialized ultrasound machine that measures fibrosis (scarring) and steatosis (fatty change) in the liver. It was required that each subject's FibroScan® assessments be done with the same type of probe at each study visit. The CAP score is a measurement of fatty change in the liver, naming the steatosis grade.The CAP score is measured in decibels per meter (dB/m). It ranges from 100 to 400 dB/m. 100 to 237 dB/M indicates no hepatic steatosis, 238 to 260 dB/m indicates mild hepatic steatosis (steatosis S1), 260 to 290 dB/m indicates moderate steatosis (steatosis S2), and a CAP score greater than 290 dB/m indicates severe steatosis (steatosis S3).
Change in Liver Stiffness From Baseline to Week 12 as Evaluated Through the Use Magnetic Resonance Elastography (MRE)	12 weeks	Liver stiffness was assessed by MRE. It was recommended that each subject's radiological assessment was performed using the same procedure for each study visit.
Change in Liver Stiffness From Baseline to End of Treatment as Evaluated Through the Use Magnetic Resonance Elastography (MRE)	24 weeks	Liver stiffness was assessed by MRE. It was recommended that each subject's radiological assessment was performed using the same procedure for each study visit.
Percent Change in Fibroblast Growth Factor 19 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Fibroblast Growth Factor 21 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples. ELF score is a continuous (not a categorical) variable with \< 9.8 indicative of low risk of progression to cirrhosis and \>=9.8 to \>11.3 indicative of mid-risk and \>=11.30 indicative of higher risk.
Change in Lumican Fractional Synthesis Rate (FSR) From Baseline to End of Treatment	From baseline to end of treatment (Visit 10, Week 24 or early termination)	Change in Lumican Fractional Synthesis Rate (FSR) from baseline to end of treatment evaluated through the use of deuterated water. Lumican is a marker indicative of hepatic fibrogenesis with its turnover assessed by Fractional Synthesis Rate (FSR). This innovative method of metabolic labelling is based on the concept that liver status could be determined by measuring the ratio of newly synthesized/pre-existing proteins. The turnover rate of newly synthesized collagen and proteins represents the hepatic fibrogenic disease activity. Patients were given "heavy water" to drink. Heavy water contains D20, deuterium being a stable isotope of hydrogen. Mass spectrometry was used to identify individual proteins and to quantify the ratio of labeled protein to total protein.
Percent Change in Liver Stiffness From Baseline to End of Treatment as Evaluated Through the Use Magnetic Resonance Elastography (MRE)	24 weeks	Liver stiffness was assessed by MRE. It was recommended that each subject's radiological assessment was performed using the same procedure for each study visit.
Percent Change in Human Chitinase 3-like 1 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Human Chitinase 3-like 1 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples. ELF score is a continuous (not a categorical) variable with \< 9.8 indicative of low risk of progression to cirrhosis and \>=9.8 to \>11.3 indicative of mid-risk and \>=11.30 indicative of higher risk.
Change in M30 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in M30 Biomarker From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in miR34a Fold From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Liver Stiffness From Baseline to End of Treatment as Evaluated by FibroScan®	24 weeks	FibroScan is a specialized ultrasound machine that measures fibrosis (scarring) and steatosis (fatty change) in the liver. It was required that each subject's FibroScan® assessments be done with the same type of probe at each study visit. The fibrosis result is measured in kilopascals (kPa) It's normally between 2 and 6 kPa indicating the abscence of abscence of fibrosis (F0) or a potential fibrosis of stage 1 (F1). The highest possible result is 75 kPa indicating advanced liver fibrosis of stage 4 (F4).
Percent Change in Liver Stiffness From Baseline to Week 12 as Evaluated Through the Use Magnetic Resonance Elastography (MRE)	12 weeks	Liver stiffness was assessed by MRE. It was recommended that each subject's radiological assessment was performed using the same procedure for each study visit.
Change in Alpha-2 Macroglobulin From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Hyaluronic Acid From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Hyaluronic Acid From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples. ELF score is a continuous (not a categorical) variable with \< 9.8 indicative of low risk of progression to cirrhosis and \>=9.8 to \>11.3 indicative of mid-risk and \>=11.30 indicative of higher risk
Change in miR34a Fold From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Pro-C3 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Pro-C3 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Pro-C6 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Pro-C6 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Procollagen 3 N-terminal Pro-peptide From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in M65 Biomarker From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in miR34a Fold From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples. ELF score is a continuous (not a categorical) variable with \< 9.8 indicative of low risk of progression to cirrhosis and \>=9.8 to \>11.3 indicative of mid-risk and \>=11.30 indicative of higher risk.
Percent Change in M30 Biomarker From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in M65 Biomarker From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in M65 Biomarker From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in M65 Biomarker From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in miR34a Fold From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Pro-C3 From Baseline to Week 12	12 weeks	The Full Analysis Set consisted of all patients who met the eligibility criteria and enrolled into the study (Visit 1 Day 1).
Percent Change in Pro-C3 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Pro-C6 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Procollagen 3 N-terminal Pro-peptide From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Procollagen 3 N-terminal Pro-peptide From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Fibrosis-4 Score From Baseline to Week 12	12 weeks	Fibrosis-4 score : FIB4 \< 1.3 is not consistent with F3-F6 disease. FIB4 of 1.3 to \<2.67 is indeterminate for F3-F6 disease. \> 2.67 is consistent F3 to F6.
Change in Fibrosis-4 Score From Baseline to End of Treatment	24 weeks	Fibrosis-4 score : FIB4 \< 1.3 is not consistent with F3-F6 disease. FIB4 of 1.3 to \<2.67 is indeterminate for F3-F6 disease. \> 2.67 is consistent F3 to F6.
Percent Change in Fibrosis-4 Score From Baseline to End of Treatment	24 weeks	Fibrosis-4 score : FIB4 \< 1.3 is not consistent with F3-F6 disease. FIB4 of 1.3 to \<2.67 is indeterminate for F3-F6 disease. \> 2.67 is consistent F3 to F6.
Change in Pro-C6 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Procollagen 3 N-terminal Pro-peptide From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to Week 12	12 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Percent Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to End of Treatment	24 weeks	Non-invasive Fibrosis Biomarkers were assessed in blood samples.
Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to End of Treatment	24 weeks	NAFLD NFS : \< -1.5 for low probability of fibrosis, \> -1.5 to \< 0.67 for intermediate probability of fibrosis, and \> 0.67 for high probability of fibrosis.
Percent Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to End of Treatment	24 weeks	NAFLD NFS : \< -1.5 for low probability of fibrosis, \> -1.5 to \< 0.67 for intermediate probability of fibrosis, and \> 0.67 for high probability of fibrosis.
Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to Week 12	12 weeks	NAFLD NFS : \< -1.5 for low probability of fibrosis, \> -1.5 to \< 0.67 for intermediate probability of fibrosis, and \> 0.67 for high probability of fibrosis.
Percent Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to Week 12	12 weeks	NAFLD NFS : \< -1.5 for low probability of fibrosis, \> -1.5 to \< 0.67 for intermediate probability of fibrosis, and \> 0.67 for high probability of fibrosis.
Change in Fibrosis-4 Score From Baseline to Week 12	12 weeks	Fibrosis-4 score : FIB4 \< 1.3 is not consistent with F3-F6 disease. FIB4 of 1.3 to \<2.67 is indeterminate for F3-F6 disease. \> 2.67 is consistent F3 to F6.