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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Number of NTZ Treated Participants Presenting Any Study Drug Related TEAE
研究概览
简要总结
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
详细描述
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®.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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:
- •Positive hepatitis B surface antigen (HBsAg)
- •Positive Hepatitis C virus (HCV) RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at Screening)
- •Suspicion of drug-induced liver disease
- •Alcoholic liver disease
- •Autoimmune hepatitis
- •Wilson's disease
- •Primary biliary cirrhosis, primary sclerosing cholangitis
- •Genetic homozygous hemochromatosis
- •Known or suspected Hepatocellular Carcinoma
- •History or planned liver transplant, or current Model for End-Stage Liver Disease score >
- •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).
研究组 & 干预措施
Open label NTZ
Open label. All patients will receive study drug
干预措施: Nitazoxanide 500mg BID (Drug)
结局指标
主要结局
Number of NTZ Treated Participants Presenting Any Study Drug Related TEAE
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Change in M30 Biomarker From Baseline to End of Treatment(24 weeks)
- Change in Liver Stiffness From Baseline to End of Treatment as Evaluated by FibroScan®(24 weeks)
- Change in Alpha-2 Macroglobulin From Baseline to Week 12(12 weeks)
- Percent Change in Alpha-2 Macroglobulin From Baseline to End of Treatment(24 weeks)
- Change in Fibroblast Growth Factor 19 From Baseline to Week 12(12 weeks)
- Change in Fibroblast Growth Factor 19 From Baseline to End of Treatment(24 weeks)
- Percent Change in Fibroblast Growth Factor 19 From Baseline to End of Treatment(24 weeks)
- Change in Fibroblast Growth Factor 21 From Baseline to Week 12(12 weeks)
- Change in Human Chitinase 3-like 1 From Baseline to Week 12(12 weeks)
- 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 Alpha-2 Macroglobulin From Baseline to Week 12(12 weeks)
- Change in Pro-C6 From Baseline to Week 12(12 weeks)
- 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(From baseline to end of treatment (Visit 10, Week 24 or early termination))
- Change in Controlled Attenuation Parameter (CAP) Score From Baseline to End of Treatment as Evaluated by FibroScan®(24 weeks)
- Percent Change in Controlled Attenuation Parameter (CAP) Score From Baseline to End of Treatment as Evaluated by FibroScan®(24 weeks)
- Change in Liver Stiffness From Baseline to Week 12 as Evaluated Through the Use Magnetic Resonance Elastography (MRE)(12 weeks)
- Change in Liver Stiffness From Baseline to End of Treatment as Evaluated Through the Use Magnetic Resonance Elastography (MRE)(24 weeks)
- Percent Change in Fibroblast Growth Factor 19 From Baseline to Week 12(12 weeks)
- Percent Change in Fibroblast Growth Factor 21 From Baseline to Week 12(12 weeks)
- Change in Fibroblast Growth Factor 21 From Baseline to End of Treatment(24 weeks)
- Percent Change in Fibroblast Growth Factor 21 From Baseline to End of Treatment(24 weeks)
- Change in Human Chitinase 3-like 1 From Baseline to End of Treatment(24 weeks)
- Percent Change in Hyaluronic Acid From Baseline to Week 12(12 weeks)
- Change in Hyaluronic Acid From Baseline to End of Treatment(24 weeks)
- Percent Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to Week 12(12 weeks)
- 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 Liver Stiffness From Baseline to End of Treatment as Evaluated Through the Use Magnetic Resonance Elastography (MRE)(24 weeks)
- Percent Change in Human Chitinase 3-like 1 From Baseline to Week 12(12 weeks)
- Percent Change in Human Chitinase 3-like 1 From Baseline to End of Treatment(24 weeks)
- Percent Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to End of Treatment(24 weeks)
- Change in M30 From Baseline to Week 12(12 weeks)
- Percent Change in M30 Biomarker From Baseline to Week 12(12 weeks)
- Change in miR34a Fold From Baseline to Week 12(12 weeks)
- Percent Change in Liver Stiffness From Baseline to End of Treatment as Evaluated by FibroScan®(24 weeks)
- Percent Change in Liver Stiffness From Baseline to Week 12 as Evaluated Through the Use Magnetic Resonance Elastography (MRE)(12 weeks)
- Change in Alpha-2 Macroglobulin From Baseline to End of Treatment(24 weeks)
- Change in Hyaluronic Acid From Baseline to Week 12(12 weeks)
- Percent Change in Hyaluronic Acid From Baseline to End of Treatment(24 weeks)
- Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to Week 12(12 weeks)
- Change in miR34a Fold From Baseline to End of Treatment(24 weeks)
- Change in Pro-C3 From Baseline to Week 12(12 weeks)
- Change in Pro-C3 From Baseline to End of Treatment(24 weeks)
- Percent Change in Pro-C6 From Baseline to End of Treatment(24 weeks)
- Change in Procollagen 3 N-terminal Pro-peptide From Baseline to Week 12(12 weeks)
- Percent Change in Pro-C3 From Baseline to Week 12(12 weeks)
- Change in Liver Fibrosis Score Enhanced Liver Fibrosis (ELF) From Baseline to End of Treatment(24 weeks)
- Percent Change in M30 Biomarker From Baseline to End of Treatment(24 weeks)
- Percent Change in M65 Biomarker From Baseline to Week 12(12 weeks)
- Percent Change in M65 Biomarker From Baseline to End of Treatment(24 weeks)
- Percent Change in miR34a Fold From Baseline to Week 12(12 weeks)
- Change in M65 Biomarker From Baseline to Week 12(12 weeks)
- Change in M65 Biomarker From Baseline to End of Treatment(24 weeks)
- Percent Change in miR34a Fold From Baseline to End of Treatment(24 weeks)
- Percent Change in Pro-C3 From Baseline to End of Treatment(24 weeks)
- Percent Change in Pro-C6 From Baseline to Week 12(12 weeks)
- Percent Change in Procollagen 3 N-terminal Pro-peptide From Baseline to Week 12(12 weeks)
- Percent Change in Procollagen 3 N-terminal Pro-peptide From Baseline to End of Treatment(24 weeks)
- Percent Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to Week 12(12 weeks)
- Percent Change in Fibrosis-4 Score From Baseline to Week 12(12 weeks)
- Change in Fibrosis-4 Score From Baseline to End of Treatment(24 weeks)
- Percent Change in Fibrosis-4 Score From Baseline to End of Treatment(24 weeks)
- Change in Pro-C6 From Baseline to End of Treatment(24 weeks)
- Change in Procollagen 3 N-terminal Pro-peptide From Baseline to End of Treatment(24 weeks)
- Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to Week 12(12 weeks)
- Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to End of Treatment(24 weeks)
- Percent Change in Tissue Inhibitor of Metalloproteinase 1 From Baseline to End of Treatment(24 weeks)
- Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to End of Treatment(24 weeks)
- Percent Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to End of Treatment(24 weeks)
- Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to Week 12(12 weeks)
- Percent Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score From Baseline to Week 12(12 weeks)
- Change in Fibrosis-4 Score From Baseline to Week 12(12 weeks)
研究者
Stephen A. Harrison
Principal Investigator
Pinnacle Clinical Research, PLLC