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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03656068
Recruitment Status : Recruiting
First Posted : September 3, 2018
Last Update Posted : January 3, 2019
Information provided by (Responsible Party):
Stephen A. Harrison, Pinnacle Clinical Research, PLLC

Brief Summary:
To evaluate the safety and tolerability of NTZ 500mg bid after 24 weeks of treatment in patients with NASH induced Stage 2 or Stage 3 fibrosis

Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis Fatty Liver Fibrosis, Liver Compensated Cirrhosis Drug: Nitazoxanide 500mg BID Phase 2

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 (viral hepatitis C) 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®.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Monocentric, Open-Label, Proof of Concept Study to Evaluate the Safety and Efficacy of NTZ at 500mg Twice Daily on Collagen Turnover in Plasma in NASH Patients With Fibrosis Stage 2 or 3
Actual Study Start Date : December 15, 2018
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : October 2020

Arm Intervention/treatment
Experimental: Open label NTZ
Open label study. All patients will receive study drug.
Drug: Nitazoxanide 500mg BID
Patients will receive 500mg of Nitazoxanide BID daily for 24 weeks

Primary Outcome Measures :
  1. Number of participants with treatment related adverse events and serious adverse events [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. Percent change in Fractional Synthesis Rate (FSR) from baseline to end of treatment evaluated through the use of deuterated water. [ Time Frame: 24 weeks ]
  2. Change in liver stiffness from baseline to end or treatment as evaluated by FibroScan® [ Time Frame: 24 weeks ]
    Range of FibroScan scores 0-75

  3. Change in liver stiffness from baseline to end of treatment as evaluated through the use Magnetic Resonance Elastography (MRE) [ Time Frame: 24 weeks ]
    kPa values (1-10) will be measured

  4. Change in FIB4 (fibrosis serum biomarker) at baseline to 12 weeks treatment and 24 weeks of treatment [ Time Frame: 24 weeks ]
    Score range 1-4, to determine fibrosis

  5. Change in Fibrotest (biomarker test) results at baseline to 12 weeks to 24 weeks [ Time Frame: 24 weeks ]
    Serum blood test, to determine fibrosis

  6. Change in NAFLD Fibrosis Score at baseline to 12 weeks to 24 weeks [ Time Frame: 24 weeks ]
    Calculated based on age, BMI, AST, ALT, Platelets and Albumin values to determine fibrosis

  7. Change in Fibrometer results at baseline to 12 weeks to 24 weeks to determine fibrosis [ Time Frame: 24 weeks ]
    Family of blood tests

  8. Change in HepaScore results at baseline to 12 weeks to 24 weeks [ Time Frame: 24 weeks ]
    Liver fibrosis blood panel

  9. Change in Enhanced Liver Fibrosis (ELF) Score (ELFTM) at baseline to 12 weeks to 24 weeks [ Time Frame: 24 weeks ]
    Combination of three serum biomarkers to obtain level of fibrosis of liver

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 CRN fibrosis staging system on a diagnostic liver biopsy (biopsy obtained within 6 months prior to Screening or during the Screening Period).

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 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 HCC
    10. History or planned liver transplant, or current MELD 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. Conjugated bilirubin >2.0 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are allowed into the study.
  20. INR >1.50 due to altered hepatic function.
  21. Platelet count <100,000/mm3 due to portal hypertension.
  22. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03656068

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Contact: Gail Hinkson 210-982-0320
Contact: Sandra Owers 210-982-0320

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United States, Texas
Pinnacle Clinical Research Recruiting
San Antonio, Texas, United States, 78229
Contact: Sandra Owers    210-982-0320      
Principal Investigator: Stephen Harrison, MD         
Sponsors and Collaborators
Pinnacle Clinical Research, PLLC
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Principal Investigator: Stephen Harrison, MD Pinnacle Clinical Research

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Responsible Party: Stephen A. Harrison, Principal Investigator, Pinnacle Clinical Research, PLLC Identifier: NCT03656068     History of Changes
Other Study ID Numbers: NTZ-218-1
First Posted: September 3, 2018    Key Record Dates
Last Update Posted: January 3, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Antiparasitic Agents
Anti-Infective Agents