Safety and Tolerability of Oral Proglumide for NASH

Study Overview
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Brief Summary
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This study is an open labelled Phase I/II clinical trial, designed to evaluate the safety and efficacy of an oral cholecystokinin (CCK) receptor antagonist, proglumide, at escalating doses in subjects with NASH. An extended use protocol has been approved for subjects completing this study that show benefit or are at risk of Liver disease progression to continue on Proglumide at 1200 mg / day for an additional 3-9 months. Subjects in the extended protocol will have telephone visits monthly and in the research unit every 3 months for safety lab tests and research blood for fibrosis analysis.

Detailed Description
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This is a Phase 1single ascending dose study in 18 patients with ultrasound evidence of fatty liver disease AND increased hepatic transaminases. Proglumide will be using the single ascending dose study design in a Phase 1 fashion to determine the recommended Phase 2 dose (RP2D). Dose levels of proglumide will be: 400mg BID (twice daily); 400 mg TID (three times daily); 800 mg BID (twice daily). Six patients will be enrolled in each cohort starting with the lowest dose of 400mg po BID (Twice daily)for 12 weeks. Patients will be monitored for safety and toxicity by laboratory blood testing, physical examinations. Blood level for proglumide will be done at before proglumide at screening or baseline, week 2 and then week 4 and week 12. Safety and toxicity will be monitored using the Common Terminology Criteria for Adverse Events v 5 and 'efficacy 'of the treatment will be evaluated by assessment of liver enzymes and fibroscan. The Phase 1 study design, we will follow the dose escalation scheme, where the dose increases after 6 subjects if a drug limiting toxicity (DLT) does not occur.

Official Title
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Phase 1 Study to Test Safety and Dose of Proglumide as an Anti-fibrotic Agent in Non-alcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Proglumide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ages 18 years to 85 with radiographic imaging (by ultrasound, MRI, or CT) of fatty liver disease AND elevation in serum transaminases (ALT or AST). AND one of the following: BMI>30, hyperlipidemia, or evidence of poorly controlled diabetes such as HgbA1C >7 Subjects on statins and with diabetes are eligible. Statins will be continued at the same dose for the duration of the study. Evidence of mild to moderate fibrosis on Fibroscan of F1 to F3 (kPa score < 14). Exclusion Criteria: Evidence of active alcohol use/abuse. Chronic viral hepatitis B or hepatitis C, autoimmune hepatitis, drug induced liver disease. Those with evidence of cirrhosis on exam, histologically, or imaging, and a history of liver cancer are excluded. Laboratory tests that warrant exclusion include: Leukocyte Count <3.5 K/UL; Hemoglobin <9.5 g/dL; Blood Urea Nitrogen >30 mg/dL (hydrated); Creatinine >2.0 mg/dL, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 5X ULN (upper limit normal), alkaline phosphatase (ALP)>2X ULN. Evidence of abnormal synthetic liver function including abnormal total bilirubin, platelet count <150,000 / mm3; and abnormal prothrombin time or increased INR (international normalized ratio) (unless on warfarin) History of gall bladder disease with gall bladder not surgically removed Estimated glomerular filtration rate (eGFR of < 90 mL/min/1.73m2 Type 1 diabetes mellitus Poorly controlled diabetes, defined by hemoglobin A1C (HbA1C) > 8, or diabetic patients that have not been on stable doses of anti-diabetic medication for at least 90 days prior to screening Pregnant or breast feeding A known preexisting medical or psychiatric condition that could interfere with the patient's ability to provide informed consent or participate in study conduct, or that may confound the study findings. Those found to have fibrosis score on Fibroscan of F0 or F4.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Sequential Assignment
Interventional Model Description: open labelled sequential Phase I ascending dose study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proglumide<br>Open labelled proglumide treated | Drug: Proglumide<br>* oral CCK receptor antagonist<br>* Other names: Milid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and toxicity | Number of participants with drug related Toxicity will follow standard Common Terminology Criteria for Adverse Events v.5,(CTCAE) criteria protocols. Toxicity is graded according to severity for symptoms obtained on the visit review of symptoms and according to blood tests collected at each scheduled visit | 12-weeks per dose | 
| Recommended Phase 2 dose | Of the 3 doses to be tested which one has the fewest Drug related toxicity | for each dose, the number of AEs described over the 12 week period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver transaminases | A decrease in the serum aminotransferases (ALT and AST) in IU by 10% or more | Comparison of baseline serum ALT and AST values to week 12 week values in IU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH