Safety and Tolerability of Oral Proglumide for NASH (STOPNASH)

Georgetown University

Status and phase

Completed

Phase 1

Conditions

Nonalcoholic Steatohepatitis

Treatments

Drug: Proglumide

Study type

Interventional

Funder types

Other

Identifiers

NCT04152473

0562

GU-3160 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

18 patients

Sex

All

Ages

18 to 85 years old

Volunteers

No Healthy Volunteers

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.