Safety and Tolerability of Oral Proglumide for NASH (STOPNASH)

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

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.

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Proglumide

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
    • Washington, District of Columbia, United States, 20422
      • Washington DC Veterans Affairs Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Proglumide; Open labelled proglumide treated	Drug: Proglumide; oral CCK receptor antagonist; Other Names: Milid

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
NASH score by Fibroscan	liver stiffness kPa score with a decrease by 4kPa and steatosis (CAPS) score in dB/m. a decline of 30 dB/m	baseline compared to week 12

Collaborators and Investigators

• Sponsor: Georgetown University

Publications and helpful links

General Publications

• Tucker RD, Ciofoaia V, Nadella S, Gay MD, Cao H, Huber M, Safronenka A, Shivapurkar N, Kallakury B, Kruger AJ, Kroemer AHK, Smith JP. A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma. Dig Dis Sci. 2020 Jan;65(1):189-203. doi: 10.1007/s10620-019-05722-3. Epub 2019 Jul 11.
• Rabiee A, Gay MD, Shivapurkar N, Cao H, Nadella S, Smith CI, Lewis JH, Bansal S, Cheema A, Kwagyan J, Smith JP. Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non-alcoholic Steatohepatitis. Clin Pharmacol Ther. 2022 Dec;112(6):1271-1279. doi: 10.1002/cpt.2745. Epub 2022 Sep 27.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2019
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): September 9, 2022

Study Registration Dates

• First Submitted: October 20, 2019
• First Submitted That Met QC Criteria: November 1, 2019
• First Posted (Actual): November 5, 2019

Study Record Updates

• Last Update Posted (Actual): October 13, 2022
• Last Update Submitted That Met QC Criteria: October 10, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Gastrointestinal Agents; Anti-Ulcer Agents; Proglumide
• Other Study ID Numbers: 0562; GU-3160 (Other Identifier: Georgetown University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The data will be uploaded on the clinical trials website at the conclusion of the study and after accepted for publication
• IPD Sharing Time Frame: After the publication at the completion of the study
• IPD Sharing Access Criteria: Available on clinicaltrials.gov website for 1 year after publication
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No