Evaluating the Efficacy and Safety of Roflumilast in Patients with NASH

Efficacy and Safety of Roflumilast in Patients with Non-Alcoholic Steatohepatitis

Study type :clinical trial Main purpose :esnsure safety and efficacy of Roflumilast to treat patients with Non-Alcoholic Steatohepatitis Background and aim: Non-alcoholic fatty liver disease is the most prevalent chronic liver disease globally. There is no defined therapy for non-alcholic steatohepatitis (NASH), therefore this study aimed at evaluating the efficacy and safety of Roflumilast in patients with non-alcoholic NASH.

Methods: This randomized controlled parallel study involved 55 patients with NASH who were randomized into vitamin E group or control group (n=24) which received vitamin E 1000 mg once daily and roflumilast group (n=31) which received roflumilast 500 μg once daily for three months.

Patients were assessed at baseline and after intervention through liver stiffness measurement (LSM) using fibro-scan and through evaluation of serum levels of tumor necrosis factor -alpha (TNF-α), Malondialdehyde (MDA), transforming growth factor-beta 1 (TGF-ß1). In addition, liver enzymes, lipid panel, fasting blood glucose and fasting insulin level with subsequent calculation of the homeostatic model assessment for Insulin resistance (HOMA-IR) were also assessed.

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: Roflumilast 500 Mcg Oral Tablet; Drug: Vitamin E capsule

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Gharbia
    • Tanta, Gharbia, Egypt, 6620010
      • Tanta University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with Cytokeratine level >240 IU/L.
• Adult patient (age > 18 years old).
• Both sex.
• Overweight and obese.
• Patients with evidence of steatosis through imaging.
• Patient with mild to moderate elevation in aminotransferase activity (>2 ,but <5 times upper limit of normal ).
• Patient with Hepatic steatosis index (HSI) > 36.
• Patient with HAIR ( hypertension ,alanine aminotransferase level ,insulin resistance ) of 2 or 3.
• Fibroscan score >7Kpa and < 12.5 Kpa (F2 - F3).

Exclusion Criteria:

• Alcohol consumer and smokers
• Patients with Wilson's disease and hemochromatosis .
• Patients with viral hepatitis.
• Patients with cirrhosis .
• Patients with inflammatory diseases .
• Patients with other comorbid disease that elevate transaminases (congestive heart failure and malignancy).
• Patients on medications that interfere with lipid and carbohydrate metabolism..
• Patients on stateogenic medications.
• Pregnancy and lactating women.
• Females on oral contraceptive pills.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Roflumilast group (n=31); Arm Description: Roflumilast group (n=31) which received roflumilast 500 μg once daily for three months. Patients were assessed at baseline and after intervention through liver stiffness measurement (LSM) using fibro-scan and through evaluation of serum levels of tumor necrosis factor -alpha (TNF-α), Malondialdehyde (MDA), transforming growth factor-beta 1 (TGF-ß1). In addition, liver enzymes, lipid panel, fasting blood glucose and fasting insulin level with subsequent calculation of homeostatic model assessment for Insulin resistance (HOMA-IR) were also assessed.	Drug: Roflumilast 500 Mcg Oral Tablet; Patients in this group received roflumilast 500 μg once daily for three months.
Active Comparator: Vitamin E group or control group (n=24); vitamin E group or control group (n=24) which received vitamin E 1000 mg once daily. Patients were assessed at baseline and after intervention through liver stiffness measurement (LSM) using fibro-scan and through evaluation of serum levels of tumor necrosis factor -alpha (TNF-α), Malondialdehyde (MDA), transforming growth factor-beta 1 (TGF-ß1). In addition, liver enzymes, lipid panel, fasting blood glucose and fasting insulin level with subsequent calculation of homeostatic model assessment for Insulin resistance (HOMA-IR) were also assessed.	Drug: Vitamin E capsule; vitamin E group or control group (n=24) which received vitamin E 1000 mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver stiffness measurement (LSM) measured by fibroscan score	Liver Stiffness measurement (LSM) by fibro-scan. Transient elastography (Fibroscan, Echosens, Paris) was used to assess liver stiffness depending up-on the method formerly prescribed .Through a single independent operator, at least ten valid measurements were obtained for each patient. Results were included in the final analysis only if the following three criteria were met: at least ten valid measurements, success rate >60% and the interquartile range (IQR)-to-liver stiffness ratio was ≤0.30. The median values of the validated measurements for each patient were representative to the liver stiffness and expressed in units of kilopascals (kPa)	12 weeks following the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in liver panel parameters	Blood sample collection and biochemical measurement of Approximately 10 ml of venous blood was taken from each patient after overnight fasting by sterile venipuncture, without frothing and after minimal venous stasis using disposable syringes. Blood samples were delivered in a vacutainer serum separator tubes. Immediate centrifugation at 3000 rpm was performed and then the serum was separated and divided into two portions. The first portion was used for determination of fasting blood glucose (glucose oxidase method), liver enzymes aspartate transaminase "AST", alanine transaminase "ALT" and gamma-glutamyl transaminase "GGT" (spectrophotometerially) and lipid panel (enzymatic colorimeteric method).	3 months after treatment
Improvement in HOMA IR	HOMA-IR is calculated as [Fasting Insulin (μg/ml)]*[Fasting Glucose (mmol/l)]/22.5,HOMA-IR values between 0.5 and 1.4 are considered normal, ≥1.9 are indicative of early IR, and ≥2.9 indicate IR	12 weeks following the end of treatment

Collaborators and Investigators

• Sponsor: Tanta University
• Investigators: Study Chair: Tarek Mohamed Mostafa, Professor of clinical pharmacy, Faculty of Pharmacy , Tanta University, Tanta, Egypt

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Actual): September 20, 2024
• Study Completion (Actual): October 15, 2024

Study Registration Dates

• First Submitted: November 1, 2024
• First Submitted That Met QC Criteria: November 6, 2024
• First Posted (Estimated): November 7, 2024

Study Record Updates

• Last Update Posted (Estimated): November 7, 2024
• Last Update Submitted That Met QC Criteria: November 6, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: NASH; MDA; Roflumilast; TNF-α; LSM; TGF-ß1
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Antioxidants; Protective Agents; Vitamins; Vitamin E
• Other Study ID Numbers: 35336/3/22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in non alcoholic steatohepatitis. Data or samples shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact Mokhtaarsalem@gmail.com
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes