A Pilot, Dose Escalating Study on VLX103 in Moderate Alcoholic Steatohepatitis

NCT03201159 | Withdrawn Phase 1 DMC FDA Drug

• 3 other identifiers: H00011711VLX103-ASH-16-01U01AA021893
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The study drug (VLX103) is being developed for the treatment of Alcoholic Steatohepatitis and other liver diseases. Alcoholic Steatohepatitis is an inflammatory (associated with irritation, swelling and cell damage) disease that affects the liver. It is associated with heavy and chronic intake of alcohol and presence of fat in the liver. Signs and symptoms often include fever, yellowing of the skin, nausea and impairment of liver function. The main objective of this study is to evaluate the safety, pharmacodynamics (what the drug does to the body) and pharmacokinetics (how the drug is handled by the human body, like absorption and elimination) of increasing doses of VLX103 in subjects with moderate Alcoholic Steatohepatitis. In other words, we will evaluate how your body tolerates VLX103 at a specific dose and the effects that this VLX103 dose has on your liver and your body in general. The secondary objectives of this study are to evaluate if VLX103 has the potential to treat Alcoholic Steatohepatitis patients, to determine the maximum dose that can be tolerated, and to measure the levels of VLX103 in your blood at different time points during the study. VLX103 is an experimental drug. Experimental means that the drug has not been approved by the Food and Drug Administration (FDA) for the treatment of Alcoholic Steatohepatitis. The active ingredient in VLX103, pentamidine, is approved for treating parasitic (microorganisms) infections. Pentamidine is currently approved and marketed in about 20 countries, including the United States, for use by injection (administered by a syringe) and by inhalation (administered by a nebulizer) for other health conditions. However, VLX103 is the first oral form of pentamidine being developed, and is administered by mouth as an oral tablet.

Conditions

Hepatic Steatosis

Keywords

ASH

Outcome Measures

Primary Outcomes (2)

• Frequencies of subjects experiencing at least one adverse event will be displayed by body system and preferred term according to MedDRA terminology

  Summary tables will present the number of subjects observed with adverse events and cooresponding percentages. The incidence of adverse events will be summarized by treatment group.

  90 days

• Distribution of laboratory measures over time will be prepared

  Listing and summary tables will be prepared for laboratory measures and will be structured to allow review of data by test as the dose is increased

  90 days

Secondary Outcomes (3)

• Preliminary efficacy of VLX103 in the target patient population

  7 days and 14 days

• Maximum Tolerated Dose of VLX103 in moderate ASH patients

  14 days

• To establish further the hepatoselectivity of VLX103 following up to 14 days of repeated oral administration, through the assessment of systemic drug exposure (serum levels) at selected time points.

  14 days

Study Arms (3)

VLX103 150mg

EXPERIMENTAL

In the first group, 150 mg dosing cohort, one VLX103 tablet will be administered daily for 14 days.

Drug: VLX103

VLX103 300mg

EXPERIMENTAL

In the second group, 300 mg dosing cohort, two VLX103 tablets will be administered daily for 14 days.

Drug: VLX103

VLX103 450mg

EXPERIMENTAL

In the third group, 450 mg dosing cohort, three VLX103 tablets will be administered daily for 14 days.

Drug: VLX103

Interventions

VLX103 DRUG

150mg tablets

Also known as: Pentamidine Isethionate

VLX103 150mg; VLX103 300mg; VLX103 450mg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and non pregnant female subjects; female subjects must use 2 reliable methods of contraception
• years
• BMI less than 30 mg/kg2
• Established diagnosis of Alcoholic Steatohepatitis (ASH), based on at least 2 of the following signs and symptoms should be present: nausea, jaundice, anorexia, right upper quadrant abdominal pain, leukocytosis or hepatomegaly AND
• Elevation of total bilirubin \> 3 mg/dL AND
• Liver biopsy showing ASH OR ultrasound of liver showing increased echogenicity OR CT scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images) History of chronic alcohol consumption, i.e. more than 50 g/day for a minimum of 6 months and at least 2 months before enrolment
• AST/ALT ratio greater than 1.5
• MELD score between 12 and 19
• Signature of a dated Informed Consent Form (ICF) indicating that the subject has been informed of all the relevant aspects of the trial prior to enrolment Willingness and ability to comply with scheduled visits and trial procedures

You may not qualify if:

• Liver disease caused by other etiologies than alcohol (except Hepatitis C and hemochromatosis)
• Baseline ALT ≥ 200 IU/L
• Baseline AST ≥ 500 IU/L
• Presence of portosystemic encephalopathy at enrolment
• Presence of cancer at enrolment
• Presence of uncontrolled diabetes, defined as Hb1Ac ≥ 8.5
• History of clinically significant hypoglycaemia, with fasting blood glucose \< 3 mmol/L within 3 months prior to enrolment
• Presence of clinically significant renal impairment, defined as serum creatinine ≥ 2.0 x ULN
• Hypotension with BP \< 80/50 mm Hg after volume repletion
• Current or recent (2 years) history or presence of pancreatitis
• History of Long QT Syndrome or any significant risk factor for clinically meaningful QT prolongation and Torsades de Pointe.
• History of significant gastrointestinal surgery that may interfere with the absorption of VLX103
• Previous treatment with corticosteroids or other immunosuppressive drugs including specific anti-TNF alpha therapy and calcineurin inhibitors within the previous 3 months. Inhaled steroids for asthma are acceptable as long as their use has not been initiated less than 10 days prior to enrolment and their dosing regimen remain stable during the study
• Concomitant therapy with probiotics, oral neomycin or polymyxin B, rifaximin or other investigational agents or participation in another clinical trial within 3 months of signature of ICF
• Previous use of pentamidine with treatment discontinuation of less than 12 months prior to study enrolment

Sponsors & Collaborators

• Gyongyi Szabo: lead
• The Cleveland Clinic: collaborator
• University of Texas Southwestern Medical Center: collaborator
• University of Louisville: collaborator
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator

Study Sites (1)

UMass Medical School

Worcester, Massachusetts, 01605, United States

Location

MeSH Terms

Conditions

Fatty Liver

Interventions

Pentamidine

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Benzamidines; Amidines; Organic Chemicals

Study Officials

• Gyongyi Szabo, MD, PhD

  UMass Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a dose escalating Phase Ib study, in which up to 3 doses of VLX103 will be assessed for safety, pharmacodynamics and pharmacokinetics in separate patient cohorts receiving sequentially increasing doses of VLX103. A maximum of 18 well-defined moderate ASH patients will be enrolled and treated in the study, i.e. 6 per dosing cohort.

Study Record Dates

• First Submitted: March 24, 2017
• First Posted: June 28, 2017
• Study Start: June 25, 2017
• Primary Completion: February 27, 2018
• Study Completion: February 27, 2018
• Last Updated: May 30, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)