Cysteine-lowering Treatment With Mesna (CYLOB)

Cysteine-lowering Treatment With Mesna Against Obesity: Phase I Dose-finding Study

The primary objective of this study is to determine the efficacy of the drug Mesna® (Uromitexan) in healthy participants with overweight or obesity with respect to change in plasma concentrations of total cysteine, following single ascending doses of oral Mesna.

Study Overview

• Status: Completed
• Conditions: Obesity; Drug Effect
• Intervention / Treatment: Drug: Mesna

Detailed Description

In both animal experiments and human studies, cysteine in the blood is strongly associated with obesity. In rodents, changes in cysteine induced by dietary means are accompanied by changes in fat mass.

In this phase I, single ascending dose study the investigators will determine the effects of Mesna in healthy volunteers with overweight and obesity with focus on its effects on plasma total cysteine concentrations. The aim of this dose-finding clinical trial is to determine the lowest single oral Mesna dose that will lower plasma total cysteine concentrations by 30% using pharmacokinetic (PK)/ pharmacodynamic (PD) modelling. The investigators will further evaluate the effect of Mesna on plasma cysteine fractions and related metabolites, urinary cysteine excretion, safety and adverse drug reactions, and plasma biomarkers.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway
    • University of Oslo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• BMI between BMI 27-40 kg/m2
• Age between 18-55 years
• Male
• Healthy as determined by medical evaluation, medical history, physical examination, 12-lead ECG, and laboratory tests

Exclusion Criteria:

• Presence of chronic disease
• Chronic drug use
• Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing
• Veganism
• Strenuous physical activity ≥3 times every week
• Smoking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mesna; Administration of a single oral dose of 400 mg, 800 mg, 1200 mg or 1600 mg	Drug: Mesna; Administration of a single oral dose, using film-coated tablets of either 400 mg or 600 mg or a combination of maximum 3 tablets up to a maximum of 1600 mg; Other Names: Uromitexan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma total cysteine concentrations following single ascending doses of oral Mesna.	Nadir plasma total cysteine concentrations	Several intervals during the first 12 hours after Mensa administration, and a fasting sample on days 2 and 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter - maximum plasma concentration (Cmax)	Maximum plasma Mesna concentration (Cmax) after a single oral Mesna dose	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Pharmacokinetic parameter - time to maximum plasma concentration (Tmax)	Time to maximum plasma Mesna concentration (Tmax) after a single oral Mesna dose	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Pharmacokinetic parameter - area under the plasma concentration-time curve (AUC)	Area under the plasma Mesna concentration-time curve (AUC)0-inf after a single oral Mesna dose	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Pharmacokinetic parameter - elimination rate constant (Kel)	Elimination rate constant (Kel) for Mesna after a single oral Mesna dose	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Pharmacokinetic parameter - dose linearity	Dose linearity of Mesna after a single oral Mesna dose	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Change in plasma cystine, free reduced cysteine, and protein bound cysteine	Estimated AUCs	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Urine excretion of cysteine	Cumulative and fractional excretion of total cysteine and Mesna	During the first 24 hours after Mesna administration
Safety of Mesna	Occurrence/prevalence of side effects, adverse events, and serious adverse events	During the first 5 days after Mesna administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in plasma and urine sulfur amino acids and related metabolites	Estimated AUCs	Several intervals during the first 12 hours after Mesna administration, and a fasting sample on days 2 and 3
Changes in plasma biomarker concentration - glucose	Estimated AUC	During the first 24 hours after Mesna administration, and a fasting sample on days 2 and 3
Changes in plasma biomarker concentration - insulin	Estimated AUC	During the first 24 hours after Mesna administration, and a fasting sample on days 2 and 3
Changes in plasma biomarker concentration - lipids	Estimated AUC	During the first 24 hours after Mesna administration, and a fasting sample on days 2 and 3

Collaborators and Investigators

• Sponsor: University of Oslo
• Collaborators: Oslo University Hospital; University of Oxford
• Investigators: Principal Investigator: Kjetil Retterstøl, MD, PhD, University of Oslo

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 2, 2020
• Primary Completion (ACTUAL): October 21, 2021
• Study Completion (ACTUAL): October 21, 2021

Study Registration Dates

• First Submitted: June 15, 2020
• First Submitted That Met QC Criteria: June 25, 2020
• First Posted (ACTUAL): June 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 19, 2022
• Last Update Submitted That Met QC Criteria: May 18, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Phase 1; Mesna; Cysteine
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Physiological Effects of Drugs; Protective Agents; Mesna
• Other Study ID Numbers: EudraCT: 2019-003412-32

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data that support the findings of this study may be available upon reasonable request from qualified users.

Drug and device information, study documents

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