Targeting Metabolic Flexibility in Amyotrophic Lateral Sclerosis (ALS) (MetFlex)

Targeting Metabolic Flexibility in ALS (MetFlex); Safety and Tolerability of Trimetazidine for the Treatment of ALS

MetFlex is an investigator led, open-label, single-arm, Phase 2a trial to determine the safety and tolerability of trimetazidine for the treatment of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND).

Study Overview

• Status: Completed
• Conditions: Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Trimetazidine Dihydrochloride

Detailed Description

The study will consist of a 4-week lead-in period to obtain a stable baseline measurement of clinical markers of disease and oxidative stress. After the lead-in phase, participants will receive trimetazidine for 12 weeks. Participants will visit the clinic at 6-week intervals, during which we will obtain a blood sample to measure the pharmacodynamic response. We will also collect information regarding the rate of disease progression (i.e. ALSFRS-R and SVC). At weeks 3 and 9 of treatment, participants will conduct a teleconference visit, during which we will collect data on ALSFRS-R. Adverse events will be collected and recorded throughout the entire trial duration. At the end of the on-treatment period, a close-out visit will occur after four weeks. The total study period per participant will be 20 weeks.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shyuan Ngo, PhD; Phone Number: +61734431133; Email: s.ngo@uq.edu.au
• Study Contact Backup: Name: Angela Schmidt, BNurse; Email: a.schmidt@uq.edu.au

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital
• Netherlands
  • Utrecht, Netherlands
    • University Medical Centre Utrecht
• United Kingdom
  • London, United Kingdom
    • King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age between 18 and 75 years
• Signed informed consent prior to the initiation of any study-specific procedures
• Familial or sporadic ALS/MND, defined as clinically possible, probable, or definite as per the El Escorial criteria
• Relative TRICALS risk score between -6.0 to -2.0 (75% of patients with ALS/MND)
• Metabolic index ≥110%, at the screening visit.
• The use of riluzole will be permitted during the study. Individuals taking riluzole must be on a stable dose for at least 30 days prior to the baseline visit, or stopped taking riluzole at least 30 days prior to the baseline visit.
• Ability to swallow tablets
• Able to lie with torso elevated at a 35° angle for 30 minutes without respiratory support
• Able to give informed consent (as judged by the investigator) and able to comply with all study visits and all study procedures

• Females must not be able to become pregnant (e.g. post-menopausal, surgically sterile or using highly effective birth control methods) for the duration of the study. Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

  • oral
  • intravaginal
  • transdermal
  • Progestogen-only hormonal contraception associated with inhibition of ovulation:
  • oral
  • injectable
  • implantable
  • intrauterine device (IUD)
  • intrauterine hormone-releasing system ( IUS)
  • vasectomised partner
• Females of child-bearing potential must have a negative serum pregnancy test at screening and baseline and be non-lactating

Exclusion Criteria:

• Unable to provide informed consent
• History of, or current diagnosis of diabetes or medical condition that impacts whole body energy expenditure (e.g. Hashimoto's, heart disease)
• Parkinson's disease or parkinsonism, tremor, restless-leg syndrome

• Safety Laboratory Criteria at screening related to significant kidney disease:

  • Creatinine clearance < 50 mL / min (Cockcroft-Gault) based on Cystatin C
• Tracheostomy or non-invasive ventilation (NIV) use > 22 hours per day
• Inability to swallow tablets

• Contraindication therapy:

  • Allergy for one of the product's active pharmaceutical ingredients (APIs) or excipients.
  • Antihypertensive treatment [Trimetazidine may cause hypotension]
• Evidence of malignant disease
• Significant neuromuscular disease other than ALS/MND
• Ongoing disease that may cause neuropathy
• Pregnancy or breastfeeding
• Females actively seeking to become pregnant who are not using an adequate form of contraceptive as detailed in the Inclusion criteria.
• Deprivation of freedom by administrative or court order

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Trimetazidine 35mg	Drug: Trimetazidine Dihydrochloride; Oral tablet, twice-daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events; Safety and Tolerability	The occurrence of adverse events, as assessed by Common Terminology Criteria for AEs Version 5, during the 12-week on-treatment period and 4-week wash-out period (16 weeks total).	16 weeks
Level of expression of oxidative stress markers in the plasma and/or serum of trial participants	Expression of oxidative stress markers (malondialdehyde, 8-hydroxy-2'-deoxyguanosine, interleukin-6; assessed by liquid chromatography-mass spectrometry/mass-spectrometry or multiplexing) in the plasma and/or serum of trial participants throughout the treatment period (12-week) and at the end of the wash-out period (4 weeks)	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of expression of oxidative stress markers in the plasma and/or serum of trial participants to inform future clinical trials in ALS/MND	Assessment of the expression of oxidative stress markers (malondialdehyde, 8-hydroxy-2'-deoxyguanosine, interleukin-6; assessed by liquid chromatography-mass spectrometry/mass-spectrometry or multiplexing) in the plasma and/or serum of trial participants throughout the treatment period (12-week) and at the end of the wash-out period (4 weeks) to determine suitability for incorporation into future trial design	16 weeks

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: King's College London; UMC Utrecht; Julius Clinical; FightMND
• Investigators: Principal Investigator: Shyuan Ngo, PhD, The University of Queensland; Principal Investigator: Robert Henderson, MBBS, PhD, Royal Brisbane & Women's Hospital; Principal Investigator: Leonard van den Berg, MD, PhD, UMC Utrecht; Principal Investigator: Ammar Al-Chalabi, MB ChB, PhD, King's College London; Principal Investigator: Frederik Steyn, PhD, The University of Queensland; Principal Investigator: Ruben van Eijk, MD, PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2021
• Primary Completion (Actual): May 24, 2023
• Study Completion (Actual): May 24, 2023

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 4, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 19, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Vasodilator Agents; Trimetazidine
• Other Study ID Numbers: MetFlex

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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