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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04788745
Recruitment Status : Recruiting
First Posted : March 9, 2021
Last Update Posted : August 25, 2021
Sponsor:
Collaborators:
FightMND
UMC Utrecht
King's College London
Julius Clinical, The Netherlands
Information provided by (Responsible Party):
The University of Queensland

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Motor Neuron Disease Drug: Trimetazidine Dihydrochloride Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, single-arm study without placebo
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeting Metabolic Flexibility in ALS (MetFlex); Safety and Tolerability of Trimetazidine for the Treatment of ALS
Actual Study Start Date : June 29, 2021
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : March 31, 2023


Arm Intervention/treatment
Experimental: Experimental
Trimetazidine 35mg
Drug: Trimetazidine Dihydrochloride
Oral tablet, twice-daily




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events; Safety and Tolerability [ Time Frame: 16 weeks ]
    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).

  2. Level of expression of oxidative stress markers in the plasma and/or serum of trial participants [ Time Frame: 16 weeks ]
    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)


Secondary Outcome Measures :
  1. Level of expression of oxidative stress markers in the plasma and/or serum of trial participants to inform future clinical trials in ALS/MND [ Time Frame: 16 weeks ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04788745


Contacts
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Contact: Shyuan Ngo, PhD +61734431133 s.ngo@uq.edu.au
Contact: Angela Schmidt, BNurse a.schmidt@uq.edu.au

Locations
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Australia, Queensland
Royal Brisbane & Women's Hospital Recruiting
Brisbane, Queensland, Australia, 4029
Contact: Robert Henderson, MBBS, PhD    +617 3646 3111    Robert.Henderson@health.qld.gov.au   
Netherlands
University Medical Centre Utrecht Not yet recruiting
Utrecht, Netherlands
Contact: Leonard van den Berg, MD, PhD    +31 88 75 554 94    lberg@umcutrecht.nl   
United Kingdom
King's College London Not yet recruiting
London, United Kingdom
Contact: Ammar Al-Chalabi, MB ChB, PhD    +44 20 7848 5192    ammar.al-chalabi@kcl.ac.uk   
Sponsors and Collaborators
The University of Queensland
FightMND
UMC Utrecht
King's College London
Julius Clinical, The Netherlands
Investigators
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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
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Responsible Party: The University of Queensland
ClinicalTrials.gov Identifier: NCT04788745    
Other Study ID Numbers: MetFlex
First Posted: March 9, 2021    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Trimetazidine
Vasodilator Agents