Targeting Metabolic Flexibility in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Amyotrophic Lateral Sclerosis, Motor Neuron Disease

Intervention / Treatment
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* Drug: Trimetazidine Dihydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, single-arm study without placebo
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Trimetazidine 35mg | Drug: Trimetazidine Dihydrochloride<br>* Oral tablet, twice-daily<br>|

What is the study measuring?
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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 |