Targeting Metabolic Flexibility in Amyotrophic Lateral Sclerosis (ALS)

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).

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.

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