Clinical trial NCT04788745: Targeting Metabolic Flexibility in Amyotrophic Lateral Sclerosis (ALS)
Official title: Targeting Metabolic Flexibility in ALS (MetFlex); Safety and Tolerability of Trimetazidine for the Treatment of ALS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: FightMND
name: UMC Utrecht
name: King's College London
name: Julius Clinical
First posted: 2021-03-09
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single-arm study without placebo
Primary purpose: TREATMENT

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).

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.

Eligibility 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

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events; Safety and Tolerability
timeFrame: 16 weeks
measure: Level of expression of oxidative stress markers in the plasma and/or serum of trial participants
timeFrame: 16 weeks
Secondary outcomes:
measure: Level of expression of oxidative stress markers in the plasma and/or serum of trial participants to inform future clinical trials in ALS/MND
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
city: London
country: United Kingdom
facility: King's College London
Study officials:
affiliation: The University of Queensland
name: Shyuan Ngo, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Brisbane & Women's Hospital
name: Robert Henderson, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Leonard van den Berg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: King's College London
name: Ammar Al-Chalabi, MB ChB, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Queensland
name: Frederik Steyn, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Ruben van Eijk, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: