Targeting metabolic flexibility in ALS (MetFlex); safety and tolerability of trimetazidine for the treatment of ALS;An investigator initiated and conducted, multicentre, international, open-label Phase 2a trial to determine the safety and tolerability of trimetazidine for the treatment of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)

ALS/MND is classified as either familial or sporadic. Approximately 10% of
cases are classified as familial, with the remaining 90% as sporadic. Familial
cases are defined by their heritability, whereby most cases are autosomal
dominant mutations in a heterogeneous set of genes. Sporadic cases of the
disease are characterised by disease incidence in the absence of an identified
inherited mutation. From a clinical and neuropathological standpoint, however,
familial and sporadic cases are indistinguishable, and a number of commonly
observed familial ALS/MND associated mutations are observed in sporadic ALS/MND
patients.
Current treatment options for ALS/MND are limited. While a number of
therapeutic candidates have demonstrated efficacy in pre-clinical models of the
disease, these outcomes have not translated into viable treatments for people
living with ALS/MND. To date, only two drugs have received US Food and Drug
Administration (FDA) approval, Riluzole and Edaravone, both of which have
limited efficacy.

The maintenance of optimal energy balance and body composition is critically
dependent on balancing energy intake with energy expenditure. In healthy
individuals, dietary intake and nutrient absorption are theoretically in
balance with resting and activity-associated energy expenditure. This balance
underpins the capacity to maintain relatively stable energy stores.
Evidence of metabolic dysfunction in ALS/MND arose in the 1980s. Since that
time, a growing number of studies have indicated that impairments in whole body
physiology and energy balance are common presentations in the disease. Of the
metabolic changes that occur in ALS/MND, hypermetabolism (defined by an
increase in resting energy expenditure) has been observed in multiple patient
cohorts. While reports of hypermetabolism in ALS/MND have increased over the
years, and a study by Jesus and colleagues in 2018 hinted at a potential
negative role of hypermetabolism in the disease, the majority of studies to
date have identified hypermetabolism using predictions of resting energy
expenditure that are based on the Harris-Benedict equation, which fails to
correct for muscle atrophy in the disease. In 2017, we published data to show
that predictions of resting energy expenditure in ALS/MND are impacted by
fat-free mass. Thus, most reports of the prevalence and impact of
hypermetabolism in ALS/MND have been confounded by incorrect estimates of
predicted resting energy expenditure.
In 2018, we published an influential and fundamental case-control study
investigating the prevalence and impact of altered energy expenditure in
ALS/MND. Our study was the first to correct predictions of resting energy
expenditure in patients relative to fat free mass, and therefore the only study
to consider the impact of the disease on muscle mass as a factor in identifying
hypermetabolism. Generating a metabolic index for each patient (MI; measured
resting energy expenditure as a % of predicted resting energy expenditure), we
confirmed that hypermetabolism (where MI >120%) was more prevalent in ALS/MND
patients when compared to age- and sex-matched controls. Moreover, we were able
to highlight the clinical significance of hypermetabolism in ALS/MND,
demonstrating that hypermetabolic patients have an aggressive disease that is
associated with faster progression of disability (i.e. faster decline in
ALSFRS-R) and increased risk for earlier death [13]. Using skeletal muscle and
plasma samples from ALS/MND patients, we have also generated published data to
show that metabolic perturbations are widespread, and that this is
characterised by increased expression of metabolic proteins (e.g. pyruvate
dehyrodenase kinase 4 (PDK4) and adipokines/ cytokines (e.g. IL-6) that play
crucial roles in controlling energy balance.
Collectively, these data highlighted the targeting of hypermetabolism and/or
metabolic perturbations as a potential therapeutic strategy for ALS/MND.
The data from this study will evaluate the safety and tolerability of
trimetazidine in patients with ALS/MND and the effect on oxidative stress
proteins (IL-6, MDA and 8-OHdG. The change in metabolic index after using
trimetazidine is an important argument to set up a phase 3 clinical trial.

The objectives of this study are to determine:
• The safety and tolerability of trimetazidine in patients with ALS/MND
• The change from baseline in oxidative stress markers in patients with ALS/MND
after the initiation of trimetazidine
• The change from baseline in energy expenditure in patients with ALS/MND after
the initiation of trimetazidine
• The preliminary pharmcodynamic properties of trimetazidine on oxidative
stress markers in patients with ALS/MND
• Exploratory associations of the effect of trimetazidine on oxidative stress
markers relative to clinical features of hypermetabolism (increased energy
expenditure) in patients with ALS/MND
• Exploratory associations of the effect of trimetazidine on oxidative stress
markers relative to clinical markers of disease progression (e.g. ALSFRS-R and
SVC) in patients with ALS/MND

This study will provide evidence for the contribution of increased energy
expenditure (i.e. hypermetabolism) in the pathophysiology of ALS/MND. It will
also assess the preliminary effect of trimetazidine on clinical outcome
measures of ALS/NMD. This information is necessary to further explore the
effect of trimetazidine on disease progression in patients with ALS/MND in a
potential phase 3 clinical trial.

The protocol describes a single-arm, Phase 2a open-label trial. Enrolment is
planned for a total of 20 ALS/MND patients (participants) across 2 sites: Royal
Brisbane & Women*s Hospital (Brisbane, Australia), and University Medical
Centre Utrecht (Utrecht, Netherlands). Each site will enrol 18 participants.
All participants will receive trimetazidine, 35mg (slow release) oral tablet,
twice-daily in an unblinded manner.
All participants will begin the study treatment sequentially, with time allowed
before dosing the following participant. Study participation will continue
until 28 days (4 weeks) after the last dose of the study drug. For each
individual, study participation will be a total of 20 weeks (140 days),
consisting of:
• 4-week (28 days) lead-in period to obtain a stable baseline measurement of
ALS/MND-related oxidative stress markers (IL-6, MDA, and 8-OHdG), clinical
markers of disease (ALSFRS-R and SVC), and to assess that measured energy
expenditure is >=110% of predicted resting energy expenditure.
• 12-week (84 days) on-treatment phase, when patients will receive
trimetazidine. Patients 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) and perform assessments to evaluate alterations in energy
expenditure. At weeks 3 and 9, we will conduct a teleconference with patients
to collect information on concomitant treatments, implement the ALSFRS-R, and
inquire about AEs/SAEs.
• 4-week (28 days) wash-out with a close-out visit planned for 28 days after
the last dose of the study drug.
AEs and SAEs will be collected and recorded throughout the entire trial
duration (140 days ± 3 days). Here, study weeks are defined as consecutive
calendar weeks, with Study Week 1 beginning from the start time of the first
day of study drug administration.

Trimetazidine is an anti-ischemic agent that is used in the treatment of
coronary artery disease. Trimetazidine has not been shown to exert any effect
on coronary flow, contractility, blood pressure, or heart rate (HR). Moreover,
it has no significant negative inotropic or vasodilatory properties, either at
rest or during exercise.
Trimetazidine is available on the market as the 20 mg immediate-release (IR)
tablets and the 35 mg modified release (MR) tablets. The 20 mg IR tablets are
administered 3 times a day, while the 35 mg MR tablets are administered twice a
day.
Trimetazidine MR tablets are orally bioavailable and the drug is rapidly
absorbed from the intestinal tract. Trimetazidine has been shown to be safe and
tolerable for long-term exposure in patients with chronic heart failure. Most
importantly, trimetazidine significantly reduced energy expenditure in patients
with chronic heart failure, and reduced the expression of oxidative (i.e.
metabolic) stress markers that arise from the degradation of lipids
(malondialdehyde (MDA) and 8-hydroxy-2*-deoxyguanosine (8-OHdG)) and
pro-inflammatory cytokines/adipokines (IL-6). These are crucial oxidative
stress markers known to be increased in ALS/MND patients and potentially
associated with disease progression. Given the compelling evidence for the
associations between oxidative stress, increased energy expenditure
(hypermetabolism) and ALS/MND, trimetazidine may positively affect disease
progression in patients with ALS/MND.

The energy metabolism and body composition are assessed using non-invasive
methods such as respiratory calorimetry and air-displacement plethysmography
(BodPod). Safety blood products will be determined by venous blood tests with a
minimal risk of complications. Participants are required to visit the hospital
5 times in 20 weeks, each visit will take place in the morning after an
overnight fasting.

All participants will receive trimetazidine 35mg (slow-release) twice a day
(TID). Trimetazidine is a registered treatment for angina pectoris by the
European Medicines Agency (EMA). Side-effects and pharmacological effect are
known. So far we know, it is the first time trimetazidine will be studies in
patients with ALS. We will study the effect of trimetazidine in patients with
ALS. As the side effects will be monitored and are mainly mild, the hypothesis
is that trimetazidine will be well tolerated. As ALS is a fatal, uncurable
disease, the risk-benefit will be clinical equipoise.