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Trial registered on ANZCTR


Registration number
ACTRN12620000945921p
Ethics application status
Not yet submitted
Date submitted
3/08/2020
Date registered
22/09/2020
Date last updated
22/09/2020
Date data sharing statement initially provided
22/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and tolerability of Trimetazidine in amyotrophic lateral sclerosis (ALS)
Scientific title
Targeting metabolic flexibility in ALS (MetFlex); Safety and tolerability of Trimetazidine for the treatment of ALS
Secondary ID [1] 301922 0
Nil known
Universal Trial Number (UTN)
Trial acronym
MetFlex
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyotrophic Lateral Sclerosis 318435 0
Condition category
Condition code
Neurological 316442 316442 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Open-label
Trimetazidine 35mg oral tablets, twice daily, for 12 weeks

Adherence to the intervention will be monitored through the use of a medication diary.
Intervention code [1] 318201 0
Treatment: Drugs
Comparator / control treatment
No comparator or control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324591 0
Safety and tolerability of trimetazidine.

Outcomes will be assessed through adverse events, physical examination, vital signs/ECGs and laboratory testing (blood samples).

Adverse events include:
• Abnormal laboratory findings as determined by clinical chemistry and haematology
• Abnormal assessments from ECG and vital signs
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition as determined by the Investigator through physical exam, vital signs, ECGs and laboratory testing (blood samples).
• New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study as determined by the Investigator through physical exam, vital signs, ECGs and laboratory testing (blood samples).

Known side effects associated with trimetazidine:
• Common (affects 1 to 10 users in 100): dizziness, headache, abdominal pain, diarrhoea, indigestion, feeling sick, vomiting, rash, itching, hives and feelings of weakness
• Rare (affects 1 to 10 users in 10000): fast or irregular heartbeats (also called palpitations), extra heartbeats, faster heartbeat, fall in blood pressure on standing-up which causes dizziness, light headedness or fainting, malaise (generally feeling unwell), dizziness, flushing
Timepoint [1] 324591 0
Outcomes will be assessed as follows:

Week 0 (commencement) - Physical examination, S/AEs, laboratory testing (blood samples for haematology, clinical chemistry, oxidative stress markers).
Week 3 (post commencement of intervention) - S/AEs
Week 6 (post commencement of intervention) - Physical examination, S/AEs, vital signs/12-lead ECG, laboratory testing (blood samples).
Week 9 (post commencement of intervention) - S/AEs
Week 12 (post commencement of intervention) - Physical examination, S/AEs, laboratory testing (blood samples).
Week 16 (post commencement of intervention) - Physical examination, S/AEs, laboratory testing (blood samples).
Primary outcome [2] 324592 0
The change from baseline of oxidative stress markers.

The change from baseline of oxidative stress markers will be determined by quantitative analyses of plasma and/or serum samples by liquid chromatography–mass spectrometry/mass-spectrometry (LC-MS/MS) and/or multiplex analysis of selected targets of interest: interleukin-6 (IL-6), malondialdehyde (MDA), 8-Oxo-2'-deoxyguanosine (8-OHdG).
Timepoint [2] 324592 0
Bloods for the assessment of oxidative stress markers will be taken for assessment at Weeks 0 (baseline), 6, 12, and 16 weeks post commencement of intervention.
Secondary outcome [1] 385128 0
Change from baseline in energy expenditure.

The change from baseline in energy expenditure will be determined based on a composite outcome of body composition and measured energy expenditure (through indirect calorimetry).
Timepoint [1] 385128 0
0, 6, 12, and 16 weeks post commencement of intervention.
Secondary outcome [2] 385129 0
The pharmacodynamic property of oxidative stress markers to be assessed is the change in levels of oxidative stress markers over time (at 6, 12, and 16 weeks post commencement of intervention), when compared to baseline levels of oxidative stress markers. The oxidative stress markers to be assessed are: interleukin-6 (IL-6), malondialdehyde (MDA), 8-Oxo-2'-deoxyguanosine (8-OHdG).

We aim to show a pharmacodynamic response in oxidative stress markers after 12 weeks of trimetazidine treatment. This will be assessed by determining the baseline of oxidative stress markers and the change in the expression of these markers over time, in response to trimetazidine. Measurement of oxidative stress markers will be determined by quantitative analyses of plasma and/or serum samples by liquid chromatography–mass spectrometry/mass-spectrometry (LC-MS/MS) and/or multiplex analysis of interleukin-6 (IL-6), malondialdehyde (MDA), 8-Oxo-2'-deoxyguanosine (8-OHdG).

Based on the study of Blasco et al 2016, we expect a mean baseline level of interleukin-6 (IL-6) of 35.0 pg/mL in patients with ALS/MND. Prior work in acute pancreatitis and coronary heart disease indicated a reduction in IL-6 towards normal levels. Control levels in the literature range from 9.0 to 20.0. We assume, conservatively, a reduction of 20.0 pg/mL in IL-6 levels after 12 weeks (from 35.0 to 15.0 with a standard deviation (SD) of 20) of treatment with trimetazidine in all dosed participants.
Timepoint [2] 385129 0
0, 6, 12, and 16 weeks post commencement of intervention.

Eligibility
Key inclusion criteria
1. Signed informed consent prior to the initiation of any study-specific procedures
2. Familial or sporadic ALS/MND, defined as clinically possible, probable, or definite as per the El Escorial criteria
3. Relative TRICALS risk profile between -6.0 to -2.0 (75% of patients with ALS/MND)
4. Metabolic index (defined as measured resting energy expenditure as a % of predicted resting energy expenditure) equal to or greater than 110%.
5. The use of riluzole will be permitted during the study. Participants 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.
6. Ability to swallow tablets
7. Able to lie with torso elevated at a 35 degree angle for 30 minutes without respiratory support
8. Aged over 18 years
9. Able to give informed consent (as judged by the investigator) and able to comply with all study visits and all study procedures
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to provide informed consent
2. History of, or current diagnosis of diabetes or medical condition that impacts whole body energy expenditure (e.g. Hashimoto’s, heart disease)
3. Tracheostomy or non-invasive ventilation (NIV) use > 22 hours per day
4. Inability to swallow tablets
5. Contraindication therapy
6. Evidence of malignant disease
7. Significant neuromuscular disease other than ALS/MND
8. Ongoing disease that may cause neuropathy
9. Pregnancy or breastfeeding
10. Deprivation of freedom by administrative or court order

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We aim to show a pharmacodynamic response in oxidative stress markers after 12 weeks of trimetazidine treatment. Based on the study of Blasco et al (1), we expect a mean baseline level of interleukin-6 (IL-6) of 35.0 pg/mL in patients with ALS. Prior work in acute pancreatitis and coronary heart disease indicated a reduction in IL-6 towards normal levels. Control levels in the literature range from 9.0 to 20.0. We assume conservatively a reduction of 20.0 pg/mL in IL-6 levels after 12 weeks (from 35.0 to 15.0 with a standard deviation (SD) of 20) of treatment with trimetazidine in all dosed participants. To obtain 90% power, with a two-sided alpha of 0.01 (adjusted for multiple testing of five biomarkers), we need 18 patients with repeated measurements. As data is limited for the other biomarkers being assessed, and there is more uncertainty about their variation, we will enrol 36 patients.

(1) Blasco, H., et al., Panel of Oxidative Stress and Inflammatory Biomarkers in ALS: A Pilot Study. Can J Neurol Sci, 2017. 44(1): p. 90-95.
Brooks, B.R., et al., El Escorial revisited:

Co-primary analysis I: safety and tolerability:
The primary aim of the analysis is to estimate the rate of adverse events and proportion of patients completing the on-treatment phase. Simple descriptives will be used to summarise the occurrence of adverse events and number of study completers. Attrition rates over time will be assessed with Kaplan-Meier curves.

Co-primary analysis II: change from baseline:
The change in pharmacodynamic markers will be assessed using linear mixed effects models (LMEs).

Secondary analyses:
The change from baseline in energy expenditure and change in pharmacodynamic properties of oxidative stress markers will be analysed using a mixed effects model.

Exploratory analyses: associations between oxidative stress markers, features of hypermetabolism and clinical markers of disease:
All additional analysis will be conducted using linear mixed models.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/01/2021
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17180 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 30880 0
4029 - Herston
Recruitment outside Australia
Country [1] 22802 0
Netherlands
State/province [1] 22802 0
Utrecht
Country [2] 22803 0
United Kingdom
State/province [2] 22803 0
London

Funding & Sponsors
Funding source category [1] 306334 0
Charities/Societies/Foundations
Name [1] 306334 0
FightMND
Country [1] 306334 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
The University of Queensland, St Lucia QLD 4072
Country
Australia
Secondary sponsor category [1] 306842 0
None
Name [1] 306842 0
Address [1] 306842 0
Country [1] 306842 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 306545 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 306545 0
Ethics committee country [1] 306545 0
Australia
Date submitted for ethics approval [1] 306545 0
25/09/2020
Approval date [1] 306545 0
Ethics approval number [1] 306545 0
Ethics committee name [2] 306560 0
University Medical Centre Utrecht Human Research Ethics Committee
Ethics committee address [2] 306560 0
Ethics committee country [2] 306560 0
Netherlands
Date submitted for ethics approval [2] 306560 0
25/09/2020
Approval date [2] 306560 0
Ethics approval number [2] 306560 0
Ethics committee name [3] 306561 0
King's College Hospital
Ethics committee address [3] 306561 0
Ethics committee country [3] 306561 0
United Kingdom
Date submitted for ethics approval [3] 306561 0
25/09/2020
Approval date [3] 306561 0
Ethics approval number [3] 306561 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104238 0
Dr Shyuan Ngo
Address 104238 0
Australian Institute for Bioengineering and Nanotechnology
Building 75, Cnr Cooper and College Roads,
The University of Queensland, St Lucia, Queensland, 4072
Country 104238 0
Australia
Phone 104238 0
+61 7 3443 1133
Fax 104238 0
Email 104238 0
[email protected]
Contact person for public queries
Name 104239 0
Shyuan Ngo
Address 104239 0
Australian Institute for Bioengineering and Nanotechnology
Building 75, Cnr Cooper and College Roads,
The University of Queensland, St Lucia, Queensland, 4072
Country 104239 0
Australia
Phone 104239 0
+61 7 3443 1133
Fax 104239 0
Email 104239 0
[email protected]
Contact person for scientific queries
Name 104240 0
Shyuan Ngo
Address 104240 0
Australian Institute for Bioengineering and Nanotechnology
Building 75, Cnr Cooper and College Roads,
The University of Queensland, St Lucia, Queensland, 4072
Country 104240 0
Australia
Phone 104240 0
+61 7 3443 1133
Fax 104240 0
Email 104240 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available as these data are not meaningful when considered independently.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.