| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mitochondrial myopathy due to mt.3243A>G mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mitochondrial myopathy is an inherited muscle disease due to impaired energy production |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027710 |
| E.1.2 | Term | Mitochondrial myopathy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The main aim of this research is to determine whether bezafibrate has an effect on the way mitochondria in muscle cells produce energy.
Our hypothesis, based on pre-clinical data is that bezafibrate will improve mitochondrial function in people with muscle disease due to mitochondrial disease.
|
|
| E.2.2 | Secondary objectives of the trial |
There are several secondary aims of this project:
• To characterise changes in mitochondria in relation to bezafibrate use;
• To obtain preliminary safety and tolerability data of bezafibrate in patients with mitochondrial muscle disease;
• To identify and characterise new blood markers of mitochondrial disease in relation to bezafibrate use and dosage;
• To assess possible magnetic resonance markers of mitochondrial disease in relation to bezafibrate use and dosage;
• To assess a high speed magnetic resonance imaging technique in mitochondrial myopathy;
• To assess the effect of bezafibrate on measures of aerobic respiration using sub-maximal exercise testing on a cycle ergometer;
• To assess the use of different functional outcome measures encompassing disease burden, activity levels and quality of life;
• To provide us with data to estimate a treatment effect size so that, if appropriate, we can determine how many patients we need to recruit to a future randomised controll |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The inclusion criteria are:
• The participant is willing and able to give informed consent for participation in the trial.
As an experimental trial, there is an inherent degree of risk. We therefore believe that all participants should have capacity to consent to the trial.
• Male or Female, aged 18 years or over and less than 65 years.
No minors will be recruited to this trial for the reasons stated above. The Summary of Product Characteristics for bezafibrate identifies that there is an increased risk of muscle complications in those over the age of 65 years. It is for this reason we have used this as the upper age limit for inclusion.
• Confirmed mt.3243A>G mutation.
We wanted to have a genetically homogeneous population. The mt.3243A>G mutation is the most common cause of muscle disease in our mitochondrial population.
• Evidence of myopathy as determined by the investigator.
The mt.3243A>G mutation can manifest in a variety of clinical ways. We wanted to ensure that participants in the trial had at least some clinical similarity in their presentation.
Additionally, we felt that participants manifesting muscle disease would be most appropriate to recruit and study given the investigative tools available to us. These include respiratory chain enzyme analysis and MRS (magnetic resonance spectroscopy) of skeletal muscle.
• Stable dose of current regular medication for at least 4 weeks prior to trial entry.
We wish to avoid recruiting participants who are likely to require frequent changes to their medication regimes. This will facilitate analysis of any changes seen in the muscle biopsies and imaging studies. In addition, there are restrictions on certain concomitant medications during the trial period. By ensuring the participant body are on relatively stable medications, we can help avoid prescribing errors.
• Not already taking fibrates.
Participants should be naive to fibrate treatment so that the baseline muscle biopsy accurately reflects their mitochondrial disease. This will enable comparison between muscle biopsy samples pre and post treatment.
• No evidence of liver impairment.
Liver impairment is a contraindication to use of bezafibrate according to the Summary of Product Characteristics. Although bezafibrate is excreted renally, it accumulates in the liver. Impaired liver function can increase liver toxicity.
• Normal renal function, with a creatinine clearance of >60ml/minute.
Bezafibrate is excreted almost entirely by the kidneys. Drug accumulation and toxicity may occur in impaired renal function.
The Summary of Product Characteristics for bezafibrate identifies that impaired renal function is a predisposing factor for muscle complications such as (worsening) myopathy and rhabdomyolysis. Given participants already have a clinically relevant myopathy, and we are using higher than licensed doses of bezafibrate in this feasibility study, we wanted to control other risk factors where possible.
• Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter.
In animal reproductive studies, although bezafibrate did not appear to affect fertility, it did demonstrate teratogenicity. Therefore, it is a requirement of the study that sexually active participants avoid conception during use of the trial drug. Clear guidance will be provided regarding contraception. In female participants, this may not include oestrogen containing contraceptives.
• In the Investigator’s opinion, is able and willing to comply with all trial requirements.
There is a considerable patient burden associated with this trial. Participants may be required to attend the Clinical Research Facility on a weekly basis for a period of 3 months. This is necessary for safety purposes and therefore participants who are unlikely or unwilling to comply with these requirements will not be recruited to the trial.
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial.
Given the complexity of mitochondrial disorders, coupled with the restrictions on certain drug prescriptions during the trial, the trial team feel it is necessary to include other health care professionals involved in the health care delivery of all participants. |
|
| E.4 | Principal exclusion criteria |
The exclusion criteria are:
• Unstable, or poorly controlled diabetes, as determined by the investigator. Participants with diabetes cannot be taking insulin or oral anti-diabetic agents.
Insulin and oral anti-diabetic agents are contraindicated with bezafibrate use. Futhermore, poorly controlled diabetes may contribute to poor muscle biopsy site healing.
• History of rhabdomyolysis
Bezafibrate can rarely cause rhabdomyolysis. As such, anyone with a previous episode of rhabdomyolysis will be excluded from the trial.
• History of sensitivity to fibrates (including photosensitivity)
This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics).
• Gallbladder disease with or without cholelithiasis
This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics) as bezafibrate may contribute to gallstone formation.
• History of liver impairment or disease
This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics).
• Alcohol misuse
Bezafibrate can rarely cause rhabdomyolysis. Excess alcohol intake is a risk factor for rhabdomyolysis with vibrates. Alcohol misuse will be determined by the investigators.
• Nephrotic syndrome
This increases the risks of drug induced side effects, in particular rhabdomyolysis.
• Significant renal impairment, or creatine clearance <60ml/minute
This increases the risks of drug induced side effects, in particular rhabdomyolysis.
• Untreated hypothyroidism
Bezafibrate can rarely cause rhabdomyolysis. Untreated hypothyroidism increases the risk of rhadomyolysis with bezafibrate use. All individuals will be required to have satisfactory thyroid function tests at screening before proceeding in the trial.
• Use of another medication that interacts with bezafibrate: colestyramine, insulin, anion exchange resins, coumarin anticoagulants, anti-diabetics, monoamine oxidase inhibitors, oestrogens, immunosuppressants, statins.
These medications are not to be used with bezafibrate concomitantly according to the SPC. These medications either affect bezafibrate metabolism; or bezafibrate affects their metabolism. Consequently, participants cannot be taking these.
• A female participant who is pregnant, lactating or planning pregnancy during the course of the trial or a male participant who is planning to conceive with their female partner.
Pre-clinical studies demonstrate teratogenic effects for both males and females taking bezafibrate at conception or during pregnancy. Consequently, anyone planning a family during the trial will not be eligible for inclusion.
• Elective or emergency surgery in the past 12 weeks.
This is to ensure validity of the results, as well as participant safety.
• Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
This is to ensure validity of the results, as well as participant safety.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
The trial requires considerable personal commitment by participants. As such, if the investigators have concerns about a participant's medical history, ability to co-operate with the trial procedures, or any other concerns, the individual will not be eligible for inclusion.
• Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
This ensures participant safety.
• Participants will be unable to undergo MRI if they have any contra-indication to MRI scanning e.g. implantable medical device, cranial aneurysm clips, metallic foreign body, however will be able to participate in other areas of the study if they meet the remaining inclusion/exclusion criteria.
• For exercise testing – any participant with ischaemic heart disease, or symptoms suggestive of this. Again, participants will be able to participate in other areas of the study if they meet the remaining inclusion/exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in respiratory chain enzyme activity (measured in mean percentage and absolute terms; and individual percentage and absolute terms). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Comparison will be made between measurements obtained at week 0 (baseline) and week 12 (after bezafibrate treatment). |
|
| E.5.2 | Secondary end point(s) |
1) The individual and mean absolute and percentage change and inter-individual variability of mitochondrial biogenesis markers:
• Citrate synthase quantification;
• Mitochondrial DNA copy number quantification.
2) The individual and mean absolute and percentage change in levels and inter-individual variability of serum biomarkers including:
• serum fibroblast growth factor-21 (FGF-21);
• serum PGC-1α;
• serum microRNAs.
3) The individual and mean absolute & percentage change, and inter-individual variability, in t 1/2 PCr measurements of skeletal muscle obtained during 31P –MRS.
4) The individual and mean absolute & percentage change, and inter- individual variability, in ATP production and muscle phosphocreatine of cardiac muscle during 31P–MRS.
5) The individual and mean absolute & percentage change, and inter-individual variability, in cardiac LV torsion measured during cine-gated cardiac MRI.
6) The individual and mean absolute & percentage change, and inter-individual variability, in skeletal muscle lipid content and volume assessed during an accelerated MRI technique.
7) The individual and mean absolute & percentage change in peak VO2; peak W and peak a-VO2 diff determined during sub-maximal exercise testing on a stationary cycle.
8) Disease burden
Individual and mean absolute and percentage change, and inter-individual variability, in NMDAS score, timed up and go (TUG), heteroplasmy levels in blood, urine and muscle and COX negative, positive and intermediate fibre quantification.
9) Activity levels
The individual and mean absolute and percentage change, and inter-individual variability, in IPAQ score, total number of daily steps, total energy expenditure, active energy expenditure and physical activity duration.
10) Quality of life measures
The individual and mean absolute and percentage change, and inter-individual variability, in NMQ , SF-12 and FIS scores.
11) Safety & Tolerability Data
Bloods (FBC, PT, U&E, LFTs, CK) will be assessed weekly throughout the trial and compared to normal reference ranges.
Adverse Event reporting will be undertaken as required and with opportunistic capture throughout the trial.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The following secondary outcome measures will be compared at week 0 (baseline) and week 12 (after bezafibrate treatment):
• Mitochondrial biogenesis markers (as above);
• Skeletal and cardiac muscle MRI/MRS (points 3,4,5 & 6 above);
• Exercise testing;
The following outcome measures will be assessed at weeks 0, 3, 6, 9 and 12:
• Serum Biomarkers (as above)
The following outcome measures will be assessed at weeks 0, 6 and 12:
• Disease burden (as above, excluding COX fibre analysis which will be done at weeks 0 & 12 only).
• Activity levels (as above)
• Quality of life (as above)
The following outcome measures will be assessed weekly throughout the trial, and as required:
• Bloods
• Adverse Event Reporting |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last telephone contact with last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
