E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Mitochondrial diseases are a group of rare, neurogenetic disorders, often found in tissues with high-energy demands. In the muscle, it displays as fatigue, exercise intolerance, myalgia and weakness. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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 primary outcome is to establish if acipimox can increase energy (ATP content) in skeletal muscle in adult patients with mitochondrial disease and muscle involvement.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives will determine any changes in the following, between the baseline visit and the end of treatment(week 12): 1. Health-related Quality of Life 2. Reported perceived fatigue 3. Symptom-limited cardiopulmonary fitness 4. Disease burden 5. Upper and lower limb function, balance and walking 6. Skeletal muscle analyses
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must be able to provide full informed consent. 2. Male or female patients ≥ 16 years of age. 3. Patients must fulfil the following: i) Genetically proven diagnosis of m.3243A>G mutation or single large-scale mtDNA deletion, and ii)Evidence of myopathy as confirmed by the investigator 4. Able and willing, in the opinion of the investigator, to comply with all trial requirements. 5. Willing for their GP and Specialist (if applicable), to be informed of their participation in the trial. 6. Be on a stable dose of any current regular medication for at least four weeks prior to trial entry.
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E.4 | Principal exclusion criteria |
1. Patients who are currently participating or have participated in a clinical trial of an investigational medicinal product within the 12 week period prior to the date of informed consent. 2. Patients who have had an elective or emergency admission to hospital within the 4 week period prior to the date of informed consent. 3. Patients with other known uncontrolled medical problems, which, in the opinion of the investigator, would preclude participation in the trial. 4. Patients who are: a) pregnant b) breast feeding c) of childbearing potential with a positive urine pregnancy test prior to starting trial IMP or; d) male or female of childbearing potential unwilling to use a double barrier method of contraception throughout the trial (postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non- childbearing potential). 5. Patients with moderate to severe renal impairment (creatinine clearance < 60 ml/min). 6. Patients with a screening AST, ALT or Gamma GT result of more than 3 times the upper limit of normal. 7. Patients with a platelet count of <50 platelets/ ul of blood 8. Patients on treatment with methotrexate or other immunosuppressant medications. 9. Patients with active known peptic ulcer or history of recurrent ulceration. 10. Patients on treatment with warfarin, clopidogrel, regular high-dose (≥300 mg OD) aspirin or other anticoagulant medications which in the opinion of the investigator precludes entry into the trial. Patients receiving high-dose aspirin who are able to come off aspirin for a period of 72 hours prior to any muscle biopsy sample will be eligible to participate. 11. Patients with a medical history which in the opinion of the investigator contraindicates the use of low-dose aspirin. 12. Patients who are already taking acipimox. 13. Patients with an elective hospital admission scheduled during the trial period, which in the opinion of the investigator would preclude participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in ATP content in skeletal muscle biopsy specimens, between baseline and end of treatment visit at week 12. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome measure is the change in ATP content in skeletal muscle biopsy specimens. Samples for analysis will be taken at baseline and end of treatment (week 12). |
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E.5.2 | Secondary end point(s) |
1. Health-related Quality of life:
- NeuroQol. - Newcastle Mitochondrial Quality of Life questionnaire (NMQ). - Visual Analogue Scales (VAS) for pain and most bothersome symptom.
2. Reported perceived fatigue: - Fatigue Impact Scale (FIS). - Fatigue Severity Scale (FSS).
3. Symptom-limited cardiopulmonary fitness. Cardiopulmonary exercise testing (CPET) to include assessments at rest, during and/or at exhaustion (peak): - VO2. - VCO2. - Anaerobic Threshold (AT). - Pulmonary Ventilation (VE). - Respiratory Exchange Ratio (RER). - Breathing Frequency (f) via breath-by-breath indirect calorimetry. - Work rate (Power measured in watts). - Heart Rate (HR). - Stroke Volume (SV). - Cardiac Output (Q). - Arteriovenous Oxygen Difference (a-VO2 difference) via non-invasive bioreactance cardiac output. - Rate of Perceived Exertion. - Blood lactate via ear prick and/ or blood test
4. Disease burden:
- Newcastle Mitochondrial Disease Adult Scale (NMDAS).
5. Upper and lower limb function, balance and walking:
- 6 Minute Walk Test (6MWT). - 10 metre timed walk (10MWT).
- Mini Balance Evaluation Systems Test (Mini-BESTest). - 9 hole peg test (9HPT). - 30 second Sit To Stand (STS).
- Ataxia Rating Scale (SARA).
6. Skeletal muscle analyses:
- ATP/ADP ratio via luminescence assay or metabolomics.
- NAD+/NADH ratio via metabolomics.
- mtDNA copy number via quantitative PCR.
- Respiratory chain deficiency via histochemistry and quadruple immunofluorescence.
- mtDNA heteroplasmy via q-RT PCR (single deletion) or pyro sequencing (m.3243A>G).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of secondary endpoints will occur at the baseline visit and at the end of treatment visit (week 12). |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5.1 | Number of sites anticipated in the EEA | 1 |
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 | Yes |
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
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The end of trial will be defined as the last patient last visit (LPLV), which will be when the last trial participant completes the telephone follow-up ‘visit’ at week 16. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 24 |