E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
A3243G mitochondrial DNA point mutation and evidence of impaired mitochondrial function |
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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 |
To establish proof-of-concept of the efficacy of A0001 in the treatment of patients with an established mitochondrial disorder using metabolic imaging, a number of functional assessments, biochemical measures and patient/clinician-rated scales. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the tolerability and safety of A0001 in this patient population.
To establish pharmacokinetics of A0001 in this patient population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient has been diagnosed as having neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation. 2. Male or female patients of any race within the age range of 18 to 70 years. 3. Sexually active participants and their partners must agree to use two forms of highly effective method of contraception or sterilisation from the time specified prior to screening through 30 days following the last dose of study drug: - Intra-uterine device (IUD) in place for at least 2 months prior to screening; - Barrier method (condom or diaphragm) with spermicide for at least 14 days prior to screening; - Stable hormonal contraceptive for at least 3 months prior to screening; - Sexually active male patients, including sterilized men, must use a condom for the duration of the trial. 4. Patient must have <1.9 PCR/ATP ratio following the Cardiac MRS at screening. 5. Willingness to abstain from Idebenone and CoQ10 for 14 days prior to study enrollment and for the duration of the study. 6. No other significant disease, medical history, clinically significant abnormal laboratory values or physical examination findings except for that attributable to the A3243G mitochondrial DNA point mutation and has normal end organ function, in the opinion of the Investigator. 7. Patient can comprehend the nature and purpose of the study and agree to comply with the requirements of the entire protocol. 8. Patient can swallow three size 0 capsules twice daily. 9. Patient has voluntarily signed a Research Ethics Committee approved informed consent form to participate in the study after all relevant aspects of the study have been explained and discussed with the patient. |
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E.4 | Principal exclusion criteria |
1. Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study. 2. Use of any investigational product within the past 30 days. 3. Patients with Dementia as defined by Mini Mental State Exam (MMSE) < 26. 4. Clinically significant renal or liver impairment (ALT, AST > 2.0 x ULN), or prior evidence of a coagulation disorder. 5. History of or current gastro-intestinal diseases influencing drug absorption. 6. Patient is pregnant or lactating. 7. History, within 3 years, of drug abuse (including Benzodiazepines, opioids, amphetamine, cocaine, and THC). 8. History of alcoholism (within two years). 9. Patients taking warfarin or other anticoagulants. 10. Any currently known or expected increased risk of bleeding. 11. Uncontrolled diabetes. 12. Diagnosis of a coagulation disorder or a clinically significant abnormality in INR (>1.25x ULN). 13. Any subject considering or having scheduled any surgical procedure during the study or within a month after administration of the last dose of study. 14. Use of any new prescription drug therapy, or change in dose of existing therapy, within two weeks prior to receiving the first dose of study medication. 15. Known hypersensitivity or allergy to A0001, vitamin E, beta-carotene, or vehicle components or known allergies to drugs of the similar class which, in the opinion of the Investigator, suggests an increased potential for an adverse hypersensitivity to A0001. 16. Any patient judged by the Investigator or Sponsor (or designee) to be inappropriate for the study. 17. Presence of ACC/AHA Stage D cardiac failure at Screening defined as refractory heart failure requiring specialized interventions 18. Abnormal Troponin I level at Screening
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E.5 End points |
E.5.1 | Primary end point(s) |
Improvement in the rate of ATP recovery (“Vmax”) in cardiac muscle as measured by 31-Phosphorous Magnetic Resonance Spectroscopy (31P-MRS) is the primary measure under investigation. Cardiac function will be assessed by several measures.
The primary endpoint is the change in rate of ATP recovery (Vmax) and will be calculated as Day 28 - Baseline such that a positive value for the difference represents an improvement for the patient, i.e., a higher rate is desirable. The difference from baseline for A0001 will be compared against the change from baseline in the placebo group. The same analysis approach proposed for the change in rate of ATP recovery will be used for the analysis of the cardiac function on MRI.
Although formally listed as a secondary endpoint, changes in LV volume and LV mass will be calculated as Day 28 - Baseline values such that a positive value for the difference represents an improvement for the patient, i.e., increased cardiac function. If a patient discontinues the study prior to obtaining the Day 28 observation, a last observation carried forward approach (LOCF) will be used to impute a Day 28 value for the change from baseline calculation. Assuming a normal distribution for the change from baseline data, an analysis of covariance (ANCOVA) will be used to evaluate the the overall effect of treatment, using the baseline disposition index as the covariate. If the distribution represents a severe departure from normality, a non-parametric approach using ranks will be considered. |
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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 | Yes |
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 | 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 | No |
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.8.3 |
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 | Information not present in EudraCT |
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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |