| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Amyotrophic lateral sclerosis (ALS). A rapidly progressive neurological disease characterized by degeneration of upper and lower motor neurons with subsequent muscle atrophy and weakness and loss of respiratory function. The latter is due to the weakness and loss of the diaphragm muscle strength. |
|
| E.1.1.1 | Medical condition in easily understood language |
| ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spine. ALS causes these nerve cells to degenerate and die. This prevents the Brain from controlling muscles. |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002026 |
| E.1.2 | Term | Amyotrophic lateral sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system 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 primary objective of the study is to investigate the efficacy of oral levosimendan on respiratory function in patients with Amyotrophic Lateral Sclerosis. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effect of oral levosimendan (IMP) on:
1- Hand grip strength
2- Hand grip endurance
3- patient quality of life
4- patient daily functions
The study will also collect data on safety and tolerability of the IMP.
The study will evaluate the concentrations of the IMP, and the substances that the human body naturally forms to metabolize the IMP (metabolites), in the blood stream.
The study will also examine how the presence of these naturally formed metabolites impact on study endpoints.
The study will also examine the effects of the IMP on another commercially available drug, called Riluzole. Those patients who are on riluzole, are required to be on a stable dose at the time of enrollment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written or verbal informed consent (IC) for participation in the study
will be obtained from the subject . In case the study subject him/herself
cannot sign the IC due to severe muscle weakness, a witness may sign
the consent form to indicate that the subject has given verbal consent.
2. Age of at least 18 years.
3. Male or female subjects with diagnosis of laboratory supported
probable, probable or definite ALS according to El Escorial revised
criteria (Brooks BR et al., 2000). Full electromyogram (EMG) report
available consistent with ALS (but not necessarily fulfilling
electrodiagnostic criteria for ALS) from an experienced
neurophysiologist.
4. Ability to swallow the study treatment capsules.
5. An upright (sitting position) Slow Vital Capacity between 60-90% of the predicted value for age, height and sex at screening visit.
6. Normal oxygen saturation during daytime (measure of ≥ 95% when steady state has been reached with a reliable read) in sitting position measured by pulse oximetry.
7. Disease duration from symptom onset (defined by first muscle
weakness or dysarthria) of 12-48 months at the time of baseline/day 1
of the first treatment period.
8. Patients with or without riluzole. If using riluzole, the dose must have
been stable for at least 4 weeks prior to screening and should not be
changed during the cross-over, doubleblind part of the study. |
|
| E.4 | Principal exclusion criteria |
1. Subject in whom other causes of neuromuscular weakness have not been excluded.
2. Subject with a diagnosis of another neurodegenerative disease
3. Assisted ventilation or gastrostomy of any type during the preceding 3 months prior to screening or predicted to be required within the randomised, double-blind cross-over part of the study
4. Recorded diagnosis or evidence of major psychiatric diagnosis, significant cognitive impairment or clinically evident dementia
5. Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy or restrictive cardiomyopathy
6. Acute myocardial infarction or any other acute coronary event within 1 month before the screening visit
7. Any major surgery within 1 month before the screening visit or patients who are scheduled for any major surgery during the planned study period
8. History of Torsades de Pointes, family history of long QT-syndrome or history of life-threatening ventricular arrhythmia within 3 months before screening
9. Heart Rate of less that 50 or greater than 100 beats per minute as an average over the 24-hour ambulatory Holter-ECG recording at screening
10. Systolic blood pressure (SBP) less than 100 mmHg or greater than 180 mmHg, or diastolic blood pressure (DBP) greater than 100 mmHg at screening.
11. Ventricular tachycardia (wide complex tachycardia greater than 100/min, greater than 5 consecutive beats) in the 24-hour ambulatory Holter-ECG recording at screening.
12. Episode of atrial fibrillation or atrial flutter lasting greater than 60 seconds in 24-hour ambulatory Holter-ECG recording at screening.
13. Second or third degree atrioventricular (AV) block in the 12-lead ECG or in the 24-hour ambulatory Holter-ECG recording at screening.
14. Potassium less than 3.7 mmol/l or greater than 5.5 mmol/l at screening
15. Creatinine greater than 170 µmol/l at screening or on dialysis.
16. Blood haemoglobin less than 10 g/dl at screening.
17. Clinically significant hepatic impairment at the discretion of the investigator.
18. Women of reproductive age without a negative pregnancy test and without a commitment to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents), if sexually active during the study, and for 1 month after the last dose of the study treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be reproductive and can be included.
19. Known hypersensitivity to levosimendan.
20. Administration of levosimendan within 30 days prior to screening visit.
21. Any botulinum toxin use within 3 months from screening. Use of
botulinum toxin is not allowed during double-blind, cross-over part of
the study.
22. Patients with known history of human immunodeficiency virus (HIV) infection.
23. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness that in the opinion of the investigator could interfere with the interpretation of the study results or constitute a health risk for the subject if he/she took part in the study.
24. Blood donation or loss of significant amount of blood within 60 days prior to screening.
25. Participation in a clinical trial with any experimental treatment within 30 days prior to the screening visit or previous participation in the present study.
26. Any other condition that in the opinion of the investigator could interfere with the interpretation of the study results or constitute a health risk for the subject if they took part in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the seated slow vital capacity (SVC) as defined as the change from baseline to the day 14 predose assessment in terms of the SVC% compared to the predicted value for age, height and sex. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary objectives of the study are to evaluate the efficacy endpoints during the double-blind cross-over part of the study. Efficacy assessments may be repeated throughout the study, however the assessment performed on day 14, pre-dose will be considered primary. The efficacy data assessed on other time points and during the open-label follow-up part will be considered supportive. All efficacy endpoints from both parts of the study will be listed and summarised by treatment groups using appropriate descriptive statistics. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
1) Respiratory function
1.1 SNP
1.2 Overnight SpO2
1.3 SVC (supine)
2) Muscle strength
2.1 Maximal hand grip strength
2.2 Submaximal hand grip endurance
3) Subject reported outcomes
3.1 Subjects’ assessment of CGI-C
3.2 Investigators’ assessment of CGI-C
3.3 Subjects’ assessment of fatigue (VAS)
4) Quality of life
4.1 EQ-5D-5L
4.2 SF-36 Acute form |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints will be evaluated primarily at the end of double-blind cross-over part.
Efficacy assessments may be repeated throughout the study for the secondary endpoint, however the assessment performed on day 14, pre-dose will be considered primary for analysis. The efficacy data assessed on other time points and from the open-label follow-up will be considered supportive. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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