Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension

Study Overview
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Brief Summary
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This study provides an opportunity for subjects in the REFALS (3119002; NCT03505021) study to continue treatment with oral levosimendan. The study will also provide more information about long-term safety and effectiveness of oral levosimendan in patients with ALS. This is an open-label study, so that all eligible subjects that complete the double-blind REFALS study (48-weeks of treatment) will have the opportunity to receive oral levosimendan treatment. The primary objective, in addition to continuing treatment for subjects enrolled in the REFALS study, is to evaluate long-term safety of oral levosimendan in ALS patients. Another important objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS. This study is open only to patients taking part in the REFALS study.

Official Title
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Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS: Open-Label Extension for Patients Completing Study 3119002

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Levosimendan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written or verbal informed consent (IC) for participation in the study Subjects who completed 48 weeks of treatment according to the REFALS study protocol Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study Exclusion Criteria: Development (or significant worsening from baseline of the REFALS study) of serious cardiovascular disease (e.g.: myocardial infarction, heart failure, arrhythmia, stroke, or second or third degree atrioventricular (AV) block) Pulse/heart rate repeatedly >100 bpm after 5-minute rest at baseline. If the pulse/heart rate is >100 bpm in the first recording, then a second recording must be done after another 5 min rest to confirm pulse/heart rate >100 bpm Systolic blood pressure (SBP) <90 mmHg Severe renal impairment (creatinine clearance < 30ml/min or creatine >170 µmol/l at 48 week visit of the REFALS study, or on dialysis Severe hepatic impairment at the discretion of the investigator Women of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g.: oral hormonal contraceptive associated with inhibition of ovulation, intrauterine devices and long acting progestin agent), 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 Subject judged to be actively suicidal by the investigator Any other clinical significant cardiovascular, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levosimendan<br>Oral Levosimendan; Levosimendan 1mg capsules for oral administration, once to twice a day, continued as long as clinically beneficial. The total study duration is up to 3 years. | Drug: Levosimendan<br>* Levosimendan 1 mg capsule for oral administration<br>* Other names: ODM-109;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Recording | Adverse Events as subject counts and proportions (%) of subject per Adverse Event | From signing informed consent until 14-25 days after the last study treatment for all patients, an average of 23.5 weeks. | 
| Pulse/Heart Rate Assessment | Actual values and changes from baseline in supine pre-dose pulse/heart rate were summarised using descriptive statistics . | Change in pulse and heart rate(from ECG recording) from Baseline, week 2, week 4, week 6 (pulse rate only), Month 3, Month 6, end of study (subject's last visit, 2-48 weeks after study entry) | 
| 12-lead Electrocardiogram Assessments | Summarisation of any abnormal 12-lead ECG findings using descriptive statistics. | Baseline, week 2, week 4, month 3, month 6, end-of-study(subject's last visit, 2-48 weeks after study entry) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression | Count of study withdrawals due to disease progression | From Baseline through study completion(subject's last visit, 2-48 weeks after study entry) | 
| Supine Slow Vital Capacity (SVC) | Change from baseline in supine and sitting SVC (all devices) through to the end of the study, expressed as a % of predicted normal | The change from Baseline, week 2, week 4, month 3, month 6, end-of-study (subject's last visit, 2-48 weeks after study entry) | 
| Revised ALS Functional Rating Scale (ALSFRS-R) | ALSFRS-R scale contains 3 parameters related to respiratory function: Severity of dyspnea, occurrence of orthopnea (shortness of breath when in supine position i.e. lying flat), and the use of mechanical ventilation for respiratory in sufficiency. These 3 parameters are combined to create the respiratory domain with a score of 0-12(where 12 is normal function). Although individual items and patients vary, ALSFRS-R typically declines at a relatively constant rate over time. Plotted over time the slope of the line obtained indicates the speed of progression and thus an effective treatment might be expected ro reduce the slope of decline. | Change from Baseline in respiratory function of ALSFRS-R at study completion (subject's last visit, 2-48 weeks after study entry) | 
| Need for Respiratory Support Device | Time to respiratory device support (non invasive) or death | Time to event at study completion (subject's last visit, 2-48 weeks after study entry) | 
| Borg Category Ratio 10 Scale (CR 10) | Patients rated their perception of the severity of their dyspnea using the Borg Category Ration 10 scale (CR 10). The scale ranges from 0(no dysponea) to 10 (maximal dyspnea). each category is numbered and most but not all have verbal cues. At each assessment the patient scored the category they felt best described their symptoms. The analysis measured change from baseline to the end of the study in both a supine and sitting position where a negative score indicates improvement and a positive score reflects worsening. | Baseline through study completion (week 2, week 4, month 3, month 6, end of study (subject's last visit, 2-48 weeks after study entry) | 
| Number of Subjects Requiring Health and Home Care Resource Use | The number of study subjects requiring Health and home care resource use was aggregated over the course of the study for each subject and summarised using descriptive statistics. | Baseline through study completion (2- 48 weeks after study entry) | 
| Subject's Status for Tracheostomy and Survival | Number of patients with the need for tracheostomy or who died whilst on treatment from baseline to the end of the study was summarised using descriptive statistics. | Baseline to end of study (average 2-48 weeks after study entry | 
| Health Care Service Use During the Study(Stays in Hospital) | The number of night stays in hospital were recorded throughout the study using a diary given to the study subjects | From baseline to the end of the study(2-48 weeks after study entry) | 
| Health Care Service Use During the Study(Visits to the Emergency Room) | The number of visits to the emergency room were recorded throughout the study using a diary given to the study subjects | From baseline to the end of the study(2-48 weeks after study entry) | 
| Health Care Service Use During the Study (Days Spent in an Institutional Facility) | The number of days spent in an institutional facility were recorded throughout the study using a diary given to the study subjects | From baseline to the end of the study(2-48 weeks after study entry) |