Amyotrophic Lateral Sclerosis
Conditions
Brief summary
This study will evaluate whether prolonged oral levosimendan can preserve respiratory function more effectively than placebo, resulting in better patient functionality as measured by the ALSFRS-R scale. In this randomized, double-blind, placebo-controlled, parallel-group, multicenter study, subjects are allocated in a 2:1 ratio to receive either levosimendan (1 -2 mg daily) or placebo for 48 weeks. The primary endpoint is slow vital capacity (SVC) at 12 weeks, with the impact on patient function assessed through 48 weeks, adjusted for patient outcome, using ALSFRS-R (combined assessment of function and survival, CAFS). Other important efficacy measures include time to respiratory events, clinical global impression (CGI), assessment of dyspnea using the Borg scale and sleep scales (Pittsburgh sleep quality index and Epworth sleepiness scale). Patient safety is monitored using conventional methods including adverse events, safety laboratory tests, vital signs and 12-lead EKG. Following screening and baseline visits, patients attend the clinic at 2, 4, 8, 12, 24, 36 and 48 weeks, with telephone assessments conducted at weeks 18, 30 and 42. An end of study visit is performed 14-25 days after the last study treatment administration. The study will be monitored by an independent data and safety monitoring board. A long-term extension study will be available for patients completing the study.
Interventions
DRUGLevosimendan
Levosimendan 1 mg capsule for oral administration
DRUGPlacebo for levosimendan
Placebo capsule for oral administration
Sponsors
Orion Corporation, Orion Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Written or verbal informed consent (IC) for participation in the study * Male or female subjects with diagnosis of laboratory supported probable, probable or definite ALS according to El Escorial revised criteria. Full electromyogram (EMG) report available consistent with ALS (but not necessarily fulfilling the electrodiagnostic criteria for ALS) from an experienced neurophysiologist * Able to swallow study treatment capsules, and in the opinion of the investigator, is expected to continue to do so during the study * Sitting SVC between 60-90% of the predicted value for age, height and sex at screening visit * Disease duration from symptom onset (defined by first muscle weakness or dysarthria) 12-48 months at the time of visit 1 (baseline) * Able to perform supine SVC in an adequate and reliable way at screening and baseline visits as judged by the investigator * Subjects with or without riluzole and/or edaravone. If using riluzole (any daily dose up to 100 mg), the dose must have been stable for at least 4 weeks before the screening visit and should not be changed during the study. If using edaravone, the treatment should have been started at least 4 weeks before the screening visit (at least one 28-day treatment cycle as indicated) and should not be changed during the study. If not on riluzole and/or edaravone, the respective treatments should not be started during the study
Exclusion criteria
* Subject in whom other causes of neuromuscular weakness have not been excluded * Subject with a diagnosis of another neurodegenerative disease (e.g. Parkinson's or Alzheimer's disease) * Assisted ventilation of any type within 3 months before the screening visit or at screening * Any use of a diaphragm pacing system (DPS) within 3 months before the screening visit * Any form of stem cell or gene therapy for the treatment of ALS * Known hypersensitivity to levosimendan * Administration of levosimendan within 3 months before the screening visit or previous participation in the present phase III study or earlier study with oral levosimendan in ALS patients (LEVALS) * Any use of tirasemtiv or reldesemtiv within 1 month before the screening visit. * Participation in a clinical trial with any experimental treatment within 30 days or within 5 half-lives of that treatment (whichever is longer) before the screening visit * Any botulinum toxin use within 3 months before the screening visit * Recorded diagnosis or evidence of major psychiatric diagnosis, significant cognitive impairment or clinically evident dementia that may interfere with the patient's ability to comply with study procedures * Pulmonary illness (e.g. asthma or COPD) requiring regular treatment * Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy or restrictive cardiomyopathy * Any cardiovascular event (e.g. myocardial infarction, HF, arrhythmia or stroke) requiring hospitalisation within 3 months before the screening visit * History of Torsades de Pointes (TdP) or diagnosed long QT-syndrome * History of life-threatening ventricular arrhythmia, unless treated with reliable measures to prevent recurrence (e.g. with placement of implantable cardioverter defibrillator \[ICD\] or catheter ablation) * History of second or third degree atrioventricular (AV) block or sinus node disease at screening, if not treated with pacemaker * HR repeatedly \> 100 bpm in the 12-lead ECG after a 5-minute rest at screening. If the HR is \> 100 bpm in the first recording, then the second recording must be done after another 5 min rest to confirm HR \> 100 bpm * Systolic blood pressure (SBP) \< 90 mmHg at screening * Potassium \< 3.7 mmol/l or \> 5.5 mmol/l at screening * Severe renal impairment (creatinine clearance \< 30 ml/min at screening), creatinine \> 170 μmol/l at screening or on dialysis * Blood haemoglobin \< 10 g/dl at screening or blood donation or loss of significant amount of blood within 60 days before the screening visit * Clinically significant hepatic impairment at the discretion of the investigator * Body mass index (BMI) ≤ 18.5kg/m2 (BMI = weight/height2) * Women who are lactating or of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g. oral hormonal contraceptives associated with inhibition of ovulation, intrauterine devices 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 * Patient judged to be actively suicidal by the investigator during 3 months before the screening visit * Patients with known history of human immunodeficiency virus (HIV) infection * Any other clinically 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Supine Slow Vital Capacity (SVC) | The change from baseline at 12 weeks | Change from baseline to 12 weeks, expressed as % of predicted normal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Combined Assessment of Function and Survival Through 48 Weeks | Mean rank at 48 weeks | Scale: The ALS Functional Rating Scale - Revised. This scale includes 12 items. Each item was scored from 0 to 4. Total score is the sum of the scores of all 12 items. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than after deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 496 (the number of participants assessed for the Outcome Measure) with larger rank score numbers associated with a better outcome. |
| Time to Respiratory Event Through 48 Weeks | Time to event through 48 weeks | ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. A reduction in any one of these items was considered a respiratory event. Not all patients receive ventilatory support, despite respiratory insufficiency: meeting protocolised criteria for NIV relates to patients without NIV whose slow vital capacity declined to a level that would ordinarily trigger such treatment. |
| Change From the Baseline in Clinical Global Impression CGI at 48 Weeks | The change from baseline at 48 weeks | Visual Analogue Scale 0-100 millimeters, rated by study subjects. Score 0 indicates that the subject is completely well without any disability and score 100 indicates the worst possible severity of the condition. |
| Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks | Slope of decline at 48 weeks | ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. These are added together to created the respiratory domain with a score range 0-12 (where 12 represents 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 to reduce the slope of decline. |
| Supine Borg Category Ratio 10 Scale at 12 Weeks | Change from baseline at 12 weeks | Patients rated their perception of the severity of their dysnoea using the Borg scale. The scale ranges from 0 (no dyspnoea) to 10 (maximal). Each category is numbered and most (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 at 12 weeks, where a negative score indicates improvement and a positive score reflects worsening. |
Countries
Australia, Austria, Belgium, Canada, Finland, France, Germany, Ireland, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Patients with amyotrophic lateral sclerosis (ALS) were recruited.
Pre-assignment details
Male or female subjects with a diagnosis of probable or definite ALS according to El Escorial revised criteria, disease duration from symptom onset of 12-48 months, written or verbal IC obtained. Able to swallow study treatment capsules. Sitting SVC between 60-90% of the predicted value at screening visit. Stable riluzole and/or edaravone allowed.
Participants by arm
| Arm | Count |
|---|---|
| Levosimendan Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks
Levosimendan: Levosimendan 1 mg capsule for oral administration | 329 |
| Placebo for Levosimendan Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.
Placebo for levosimendan: Placebo capsule for oral administration | 167 |
| Total | 496 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 9 |
| Overall Study | Consent withdrawn by subject | 6 | 1 |
| Overall Study | Death | 9 | 8 |
| Overall Study | Disease progression | 33 | 17 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Other | 11 | 5 |
| Overall Study | Personal reason | 21 | 12 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo for Levosimendan | Total | Levosimendan |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 10.8 | 59.3 years STANDARD_DEVIATION 11.1 | 59 years STANDARD_DEVIATION 11.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 10 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) White | 157 Participants | 462 Participants | 305 Participants |
| Region of Enrollment Australia | 6 participants | 20 participants | 14 participants |
| Region of Enrollment Austria | 1 participants | 7 participants | 6 participants |
| Region of Enrollment Belgium | 10 participants | 22 participants | 12 participants |
| Region of Enrollment Canada | 22 participants | 47 participants | 25 participants |
| Region of Enrollment Finland | 3 participants | 13 participants | 10 participants |
| Region of Enrollment France | 5 participants | 8 participants | 3 participants |
| Region of Enrollment Germany | 26 participants | 80 participants | 54 participants |
| Region of Enrollment Ireland | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Italy | 16 participants | 34 participants | 18 participants |
| Region of Enrollment Netherlands | 8 participants | 16 participants | 8 participants |
| Region of Enrollment Spain | 15 participants | 59 participants | 44 participants |
| Region of Enrollment Sweden | 7 participants | 26 participants | 19 participants |
| Region of Enrollment United Kingdom | 1 participants | 9 participants | 8 participants |
| Region of Enrollment United States | 45 participants | 150 participants | 105 participants |
| Sex: Female, Male Female | 67 Participants | 189 Participants | 122 Participants |
| Sex: Female, Male Male | 100 Participants | 307 Participants | 207 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 326 | 17 / 166 |
| other Total, other adverse events | 312 / 326 | 157 / 166 |
| serious Total, serious adverse events | 89 / 326 | 45 / 166 |
Outcome results
Primary
Supine Slow Vital Capacity (SVC)
Change from baseline to 12 weeks, expressed as % of predicted normal.
Time frame: The change from baseline at 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Levosimendan | Supine Slow Vital Capacity (SVC) | -6.731 percentage |
| Placebo for Levosimendan | Supine Slow Vital Capacity (SVC) | -6.988 percentage |
p-value: 0.825395% CI: [-2.032, 2.547]ANCOVA
Secondary
Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks
ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. These are added together to created the respiratory domain with a score range 0-12 (where 12 represents 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 to reduce the slope of decline.
Time frame: Slope of decline at 48 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks | -0.191 Score on a scale/month | Standard Error 0.015 |
| Placebo for Levosimendan | Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks | -0.205 Score on a scale/month | Standard Error 0.022 |
p-value: 0.62395% CI: [-0.04, 0.066]Mixed Models Analysis
Secondary
Change From the Baseline in Clinical Global Impression CGI at 48 Weeks
Visual Analogue Scale 0-100 millimeters, rated by study subjects. Score 0 indicates that the subject is completely well without any disability and score 100 indicates the worst possible severity of the condition.
Time frame: The change from baseline at 48 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Levosimendan | Change From the Baseline in Clinical Global Impression CGI at 48 Weeks | 17.048 units on a scale |
| Placebo for Levosimendan | Change From the Baseline in Clinical Global Impression CGI at 48 Weeks | 13.285 units on a scale |
p-value: 0.129595% CI: [-1.129, 8.654]ANCOVA
Secondary
Combined Assessment of Function and Survival Through 48 Weeks
Scale: The ALS Functional Rating Scale - Revised. This scale includes 12 items. Each item was scored from 0 to 4. Total score is the sum of the scores of all 12 items. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than after deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 496 (the number of participants assessed for the Outcome Measure) with larger rank score numbers associated with a better outcome.
Time frame: Mean rank at 48 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Combined Assessment of Function and Survival Through 48 Weeks | 239.85 Scores on a rank scale | Standard Error 10.98 |
| Placebo for Levosimendan | Combined Assessment of Function and Survival Through 48 Weeks | 229.16 Scores on a rank scale | Standard Error 13.31 |
p-value: 0.427795% CI: [-15.74, 37.12]ANCOVA
Secondary
Supine Borg Category Ratio 10 Scale at 12 Weeks
Patients rated their perception of the severity of their dysnoea using the Borg scale. The scale ranges from 0 (no dyspnoea) to 10 (maximal). Each category is numbered and most (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 at 12 weeks, where a negative score indicates improvement and a positive score reflects worsening.
Time frame: Change from baseline at 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Supine Borg Category Ratio 10 Scale at 12 Weeks | -0.152 score on a scale | Standard Error 0.138 |
| Placebo for Levosimendan | Supine Borg Category Ratio 10 Scale at 12 Weeks | 0.120 score on a scale | Standard Error 0.186 |
p-value: 0.175295% CI: [-0.666, 0.122]ANCOVA
Secondary
Time to Respiratory Event Through 48 Weeks
ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. A reduction in any one of these items was considered a respiratory event. Not all patients receive ventilatory support, despite respiratory insufficiency: meeting protocolised criteria for NIV relates to patients without NIV whose slow vital capacity declined to a level that would ordinarily trigger such treatment.
Time frame: Time to event through 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levosimendan | Time to Respiratory Event Through 48 Weeks | 90 Days |
| Placebo for Levosimendan | Time to Respiratory Event Through 48 Weeks | 126 Days |
p-value: 0.673395% CI: [0.833, 1.327]Regression, Cox