Trial Outcomes & Findings for Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS (NCT NCT03505021)

NCT ID: NCT03505021

Last Updated: 2022-05-11

Results Overview

Change from baseline to 12 weeks, expressed as % of predicted normal.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

496 participants

Primary outcome timeframe

The change from baseline at 12 weeks

Results posted on

2022-05-11

Participant Flow

Patients with amyotrophic lateral sclerosis (ALS) were recruited.

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.

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	329	167
Overall Study COMPLETED	217	112
Overall Study NOT COMPLETED	112	55

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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
Overall Study Protocol Violation	1	0
Overall Study Death	9	8
Overall Study Consent withdrawn by subject	6	1
Overall Study Lost to Follow-up	5	3
Overall Study Adverse Event	26	9
Overall Study Disease progression	33	17
Overall Study Other	11	5
Overall Study Personal reason	21	12

Baseline Characteristics

Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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	Total n=496 Participants Total of all reporting groups
Age, Continuous	59 years STANDARD_DEVIATION 11.2 • n=93 Participants	59.7 years STANDARD_DEVIATION 10.8 • n=4 Participants	59.3 years STANDARD_DEVIATION 11.1 • n=27 Participants
Sex: Female, Male Female	122 Participants n=93 Participants	67 Participants n=4 Participants	189 Participants n=27 Participants
Sex: Female, Male Male	207 Participants n=93 Participants	100 Participants n=4 Participants	307 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	9 Participants n=93 Participants	1 Participants n=4 Participants	10 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	5 Participants n=93 Participants	3 Participants n=4 Participants	8 Participants n=27 Participants
Race (NIH/OMB) White	305 Participants n=93 Participants	157 Participants n=4 Participants	462 Participants n=27 Participants
Race (NIH/OMB) More than one race	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	9 Participants n=93 Participants	6 Participants n=4 Participants	15 Participants n=27 Participants
Region of Enrollment United States	105 participants n=93 Participants	45 participants n=4 Participants	150 participants n=27 Participants
Region of Enrollment United Kingdom	8 participants n=93 Participants	1 participants n=4 Participants	9 participants n=27 Participants
Region of Enrollment Spain	44 participants n=93 Participants	15 participants n=4 Participants	59 participants n=27 Participants
Region of Enrollment Canada	25 participants n=93 Participants	22 participants n=4 Participants	47 participants n=27 Participants
Region of Enrollment Austria	6 participants n=93 Participants	1 participants n=4 Participants	7 participants n=27 Participants
Region of Enrollment Netherlands	8 participants n=93 Participants	8 participants n=4 Participants	16 participants n=27 Participants
Region of Enrollment Sweden	19 participants n=93 Participants	7 participants n=4 Participants	26 participants n=27 Participants
Region of Enrollment Belgium	12 participants n=93 Participants	10 participants n=4 Participants	22 participants n=27 Participants
Region of Enrollment Ireland	3 participants n=93 Participants	2 participants n=4 Participants	5 participants n=27 Participants
Region of Enrollment Finland	10 participants n=93 Participants	3 participants n=4 Participants	13 participants n=27 Participants
Region of Enrollment Italy	18 participants n=93 Participants	16 participants n=4 Participants	34 participants n=27 Participants
Region of Enrollment Australia	14 participants n=93 Participants	6 participants n=4 Participants	20 participants n=27 Participants
Region of Enrollment France	3 participants n=93 Participants	5 participants n=4 Participants	8 participants n=27 Participants
Region of Enrollment Germany	54 participants n=93 Participants	26 participants n=4 Participants	80 participants n=27 Participants

PRIMARY outcome

Timeframe: The change from baseline at 12 weeks

Change from baseline to 12 weeks, expressed as % of predicted normal.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Supine Slow Vital Capacity (SVC)	-6.731 percentage Interval -8.29 to -5.171	-6.988 percentage Interval -9.052 to -4.925

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Combined Assessment of Function and Survival Through 48 Weeks	239.85 Scores on a rank scale Standard Error 10.98	229.16 Scores on a rank scale Standard Error 13.31

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Time to Respiratory Event Through 48 Weeks	90 Days Interval 82.0 to 144.0	126 Days Interval 82.0 to 169.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Change From the Baseline in Clinical Global Impression CGI at 48 Weeks	17.048 units on a scale Interval 14.111 to 19.984	13.285 units on a scale Interval 9.252 to 17.318

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks	-0.191 Score on a scale/month Standard Error 0.015	-0.205 Score on a scale/month Standard Error 0.022

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Levosimendan n=329 Participants 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	Placebo for Levosimendan n=167 Participants 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
Supine Borg Category Ratio 10 Scale at 12 Weeks	-0.152 score on a scale Standard Error 0.138	0.120 score on a scale Standard Error 0.186

Adverse Events

Levosimendan

Serious events: 89 serious events

Other events: 312 other events

Deaths: 27 deaths

Placebo for Levosimendan

Serious events: 45 serious events

Other events: 157 other events

Deaths: 17 deaths

Serious adverse events

Other adverse events

Additional Information

Director, Clinical Operations

Orion Corporation

Phone: 358104261

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Levosimendan n=326 participants at risk 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	Placebo for Levosimendan n=166 participants at risk 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
Blood and lymphatic system disorders Breast cancer	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Blood and lymphatic system disorders Hypopharyngeal cancer	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Blood and lymphatic system disorders Invasive ductal breast carcinoma	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Blood and lymphatic system disorders Metastases to liver	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Acute myocardial infarction	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Atrial fibrillation	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Cardiac arrest	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Cardiac failure	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Coronary artery disease	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Coronary artery dissection	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Diastolic dysfunction	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Myocardial infarction	0.92% 3/326 • Number of events 3 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Sinus tachycardia	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Stress cardiomyopathy	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Supraventricular tachycardia	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Tachycardia	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Congenital, familial and genetic disorders Hypertrophic cardiomyopathy	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Ear and labyrinth disorders Vertigo positional	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Abdominal distension	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Abdominal pain	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Diarrhoea	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Dysphagia	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Gastric ulcer hemorrhage	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Gastritis	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Gastroesophageal reflux disease	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Ileus	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Ileus paralytic	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Nausea	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Peptic ulcer	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Vomiting	0.61% 2/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Asthenia	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Cardiac death	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Catheter site inflammation	0.31% 1/326 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Chest pain	1.2% 4/326 • Number of events 4 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Death	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Euthanasia	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Sudden death	0.00% 0/326 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Hepatobiliary disorders Cholelithiasis	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Infections and infestations Appendicitis	0.31% 1/326 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.

Other adverse events
Measure	Levosimendan n=326 participants at risk 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	Placebo for Levosimendan n=166 participants at risk 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
Cardiac disorders Palpitations	5.2% 17/326 • Number of events 23 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	2.4% 4/166 • Number of events 4 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Sinus tachycardia	4.0% 13/326 • Number of events 14 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.00% 0/166 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Cardiac disorders Tachycardia	9.8% 32/326 • Number of events 41 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	4.8% 8/166 • Number of events 11 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Abdominal pain	3.7% 12/326 • Number of events 13 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	1.2% 2/166 • Number of events 2 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Constipation	11.7% 38/326 • Number of events 41 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	12.7% 21/166 • Number of events 22 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Diarrhoea	8.0% 26/326 • Number of events 31 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	8.4% 14/166 • Number of events 18 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Dysphagia	14.4% 47/326 • Number of events 55 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	16.3% 27/166 • Number of events 31 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Nausea	8.9% 29/326 • Number of events 35 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	9.0% 15/166 • Number of events 17 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Gastrointestinal disorders Salivary hypersecretion	6.7% 22/326 • Number of events 23 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	5.4% 9/166 • Number of events 10 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Asthenia	4.9% 16/326 • Number of events 19 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	0.60% 1/166 • Number of events 1 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Fatigue	9.2% 30/326 • Number of events 33 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	6.0% 10/166 • Number of events 11 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
General disorders Oedema peripheral	8.0% 26/326 • Number of events 28 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	7.2% 12/166 • Number of events 14 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Infections and infestations Nasopharyngitis	16.0% 52/326 • Number of events 62 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	15.7% 26/166 • Number of events 31 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Infections and infestations Upper respiratory tract infection	4.0% 13/326 • Number of events 16 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	3.0% 5/166 • Number of events 5 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Infections and infestations Urinary tract infection	7.7% 25/326 • Number of events 31 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	10.2% 17/166 • Number of events 22 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Investigations Heart rate increased	19.6% 64/326 • Number of events 68 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	3.0% 5/166 • Number of events 5 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Investigations Weight decreased	8.0% 26/326 • Number of events 27 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	9.0% 15/166 • Number of events 15 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Injury, poisoning and procedural complications Contusion	6.4% 21/326 • Number of events 23 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	4.8% 8/166 • Number of events 9 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Injury, poisoning and procedural complications Fall	26.4% 86/326 • Number of events 150 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	27.1% 45/166 • Number of events 100 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Injury, poisoning and procedural complications Skin laceration	5.2% 17/326 • Number of events 20 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	7.2% 12/166 • Number of events 15 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 13/326 • Number of events 15 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	5.4% 9/166 • Number of events 9 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Back pain	4.3% 14/326 • Number of events 16 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	4.2% 7/166 • Number of events 11 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Muscle spasms	5.2% 17/326 • Number of events 21 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	4.2% 7/166 • Number of events 8 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Muscular weakness	9.5% 31/326 • Number of events 39 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	10.8% 18/166 • Number of events 18 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.3% 14/326 • Number of events 17 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	4.8% 8/166 • Number of events 8 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Neck pain	3.1% 10/326 • Number of events 11 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	3.6% 6/166 • Number of events 6 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Musculoskeletal and connective tissue disorders Pain in extremity	7.4% 24/326 • Number of events 28 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	3.6% 6/166 • Number of events 6 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Nervous system disorders Dizziness	6.4% 21/326 • Number of events 35 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	7.8% 13/166 • Number of events 14 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Nervous system disorders Headache	31.0% 101/326 • Number of events 142 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	21.7% 36/166 • Number of events 49 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Psychiatric disorders Anxiety	5.5% 18/326 • Number of events 18 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	3.6% 6/166 • Number of events 6 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Psychiatric disorders Depression	4.0% 13/326 • Number of events 13 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	2.4% 4/166 • Number of events 4 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Psychiatric disorders Insomnia	6.7% 22/326 • Number of events 22 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	6.0% 10/166 • Number of events 10 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Respiratory, thoracic and mediastinal disorders Cough	4.9% 16/326 • Number of events 19 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	7.8% 13/166 • Number of events 15 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.6% 54/326 • Number of events 61 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	18.1% 30/166 • Number of events 35 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Respiratory, thoracic and mediastinal disorders Respiratory failure	5.2% 17/326 • Number of events 17 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	7.2% 12/166 • Number of events 12 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.
Vascular disorders Hypertension	2.5% 8/326 • Number of events 8 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.	5.4% 9/166 • Number of events 10 • From signing an informed consent until 25 days from stopping the treatment, up to 51 weeks. Four randomised patients - three in the levosimendan group and one in the placebo group - did not start study treatment and so are not included in the safety population.