Conditions: Amyotrophic Lateral Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 496
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks arm 2: Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.

Interventions: intervention 1: Levosimendan intervention 2: Placebo for levosimendan
Intervention descriptions: intervention 1: Levosimendan 1 mg capsule for oral administration intervention 2: Placebo capsule for oral administration

Protocol document:
Prot_000.pdf: 
 
 
Document type: 
Clinical study protocol 
Title: 
Effects of oral levosimendan (ODM-109) on respiratory function in 
patients with ALS 
NCT Number: 
NCT03505021 
Document date: 
26 March 2020 
 




ODM-109
Clinical study protocol 3119002 – Amendment 3
Sponsor approvals:
 
 
 
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................... 3
LIST OF TABLES........................................................................................................................... 6
SYNOPSIS .................................................................................................................................... 7
ABBREVIATIONS AND DEFINITION OF TERMS............................................................................. 10
1.
INTRODUCTION ................................................................................................................ 13
1.1
Background................................................................................................................ 13
1.2
Rationale of the study ................................................................................................ 16
1.2.1
Rationale of the study design ................................................................................ 16
1.2.2
Rationale for selected doses.................................................................................. 16
1.3
Benefit-risk assessment.............................................................................................. 17
1.3.1
Potential benefits associated with levosimendan .................................................. 17
1.3.2
Potential risks associated with levosimendan ....................................................... 17
1.3.3
Potential risks associated with the study assessments........................................... 17
2.
STUDY OBJECTIVES.......................................................................................................... 18
2.1
Primary objective....................................................................................................... 18
2.2
Secondary objective................................................................................................... 18
2.3
Other objectives ......................................................................................................... 18
2.4
Exploratory objectives ............................................................................................... 18
3.
OVERALL STUDY DESIGN AND PLAN................................................................................. 19
4.
SELECTION OF STUDY POPULATION.................................................................................. 19
4.1
Number of subjects .................................................................................................... 19
4.2
Inclusion criteria ........................................................................................................ 19
4.3
Exclusion criteria ....................................................................................................... 20
4.4
Information collected on screening failures............................................................... 22
4.5
Removal of subjects from treatment or assessment................................................... 22
5.
STUDY TREATMENTS........................................................................................................ 23
5.1
Investigational product............................................................................................... 23
5.2
Reference product ...................................................................................................... 23
5.3
Dosing........................................................................................................................ 23
5.3.1
Selection and timing of doses................................................................................ 23
5.3.2
Dose adjustment .................................................................................................... 23
5.4
Method of assigning study subjects to treatment groups........................................... 24
5.5
Blinding...................................................................................................................... 24
5.6
Emergency procedures............................................................................................... 24
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5.6.1
Treatment of emergencies..................................................................................... 25
5.7
Prior and concomitant treatments .............................................................................. 25
5.7.1
Prohibited treatments during the study.................................................................. 25
5.7.2
Permitted treatments during the study................................................................... 25
5.8
Treatment compliance and exposure ......................................................................... 26
5.9
Availability of investigational medicinal product after termination of study............ 26
6.
STUDY PROCEDURES AND ASSESSMENTS.......................................................................... 26
6.1
Study procedures........................................................................................................ 26
6.1.1
Procedures during the screening period ................................................................ 29
6.1.2
Procedures during the treatment period ................................................................ 29
6.1.3
Telephone contacts................................................................................................ 31
6.1.4
Additional visits .................................................................................................... 31
6.1.5
Procedures during the post-treatment period ........................................................ 32
6.1.6
Follow-up period for subjects who have discontinued the study medication ....... 32
6.2
Efficacy assessments.................................................................................................. 32
6.2.1
Slow Vital Capacity .............................................................................................. 32
6.2.2
Revised ALS Functional Rating Scale.................................................................. 33
6.2.3
Time to respiratory event ...................................................................................... 33
6.2.4
Clinical Global Impression.................................................................................... 33
6.2.5
Borg Category Ratio 10 Scale............................................................................... 34
6.2.6
Epworth Sleepiness Scale...................................................................................... 34
6.2.7
Pittsburgh Sleep Quality Index ............................................................................. 34
6.2.8
Health care and home care resource use ............................................................... 34
6.2.9
Other assessments ................................................................................................. 35
6.3
Pharmacokinetic assessments .................................................................................... 35
6.3.1
Blood sampling ..................................................................................................... 35
6.3.2
Determination of levosimendan, OR-1855 and OR-1896 concentrations in 
plasma.................................................................................................................... 35
6.3.3
Determination of riluzole concentrations in plasma ............................................. 35
6.3.4
Calculation of pharmacokinetic variables............................................................. 35
6.4
Biomarker, pharmacogenomic and other specific biological variables..................... 36
6.4.1
Biomarkers ............................................................................................................ 36
6.4.2
Pharmacogenomics................................................................................................ 36
6.5
Safety assessments..................................................................................................... 37
6.5.1
Adverse events ...................................................................................................... 37
6.5.1.1
Definitions ........................................................................................................ 37
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6.5.1.2
Assessment of adverse events .......................................................................... 38
6.5.1.3
Reporting of serious adverse events by the investigator .................................. 38
6.5.1.4
Reporting of serious adverse events to competent authorities and ethics 
committees........................................................................................................ 39
6.5.2
Special situations................................................................................................... 40
6.5.3
Pregnancy during the study................................................................................... 40
6.5.4
Clinical safety assessments ................................................................................... 40
6.5.5
Assessment of suicidality...................................................................................... 41
6.5.6
Laboratory safety assessments .............................................................................. 41
6.6
Changes implemented due to COVID-19 pandemic ................................................. 42
7.
DATA COLLECTION AND MANAGEMENT........................................................................... 44
8.
STATISTICAL METHODS.................................................................................................... 45
8.1
Statistical hypotheses................................................................................................. 45
8.2
Estimation of sample size .......................................................................................... 45
8.3
Analysis populations.................................................................................................. 46
8.4
Statistical analyses ..................................................................................................... 46
8.4.1
Demographic and other baseline characteristics ................................................... 46
8.4.2
Treatment compliance and extent of exposure...................................................... 46
8.4.3
Analysis of efficacy............................................................................................... 46
8.4.4
Pharmacokinetic analysis ...................................................................................... 47
8.4.5
Population PK/PD modelling................................................................................ 47
8.4.6
Evaluation of pharmacogenomics......................................................................... 47
8.4.7
Evaluation of exploratory biomarkers................................................................... 48
8.4.8
Safety analysis....................................................................................................... 48
8.4.8.1
Analysis of adverse events ............................................................................... 48
8.4.8.2
Clinical safety analysis..................................................................................... 48
8.4.8.3
Laboratory safety analysis................................................................................ 48
8.4.8.4
Analysis of prior and concomitant treatments.................................................. 49
8.4.8.5
Analysis of suicidality...................................................................................... 49
8.5
Interim analyses ......................................................................................................... 49
9.
DATA QUALITY ASSURANCE............................................................................................. 49
9.1
Training...................................................................................................................... 49
9.2
Case report forms....................................................................................................... 49
9.3
Monitoring, audits and inspections............................................................................ 49
9.4
Laboratories and other vendors.................................................................................. 50
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10.
FURTHER REQUIREMENTS AND GENERAL INFORMATION.................................................. 50
10.1
Investigators and study administrative structure........................................................ 50
10.1.1
Investigators .......................................................................................................... 50
10.1.2
Data and safety monitoring board ......................................................................... 50
10.2
Amendments to the study protocol ............................................................................ 51
10.3
Insurance.................................................................................................................... 51
10.4
Financial disclosure ................................................................................................... 51
10.5
Completion of the study............................................................................................. 51
10.6
Reports, publications and communication of results................................................. 52
10.7
Retention of records................................................................................................... 52
11.
ETHICS............................................................................................................................. 52
11.1
Ethics committee........................................................................................................ 52
11.2
Ethical conduct of the study....................................................................................... 52
11.3
Subject information and informed consent................................................................ 53
11.4
Subject data protection............................................................................................... 53
12.
REFERENCE LIST .............................................................................................................. 54
13.
SUMMARY OF CHANGES TO AMENDMENT 2 ..................................................................... 56
13.1
Revision history ......................................................................................................... 56
13.2
Summary of changes.................................................................................................. 56
14.
APPENDICES..................................................................................................................... 58
LIST OF TABLES
Table 1.
Schedule of study events....................................................................................... 27
Table 2.
Procedures at visit 1 (baseline).............................................................................. 30
Table 3.
Procedures at visits 2-8 ......................................................................................... 31
Table 4.
Procedures during additional visits ....................................................................... 32
Table 5. 
Blood sampling for the determination of levosimendan and its metabolites 
concentrations........................................................................................................ 35
Table 6.
Mean (SD) change from baseline SVC (supine)................................................... 46
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SYNOPSIS
Sponsor: Orion Corporation Orion Pharma
Finished product: Not applicable
Active pharmaceutical ingredient: Oral levosimendan (ODM-109)
Study title: Effects of oral levosimendan (ODM-109) on respiratory function in patients with ALS
Study code: 3119002
Investigator: The study coordinating investigator is Merit Cudkowicz.
Study centres: This will be a multinational study in approximately 100 centres.
Development phase: III
Objectives: The primary objective of this study is to confirm that levosimendan can significantly improve 
respiratory function measured by supine slow vital capacity (SVC) in amyotrophic lateral sclerosis (ALS) patients.
The secondary objective is to confirm that levosimendan improves the functionality of subjects, measured by 
Revised ALS Functional Rating Scale (ALSFRS-R), Clinical Global Impression (CGI), Borg Category Ratio 10 
(CR10) scale on dyspnoea, Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). The latter 
two are sleep scales assessing daytime somnolence and sleep quality, respectively. In addition, the long-term 
tolerability and safety of levosimendan in ALS patients will be evaluated, assessing up to 48 weeks of exposure. 
Other objectives: For the purposes of potential later pharmacoeconomic analysis, the use of specific health and home 
care resources and assistive devices will be quantified. This will include both in and outpatient care, as well as formal 
and informal home care.
Exploratory objectives: The plasma concentrations of levosimendan and the metabolites OR-1855 and OR-1896 will 
be determined. In addition, a population pharmacokinetic/pharmacodynamic (PK/PD) model between OR-1855 and 
OR-1896 exposure and efficacy related endpoints and heart rate (HR) will be explored. Plasma concentrations of 
riluzole will also be determined. The effects of levosimendan, OR-1855 and OR-1896 on plasma trough 
concentrations of riluzole will be evaluated. The acetylation status will be determined for all subjects to assess 
whether it affects the PD responses of levosimendan in patients with ALS.
Methodology: This is a randomised, double-blind, placebo-controlled, parallel-group, multinational, multicentre 
study. The subjects will be allocated to 2 parallel groups receiving either levosimendan 1-2 mg daily or placebo in 
2:1 ratio. There will be a screening visit, a baseline visit followed by visits at 2, 4, 8, 12, 24, 36 and 48 weeks, and 
telephone contacts during weeks 18, 30 and 42. An end-of-study visit will take place 14-25 days after the last study 
treatment administration for each subject. The total study duration for each subject will be about 51-52 weeks 
including the end-of-study visit.
Number of subjects: The planned number of subjects is approximately 450.
Diagnosis and main criteria for inclusion: Male or female subjects with diagnosis of ALS, disease duration from 
symptom onset of 12-48 months, written or verbal informed consent (IC) obtained from the subject. Age at least 18 
years. 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. 
Able to perform supine SVC at screening and baseline visits. 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.
Investigational medicinal product, dose and mode of administration: Levosimendan 1 mg capsule
Reference product, dose and mode of administration: Placebo Levosimendan capsule
Frequency/duration of treatment: The daily doses of oral levosimendan will be 1-2 mg depending on the 
tolerability (mainly judged by HR). The subjects will start with a 1 mg dose (in the morning) for 2 weeks.
Administration of placebo (1 or 2 capsules per day) will be based on the same criteria as for levosimendan.
Bioanalytical methods: The concentrations of levosimendan, OR-1855, OR-1896 and riluzole in plasma will be 
determined by validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods.
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Variables and methods of assessments:
Efficacy:

The primary efficacy variable will be the change from baseline at 12 weeks in SVC measured in supine position, 
SVC (supine). All SVC measurements prior to 12 weeks will be included in the statistical model. SVC is the 
maximum volume of air that can be exhaled slowly after slow maximum inhalation.

ALSFRS-R will be assessed. The variables derived will be the scores of the 12 separate items, the total scores 
of each subdomain and the total score of ALSFRS-R. 

The ‘Time to respiratory event’ composite endpoint will be used to validate the changes seen in supine SVC. 
This variable consists of the following events:
-
At least 1 point decrease in ALSFRS-R respiratory function score 10, 11 or 12
-
Meeting ‘protocolised’ criteria for NIV: supine SVC ≤ 50% predicted
-
Starting NIV (actual start or attempt to start NIV)
-
Invasive mechanical ventilation by intubation or tracheostomy or death
Time to respiratory event will be reached whenever any of the 4 criteria listed above has been first met.

CGI is used to rate the severity of subjects’ clinical condition. Clinical condition is assessed by the subjects 
themselves with a visual analogue scale (VAS).

Perception on the intensity of dyspnoea will be assessed by Borg CR10 scale in supine and sitting position.

Daytime somnolence will be assessed by ESS.

Sleep quality and disturbances will be assessed by PSQI.

Health care and home care resource use will be assessed for possible later use in pharmacoeconomic analysis.

Other assessments: Subject’s status for NIV support, invasive mechanical ventilation by intubation or 
tracheostomy and survival will be recorded at all visits.
Pharmacokinetics (PK): Blood samples for the determination of levosimendan, its metabolites OR-1855 and OR-
1896 and riluzole concentrations in plasma will be collected.
Biomarkers: Blood samples will be collected for exploratory biomarker analyses which may give supportive data 
related to the disease state of the subjects.
Pharmacogenomics (PG): All subjects will provide a blood sample for determination of subjects’ acetylation status 
(NAT polymorphisms). The DNA of subjects who have given a separate PG IC will be stored to allow possible 
exploratory PG research to assess whether genetic polymorphisms relate to the absorption, distribution, metabolism, 
excretion, pharmacodynamics or safety of levosimendan.
Safety: Safety will be assessed by adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), physical 
examination, weight, laboratory tests and by assessment of suicidality.
Statistical methods: The primary efficacy variable SVC (supine) will be compared between the treatment arms 
using the mixed model for repeated measures (MMRM) with between subject effects for treatment, centre and 
randomisation strata, time as within subject effect, and baseline value (visit 1) as a covariate. Primary efficacy will 
be evaluated at 12 weeks using contrasts to obtain estimates from the primary model including all SVC 
measurements prior to 12 weeks. Any missing data will be imputed using multiple imputation method. Effect of 
missing data imputation will be evaluated analysing observed data only and estimating the slope of decline using 
the random slope model. Several sensitivity subgroup analyses will be performed and defined in the statistical 
analysis plan (SAP). Additional evaluations will be performed including all data through 48 weeks, using MMRM.
Secondary efficacy endpoints will be tested in following hierarchy to preserve the overall alpha level:
1.
Combined assessment of ALSFRS-R function and survival through 48 weeks
2.
Time to respiratory event through 48 weeks
3.
CGI through 48 weeks
4.
Supine Borg CR 10 scale at 12 weeks
5.
Slope of decline in respiratory function of ALSFRS-R through 48 weeks
The efficacy variables time to respiratory event, time to NIV or death, time to SVC (supine) decline of 20%, time to 
SVC (supine) ≤50% of predicted, time to ALSFRS-R total score decline of 20% and time to decline in ALSFRS-R 
respiratory domain will be evaluated using Cox’s proportional regression model. The model will include effect for 
treatment and will be adjusted for randomisation strata. Premature discontinuations will be censored from the 
analyses. Censoring rules will be defined in the SAP.
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The efficacy variables ALSFRS-R total score and its subdomain scores will be performed through 48 weeks. Primary 
analysis will combine change from baseline to 48 weeks and survival through 48 weeks in joint rank analysis using 
Wilcoxon-Mann-Whitney test. Slope of decline will be estimated using the random slope model. Additional analyses 
will be conducted using the MMRM and estimates for individual time points will be done using contrasts. Imputation 
of missing data using the multiple imputation method will be considered.
CGI, Borg CR10 (sitting, supine and orthostatic changes), ESS and PSQI will be evaluated using the MMRM and 
estimates for individual time points will be done using contrasts. In addition categorical analyses for ESS and PSQI 
will be performed using repeated measures logistic regression using the generalised estimating equation (GEE) 
approach.
All efficacy data will be listed and summarised over the time and by treatment groups using appropriate descriptive 
statistics.
Standard safety evaluations will be performed for AEs, vital signs, 12-lead ECG, safety laboratory variables and 
suicidality.
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ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event 
ALP
Alkaline phosphatase
ALS
Amyotrophic lateral sclerosis
ALSFRS-R
Revised ALS Functional Rating Scale
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AV
Atrioventricular
b.i.d.
Twice a day
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
CA
Competent authority
CAFS
Combined assessment of function and survival
CHF
Chronic heart failure
CGI(-C)
Clinical Global Impression (of Change)
Cmax
Maximum concentration
CMV
Cytomegalovirus
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease 
CR10
Category Ratio 10
CRO
Contract research organisation
CRF
Case report form
DSMB
Data and safety monitoring board
EBV
Epstein-Barr virus 
EC
Ethics committee
ECG
Electrocardiogram
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eCRF
Electronic case report form
EDC
Electronic data capture
EMG
Electromyogram
ESS
Epworth Sleepiness Scale
FAS
Full analysis set
FDA
U.S. Food and Drug Administration
GCP
Good clinical practice
GGT
Gamma-glutamyl transferase
GMP
Good manufacturing practice 
HADS
Hospital Anxiety and Depression Scale
HAV
Hepatitis-A virus
HBc
Hepatitis B virus core antigen
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HCVAb
Hepatitis C virus antibody
HEV
Hepatitis-E virus
HF
Heart failure
HIV
Human immunodeficiency virus
HR
Heart rate
IC
Informed consent
ICD
Implantable cardioverter defibrillator
INR
International normalised ratio
IRB
Institutional review board
ITT
Intent-to-treat
i.v.
Intravenous
IWRS
Interactive web response system
LC-MS/MS
Liquid-chromatography-tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
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MG
Myasthenia gravis
MHRA
The Medicines and Healthcare Products Regulatory Agency
MMRM
Mixed model for repeated measures
NIV
Non-invasive mask ventilation
PD
Pharmacodynamic(s)
PG
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PP
Per-protocol
QTcF
QTc Fridericia
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SNP 
Sniff nasal pressure
SVC
Slow vital capacity
t1/2
Terminal elimination half-life
TdP
Torsades de Pointes
TIA
Transient ischemic attack
TSH
Thyroid-stimulating hormone
VAS
Visual analogue scale
ULN
Upper limit of normal
Note on usage of terms:
Orion Corporation Orion Pharma is hereafter in this document called “Orion” or sponsor.
The term ‘investigator’ in the text of the protocol refers to the principal investigator or co-
investigator. 
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1.
INTRODUCTION
1.1
Background
Amyotrophic lateral sclerosis (ALS) is a rare, rapidly progressive neurological disease 
characterised 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 diaphragm muscle strength. The median survival time from symptom onset is approximately 
3 years (Turner MR et al., 2013). There is an unmet need for new treatments in ALS. There are 
3 drugs currently indicated for ALS. The first was riluzole, which has only modest effects 
(approx. 3 months) on the survival of ALS patients (Bensimon G et al., 1994) and no
symptomatic effects. Riluzole is globally available. In addition, two new drugs have recently 
been approved for ALS in the US. Edaravone has modest effects on the Revised ALS Functional 
Rating Scale (ALSFRS-R), but does not specifically address muscle weakness and respiratory 
insufficiency in ALS. The other one is dextromethorphan/quinidine indicated for the 
symptomatic treatment of pseudobulbar affect. In later stage patients with significantly 
compromised respiratory function, it is a common practice to initiate non-invasive mask 
ventilation (NIV) to improve patients’ quality of life and survival (Andersen PM et al., 2012, 
NICE guideline [NG42], 2016).
Almost all of the new molecules under development are disease modifying in nature (Zinman L 
et al., 2011). Exceptions are fast skeletal muscle troponin activators, tirasemtiv and reldesemtiv
(CK-2127107), which increase the efficiency of muscle contraction. Despite promising effects 
on respiratory function (slow vital capacity [SVC]) in a 3-month phase II study in patients with 
ALS (Shefner JM et al., 2016) tirasemtiv did not show benefits over placebo in any of the 
primary or secondary endpoints in a recently completed phase III study (Press release, 2017). A 
phase II study investigating the effects of reldesemtiv on measures of respiratory function and 
skeletal muscle function in patients with ALS is currently ongoing.
Levosimendan is an inodilator originally developed for the treatment of heart failure (HF). The 
clinical intravenous (i.v.) programme included about 3400 patients, of whom almost 2000 
patients received levosimendan. Currently i.v. formulation of levosimendan (Simdax®) is 
registered in 60 countries. In these patients, levosimendan significantly increases cardiac output 
thus providing inotropic support to overcome the acute worsening of HF. The main mechanism 
of action of levosimendan is a selective binding to troponin C (Haikala H et al., 1995) and 
subsequent sensitisation of cardiac and fast and slow skeletal muscles to calcium. In addition, 
levosimendan opens ATP-sensitive potassium channels on the sarcolemma of smooth muscle 
cells and in the mitochondria of cardiomyocytes and has vasodilatory effects via potassium 
channel opening and antiaggregatory effects on thrombocytes. Levosimendan does not increase 
consumption of ATP or oxygen (Deschodt-Arsac V et al., 2010) and does not have any direct 
central nervous system (CNS) effects in laboratory animals with plasma concentrations up to 
> 10-100 times higher than those seen with daily oral levosimendan doses of 1-2 mg in man.
Levosimendan is metabolised by intestinal bacteria to OR-1855, which is further acetylated to 
OR-1896. About 5% of the levosimendan dose is converted to OR-1896. Both metabolites are 
active, but OR-1855 to a much lesser extent. 
The acetylation status of a subject affects the formation of the active metabolites so that rapid 
acetylators produce more OR-1896 than slow acetylators. However, the haemodynamic effects 
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in rapid and slow acetylators have been similar in clinical studies. The effect of levosimendan is 
thus the sum of the effect of the parent drug and its metabolites; the main effect thought to be 
derived mainly from the long-acting metabolite OR-1896. 
After oral administration in healthy subjects, the maximum concentration (Cmax) of 
levosimendan (mean approx. 45 ng/ml) in plasma was seen at 1 hour after doses of 1 mg once a 
day or 1 mg twice a day (b.i.d.). However, the active metabolite (OR-1896) concentrations 
increase slowly and steady-state is achieved after 12-14 days with constant daily dosing. The 
mean Cmax of OR-1896 after 14 days of dosing with daily levosimendan doses of 1 and 2 mg 
were 1.6 and 2.8 ng/ml, respectively. The elimination half-life (t1/2) of levosimendan is about 1 
hour and that of the active metabolites 60 hours in healthy subjects. 
Before the first phase IIa study in ALS (LEVALS, 3119001), oral levosimendan has been studied 
in healthy subjects, in patients with HF and in a small number of patients with a recent history 
of ischemic stroke/transient ischemic attack (TIA). 
In the 2 earlier dose-ranging studies in 90 patients with HF, 5 doses of oral levosimendan from 
0.25 to 4 mg or placebo were administered 4 times daily for 2-4 weeks. Daily doses of 4-16 mg 
had beneficial haemodynamic effects, but daily doses of 8-16 mg were associated with increased 
(> 10 beats per minute [bpm]) heart rate (HR). Despite high plasma levels of the active 
metabolite OR-1896 (1.3 to 28.5 ng/ml in the different dose groups), no signs of acute 
tolerability problems were seen. 
The largest study with oral levosimendan, the PERSIST study (Nieminen MS et al., 2008), was 
a placebo-controlled study in 307 patients with severe chronic heart failure (CHF). The studied 
levosimendan doses were 1 mg once a day or 1 mg b.i.d. and the duration of exposure was at 
least 180 days. The results were inconclusive; quality of life (QoL) improved and the number of 
worsening HF events decreased, but mortality was numerically higher in levosimendan treated 
patients. The low overall mortality and the fact that the highest number of deaths was seen in the 
levosimendan 1 mg dose group with the most severe HF at baseline suggests that chance may 
have played an important role in distribution of deaths. HR increased by approximately 8 bpm 
compared to placebo in both levosimendan groups. In this study, HR increase and palpitations 
were the only adverse events (AEs) reported statistically more frequently with levosimendan 
compared to placebo. The numbers of atrial fibrillations or ventricular arrhythmias reported were
similar between patients receiving levosimendan and placebo.
In a small study (5 and 16 patients randomised to placebo and levosimendan, respectively) 
conducted in TIA/stroke patients with increasing doses of oral levosimendan (from 0.125 mg up 
to 2 mg daily), all doses increased cerebral blood flow velocity (Kivikko M et al., 2015). Systolic 
and/or diastolic blood pressure (BP) decreased by approx. 5-7 mmHg with daily levosimendan 
doses of 1-2 mg. In turn, HR increased by approx. 6-8 bpm with daily doses of 0.5-2 mg. Only 
the 2 mg daily dose increased the number of ventricular extrasystoles per hour above a 
predefined limit (set to reflect the possible increased risk of proarrhythmic effects in 
cardiovascular patients) compared to baseline. There were no significant differences in 
arrhythmias or adverse events (AEs) reported between placebo and levosimendan. 
Levosimendan has been shown to improve the force generation of diaphragm muscle fibres 
obtained from a rat model of HF (van Hees HW et al., 2011). The same has been reported with 
diaphragm muscle fibres obtained from lung cancer patients during surgery (van Hees HW et 
al., 2009). Both of these studies reported that the beneficial force generating effects of 
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levosimendan were seen both in slow and fast muscle fibres. In addition, the same group 
demonstrated that levosimendan (i.v.) improved the neuromechanical efficiency and 
contractility of human diaphragm function in healthy subjects (Doorduin J et al., 2012). In an 
antibody-induced myasthenia gravis (MG) rat model, levosimendan (0.25 mg/kg orally) and its 
long-acting metabolite OR-1896 (0.025 mg/kg) given as a single dose significantly improved 
motor performance in the accelerating RotaRod test as well as exercise capacity in the Treadmill 
test. These beneficial effects are thought to be due to improved skeletal muscle strength and 
endurance (Orion Report).
LEVALS (3119001) was a randomised, double-blind, placebo-controlled, crossover, 3-period, 
multicentre phase IIa study in 66 ALS patients with a 6-month open-label part. Randomised 
treatments for the crossover part were placebo and levosimendan with 1 mg and 2 mg daily 
doses. Each treatment period during the double-blind, placebo-controlled part lasted for 14 (± 2) 
days separated by a 19-23 days wash-out period. 
In the primary efficacy variable, SVC% (sitting) there was a clear period effect in the data. 
Therefore, period-wise baselines were justified and used in efficacy analyses (post-hoc). The 
estimated mean changes from baseline were -0.67, -0.98 and -0.01% points for placebo, 
levosimendan 1 mg daily (p = 0.97 vs. placebo) and levosimendan 2 mg daily (p = 0.85 vs. 
placebo), respectively.
Secondary and other efficacy variables were analysed using period-wise baselines (post-hoc 
analysis). In the secondary efficacy variable SVC% (supine), the estimated mean differences 
from baseline were -3.62, +0.77 and +2.38 % points for placebo, levosimendan 1 mg daily (p = 
0.018 vs. placebo) and levosimendan 2 mg daily (p = 0.001 vs. placebo), respectively. In other 
words, both levosimendan doses (in a dose-dependent manner) improved SVC% (supine) values 
during the 2-week treatment period, whereas SVC% (supine) decreased during placebo. The 
treatment effects between placebo and levosimendan 1 mg and 2 mg were 4.39% and 6.00%, 
respectively, favouring levosimendan. Both levosimendan doses were numerically better 
compared to placebo in the ALSFRS-R total score. The estimated mean differences from 
baseline were -0.82, -0.46 and -0.37 for placebo, levosimendan 1 mg daily (p = 0.49 vs. placebo) 
and levosimendan 2 mg daily (p = 0.34 vs. placebo), respectively. For the ALSFRS-R respiratory 
domain the estimated mean differences from baseline were -0.22, +0.04 and +0.05 for placebo, 
levosimendan 1 mg daily (p = 0.13 vs. placebo) and levosimendan 2 mg daily (p = 0.12 vs. 
placebo), respectively. These small numerical trends seen in the ALSFRS-R total and respiratory 
domain scores provide support for supine SVC results. 
There were no statistically significant differences seen between placebo and levosimendan 1 mg 
and 2 mg daily treatments in sniff nasal pressure (SNP), visual analogue scale (VAS) of fatigue, 
overnight oxygen saturation (SpO2) measured by a pulse oximeter, maximal hand grip strength 
and submaximal hand grip endurance or Clinical Global Impression of Change (CGI-C) assessed 
by the investigator and the subject. 
Tolerability and safety were good in general in the LEVALS study and similar to previous 
studies with oral levosimendan. As expected, AEs of headache and increased HR were more 
common during levosimendan (in a dose-dependent manner) and the latter led to study treatment
discontinuations based on a predefined criterion (increase in HR > 15 bpm compared with 
screening). The numbers of severe AEs or serious adverse events (SAEs) were similar between 
levosimendan and placebo. There were no differences either in supraventricular or ventricular 
tachyarrhythmias between the treatments. 
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In conclusion, there is both experimental and clinical evidence that levosimendan improves 
diaphragmatic function. In addition, levosimendan improved motor function and endurance in a 
rat model of MG functionally mimicking impaired motoneuron function in ALS. The phase IIa
placebo-controlled results from the LEVALS study also indicated that there was a dose-related 
treatment effect favouring levosimendan in SVC% supine after 2 weeks treatment. 
Collectively these results indicate that levosimendan is able to improve the muscle strength 
endurance of diaphragm and therefore respiratory function in patients with ALS.
1.2
Rationale of the study
1.2.1
Rationale of the study design
The aim of this pivotal phase III study is to confirm the positive findings of the supine SVC% 
results seen in the LEVALS phase IIa study and to demonstrate benefit on supporting endpoints
such as ALSFRS-R and the composite of ‘time to’ respiratory events.
The target population is subjects with diagnosis of laboratory supported probable, probable or 
definite ALS according to the El Escorial revised criteria (Brooks BR et al., 2000). The main 
inclusion criterion will be SVC% (sitting) between 60-90% of predicted. It is believed that 
enrolling patients who already have some respiratory compromise will increase the ability to 
identify positive effects of levosimendan. This might be the case particularly on respiratory 
symptoms, which are not present early in the disease. The SVC% (supine) results in the 
LEVALS study support using this SVC% range also in this phase III study.
SVC% assessed in the supine position will be the primary efficacy variable. In the LEVALS 
study, both levosimendan doses were superior to placebo in supine SVC%. Assessing SVC in 
the supine position is also clinically relevant, because the first clinical signs of respiratory 
insufficiency often appear during sleep or when lying down. There is also evidence that vital 
capacity measured in the supine position correlates better with diaphragmatic weakness than that 
measured in upright position (Lechtzin N et al., 2002) and is a better predictor of survival 
compared with upright vital capacity (Schmidt EP et al., 2006, Baumann F et al., 2010).
There will be 2 futility/interim analyses, first when about 50% and second when 100% of 
subjects have been treated for 12 weeks. Based on these analyses, the study will be stopped in 
case the futility/interim analysis indicates that statistically significant differences between the 
treatment arms are unlikely at the planned study end.
The double-blind treatment duration will be 48 weeks in order to collect controlled long-term 
safety and efficacy data. The primary efficacy variable (SVC% supine) will be analysed at 12 
weeks. Supporting secondary variables such as ‘time to’ respiratory endpoints and ALSFRS-R 
require longer treatment duration to demonstrate benefit and will be examined at 48 weeks.
1.2.2
Rationale for selected doses
The LEVALS phase IIa study included treatment periods with 1 mg once a day and 1 mg b.i.d.
of levosimendan. These two daily doses of levosimendan showed significant benefits over 
placebo in supine SVC in a dose-dependent manner. Based on the LEVALS results and studies 
in cardiac and other patient populations, higher doses are associated with increased HR. 
Therefore Orion concludes that no further dose finding is needed. The target maintenance dose 
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of levosimendan in the phase III study will be 2 mg per day administered as 1 mg b.i.d. Using 
flexible dosing, the levosimendan arm will start with a 1 mg daily dose for 2 weeks. Previous 
studies have shown that levosimendan may be associated with headache in a dose-dependent 
manner, lasting for about 2-3 days. Starting with 1 mg per day will therefore decrease the 
occurrence of headache. HR has also been shown to increase dose-dependently with 
levosimendan. If tolerability allows (e.g. based on HR) at 2 weeks, the dose will be increased to 
1 mg b.i.d. If required due to any tolerability issues (e.g. based on HR) during 1 mg b.i.d. dosing, 
the dose can be decreased to 1 mg per day. During b.i.d. dosing the 2nd daily dose will normally 
be taken at 12 hours, but to best meet the clinical needs of the subject, the investigator may 
instead specify taking the 2nd daily dose at 6 hours after the morning dose or when the subject
goes to bed.
1.3
Benefit-risk assessment
1.3.1
Potential benefits associated with levosimendan
SVC assessed in the supine position in the LEVALS study indicated that levosimendan can 
significantly improve the skeletal muscle function of the diaphragm, thereby supporting 
respiratory function in ALS patients. This in turn is expected to improve patients’ well-being 
and functional ability.
1.3.2
Potential risks associated with levosimendan
Although the extent of safety data with oral levosimendan is still limited, available data suggest 
that levosimendan or its active metabolites are not likely to cause clinically significant direct 
CNS effects. Myocardial and arterial changes such as hypertrophy, myocarditis and vasculitis 
have been observed in toxicity studies in animal species, dog being the most sensitive species 
with first signs of toxicity appearing at 2-5 fold clinical exposure. The clinical relevance of these 
findings is not known. Based on the safety data originating from the completed clinical trials 
with oral levosimendan (administered 1-2 mg daily for longer than 180 days), safety signals of 
increased heart rate and palpitations have been detected and are considered as potential risks for 
oral levosimendan use. No other safety concerns related to cardiac function have been identified
from these data. Arrhythmias are known AEs for i.v. levosimendan in patients with severe CHF. 
However, there is no such evidence for oral levosimendan in healthy subjects. In addition, the 
LEVALS phase IIa study conducted in ALS patients did not find any differences in 
supraventricular or ventricular tachyarrhythmias between placebo and levosimendan. There 
were no differences either in the numbers of severe AEs or SAEs between the treatments. 
However, special attention should be paid to symptoms potentially connected with cardiac 
arrhythmias, such as palpitations, dizziness and loss of consciousness. Headache (due to 
vasodilatation), increased HR and palpitations have been the most commonly reported adverse 
drug reactions in healthy subjects and/or ALS patients treated with levosimendan. In laboratory 
parameters, slight decreases in red cell parameters and serum potassium have been observed in 
some studies.
1.3.3
Potential risks associated with the study assessments
Blood samples will be
collected for safety laboratory, pharmacokinetic (PK)
and 
pharmacogenomic (PG) analyses. The risks of blood sampling include fainting and pain, 
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bruising, swelling or rarely infection of the injection site. Electrocardiogram (ECG) pads can 
cause skin irritation and the removal of the pads can be painful. Repeated respiratory assessments 
may be burdensome for patients with ALS.
2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective of this study is to confirm that levosimendan can significantly improve 
respiratory function measured by supine SVC in ALS patients.
2.2
Secondary objective
The secondary objective is to confirm that levosimendan improves the functionality of subjects
measured by ALSFRS-R, CGI, Borg Category Ratio 10 (CR10) scale on the intensity of 
dyspnoea, Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). The latter 
two are sleep scales assessing daytime somnolence and sleep quality, respectively. In addition,
the long-term tolerability and safety of levosimendan in ALS patients will be evaluated, 
assessing up to 48 weeks of exposure.
2.3
Other objectives
For the purposes of potential later pharmacoeconomic analysis, the use of specific health care 
resources will be quantified on weekly basis, including:

The number of days spent in hospital care.

The number of additional visits to a hospital emergency unit.

The average number of formal home care hours per day on the given week (paid/public 
services obtained) and the number of times such care was received during a usual night.

The average number of informal home care hours per day on the given week (unpaid; by 
family, other relative, friend or volunteer) and the number of times such care was 
received during a usual night. 

The number of days spent in institutional care other than hospital (e.g. 
respite/hospice/nursing home/rehabilitative care).

Receipt of new, non-medicinal assistive devices and other aids.
2.4
Exploratory objectives
The plasma concentrations of levosimendan and the metabolites OR-1855 and OR-1896 will be 
determined. In addition, a population pharmacokinetic/pharmacodynamic (PK/PD) model 
between OR-1855 and OR-1896 exposure and efficacy related endpoints and HR will be 
explored. Plasma concentrations of riluzole will also be determined. The effects of 
levosimendan, OR-1855 and OR-1896 on plasma trough concentrations of riluzole will be 
evaluated.
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The acetylation status will be determined for all subjects to assess whether it affects the PD
responses of levosimendan in patients with ALS.
3.
OVERALL STUDY DESIGN AND PLAN
This is a randomised, double-blind, placebo-controlled, parallel-group multinational, 
multicentre phase III study. The subjects will be allocated to 2 parallel groups receiving either 
levosimendan 1-2 mg daily or placebo in 2:1 ratio. The study will be conducted globally. The 
estimated number of sites will be approximately 100.
The total duration for double-blind comparison will be 48 weeks. A futility/interim analysis will 
be conducted when approximately 50% and all of the subjects have been treated for 12 weeks. 
An independent data and safety monitoring board (DSMB) will be established for this and for 
safety monitoring purposes.
There will be a screening visit, a baseline visit (V1) followed by visits at 2 weeks (V2), 4 weeks 
(V3), 8 weeks (V4), 12 weeks (V5), 24 weeks (V6), 36 weeks (V7) and 48 weeks (V8), and 
telephone contacts during weeks 18, 30 and 42. An end-of-study visit will take place 14-25 days 
after the last study treatment administration for each subject. Additional visits may take place 
after visit 3 and after later visits (see section 5.3.2). The total study duration for each subject will 
be about 51-52 weeks including the end-of-study visit. The study design is presented in Figure 
1.
Figure 1.
Study design
4-14 d
1 Dose will be increased if the 1 mg/day dosing was well tolerated
2 Dose can be decreased back to 1 mg/day if required for any reason  In case the dose was decreased due to 
HR increase > 30 bpm, additional visit will take place after approx  2 weeks
3 Any time during the week
2 wks 
± 3 d
14-25 d
V1
Baseline
V21
V32
V52
V72
End-of-study 
visit
36 wks
± 5 d
V62
24 wks
± 5 d
12 wks
± 5 d
4 wks
± 3 d
Screening
visit
Post-treatment
period 
Screening
Placebo
V42
8 wks
± 5 d
V8
48 wks
± 5 d
Levosimendan 
1 mg/day
TC3
TC3
TC3
18 wks
30 wks
42 wks
Levosimendan 
2 mg/day
4.
SELECTION OF STUDY POPULATION
4.1
Number of subjects
The planned number of subjects is approximately 450. 
4.2
Inclusion criteria
The subjects must meet all of the following criteria to be included into the study:
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1.
Written or verbal informed consent (IC) for participation in the study will be obtained from 
the subject. In case that 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 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 
the electrodiagnostic criteria for ALS) from an experienced neurophysiologist.
4.
Able to swallow study treatment capsules, and in the opinion of the investigator, is expected 
to continue to do so during the study.
5.
Sitting SVC between 60-90% of the predicted value for age, height and sex at screening 
visit.
6.
Disease duration from symptom onset (defined by first muscle weakness or dysarthria) 12-
48 months at the time of visit 1 (baseline). 
7.
Able to perform supine SVC in an adequate and reliable way at screening and baseline visits 
as judged by the investigator.
8. 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.
4.3
Exclusion criteria
Subjects will not be included into this study if they meet any of the following criteria:
1.
Subject in whom other causes of neuromuscular weakness have not been excluded.
2.
Subject with a diagnosis of another neurodegenerative disease (e.g. Parkinson’s or 
Alzheimer’s disease).
3.
Assisted ventilation of any type within 3 months before the screening visit or at screening.
4.
Any use of a diaphragm pacing system (DPS) within 3 months before the screening visit.
5.
Any form of stem cell or gene therapy for the treatment of ALS.
6.
Known hypersensitivity to levosimendan.
7.
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). 
8.
Any use of tirasemtiv or reldesemtiv within 1 month before the screening visit.
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9.
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.
10. Any botulinum toxin use within 3 months before the screening visit. 
11. 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.
12. Pulmonary illness (e.g. asthma or COPD) requiring regular treatment.
13. Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy 
or restrictive cardiomyopathy. 
14. Any cardiovascular event (e.g. myocardial infarction, HF, arrhythmia or stroke) requiring 
hospitalisation within 3 months before the screening visit.
15. History of Torsades de Pointes (TdP) or diagnosed long QT-syndrome.
16. 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).
17. History of second or third degree atrioventricular (AV) block or sinus node disease at 
screening, if not treated with pacemaker.
18. 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.
19. Systolic blood pressure (SBP) < 90 mmHg at screening.
20. Potassium < 3.7 mmol/l or > 5.5 mmol/l at screening.
21. Severe renal impairment (creatinine clearance < 30 ml/min at screening), creatinine > 
170 µmol/l at screening or on dialysis.
22. Blood haemoglobin < 10 g/dl at screening or blood donation or loss of significant amount 
of blood within 60 days before the screening visit.
23. Clinically significant hepatic impairment at the discretion of the investigator.
24. Body mass index (BMI) ≤ 18.5kg/m2 (BMI = weight/height2).
25. 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.
26. Patient judged to be actively suicidal by the investigator during 3 months before the 
screening visit.
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27. Patients with known history of human immunodeficiency virus (HIV) infection.
28. 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.
4.4
Information collected on screening failures
For subjects screened but not included in the study, the following case report forms (CRFs) will 
be completed: date of the screening visit, IC, demography (birth year, age, sex and race), criteria 
causing the exclusion and decision of entry. In addition, all information (including concomitant 
treatments and medical history) about AEs related to study assessments and SAEs must be 
collected. If according to the source data there are no AEs, the AE CRF can be inactivated. 
4.5
Removal of subjects from treatment or assessment
Study subjects are free to discontinue the study at any time without providing a reason. However, 
the investigator should try to identify the reason and document it in the CRF. 
A subject must discontinue the study treatment for the following reasons: 

HR increase of > 30 bpm from baseline (visit 1) at the dose level of 1 mg once daily in 
3 separate ECG recordings, taken within 5-10 minutes from each other before the 
morning dose of the study drug (see also section 6.5.4).

Life-threatening supraventricular or ventricular arrhythmia.

The investigator judges that it is in the best interest of the subject to stop the study 
treatment due to any other abnormality compromising patient safety. However, the 
investigator should consult the medical monitor whenever possible in these instances.

Pregnancy.

Invasive mechanical ventilation by intubation or tracheostomy. 
The subjects who have discontinued the study medication, but continue in the study, are 
encouraged to follow the study visit and phone call schedule according to the study protocol for 
recording ALSFRS-R, ventilatory support and survival status. End-of-study visit assessments 
for these subjects will be performed 14-25 d after the last study treatment administration. 
A subject must discontinue the study if the investigator or the sponsor considers the 
discontinuation to be medically necessary or in the best interest of the subject. 
Irrespective of the reason for discontinuation, the subject should be invited to end-of-study 
assessments as soon as possible. As long as the subject consents, all relevant assessments, at 
least those of safety, should be performed, preferably according to the schedule for the end-of-
study assessments.
The study monitor should be notified about premature discontinuations by email/phone/fax 
within 24 hours in the event of discontinuation due to an SAE (see section 6.5.1.3) or within 
7 days in the event of discontinuation due to another reason.
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Subjects who prematurely discontinue will not be replaced. Discontinued subjects are not 
allowed to re-enter the study.
5.
STUDY TREATMENTS
Manufacturing, packaging, and labelling of the study treatments will comply with good 
manufacturing practice (GMP) regulations (Annex 13 of EU guide to GMP). The capsules will 
be stored below 30C and the container kept tightly closed.
5.1
Investigational product
Investigational product will be Levosimendan 1 mg capsules for oral administration.
5.2
Reference product
Placebo Levosimendan capsule for oral administration containing only excipients.
5.3
Dosing
5.3.1
Selection and timing of doses
The subjects will be randomised centrally to receive either levosimendan or placebo. The daily 
dose of oral levosimendan will be 1-2 mg (see section 5.3.2). The subjects will take the study 
treatment in the morning and when the dose is increased to 1 mg b.i.d., the second dose will 
normally be taken 12 hours later. Alternatively the investigator may specify to take the 2nd daily 
dose 6 hours after the morning dose or when going to bed, according to the clinical needs of the 
subject. The prescribed time of the second dose will be recorded in the CRF and should be the 
same each day unless changed by the investigator. It is recommended to take the study treatment 
about 1 hour before food intake or on an empty stomach. The morning dose of study treatment 
will be administered at the study centre during the visit days.
The total duration of study treatments will be 48 weeks.
5.3.2
Dose adjustment
The daily doses of oral levosimendan will be 1-2 mg depending on the tolerability (mainly 
judged by HR). The subjects will start with a 1 mg dose (in the morning) for 2 weeks. 
HR will be assessed in the morning before study drug intake:

At visit 2 (2 weeks):
-
If the HR in the 12-lead ECG has increased ≤ 15 bpm from baseline, the subject will 
increase the dose to 1 mg b.i.d.
-
If the HR in the 12-lead ECG has increased > 15 bpm from mean baseline value, the 
subject will continue with the 1 mg once daily. If the increase in HR is > 30 bpm in 
3 separate recordings, the subject must discontinue the study treatment (see section 
4.5).
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
At visit 3 (4 weeks) or later visits:
-
If the HR in the 12-lead ECG has increased ≤ 20 bpm from baseline, no changes to 
the dosing regimen are made.
-
If the HR in the 12-lead ECG has increased > 20 bpm from baseline in 3 separate 
recordings taken within 5-10 minutes from each other, the subject will decrease the 
dose back to 1 mg once daily if treated with 1 mg b.i.d. In case the increase in HR is 
> 30 bpm in each of the 3 separate ECG recordings, the HR must be checked again 
at an additional visit approximately 2 weeks after the dose decrease. If the increase 
> 30 bpm is recorded at the dose level of 1 mg once daily in 3 separate recordings, 
the subject must discontinue the study treatment (see section 4.5).
Administration of placebo (1 or 2 capsules per day) will be based on the same criteria as
described for levosimendan above.
5.4
Method of assigning study subjects to treatment groups
The study subjects will be randomly allocated to treatment groups by interactive web response 
system (IWRS) using a complete randomisation scheme to eliminate the possible bias due to 
predictability of treatment assignment (Hewitt CE et al., 2006). The subjects will be allocated at 
random to the levosimendan and placebo groups at a ratio of 2:1 using permuted blocks.
The subjects will be stratified via IWRS for bulbar and spinal onset patients, use of edaravone
and in regard to geographical region for Northern America vs. regions outside Northern 
America, so that in these groups the treatment allocations will be balanced. Stratification will 
occur on a study level rather than on a centre level. Enrolment by stratum is not constrained.
To ensure random allocation of the study treatments, all subjects to be randomly allocated will 
receive the treatment that corresponds to the next consecutive subject number.
5.5
Blinding
Placebo levosimendan capsules are identical in appearance to the active treatment. Packaging 
and labelling will ensure the blinding.
None of the persons directly involved in the conduct of the study will have access to the 
treatment code. The DSMB will have access to the treatment code. In addition, the bioanalytical 
laboratories will have access to the treatment code. The treatment code will be opened after the 
study database has been locked.
5.6
Emergency procedures
In case of an emergency requiring immediate knowledge of the study treatment, the treatment 
code may be broken by the investigator through the IWRS. As a back-up to the IWRS, there will 
be a 24x7x365 Customer Help Desk available to support the investigators in unblinding. 
Whenever possible, the investigator should discuss the case with the medical monitor prior to 
unblinding. If not possible, the medical monitor should be notified immediately after breaking 
the treatment code.
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The sponsor’s personnel may unblind the treatment assignment for an individual subject’s SAE 
in order to fulfil expedited regulatory reporting requirements.
5.6.1
Treatment of emergencies
Emergencies will be treated according to the decision of the physician in charge or the 
investigator, when available.
5.7
Prior and concomitant treatments
All concomitant treatments during the study, including the post-treatment period, must be 
recorded. No other investigational medicinal product is allowed to be used concomitantly with 
the study treatment. The study subject must not have been administered another investigational 
medicinal product within 30 days before the screening visit. The use of tirasemtiv or reldesemtiv
within 1 month or botulinum toxin within 3 months before the screening visit is prohibited.
5.7.1
Prohibited treatments during the study
The use of tirasemtiv or reldesemtiv is prohibited during the study due to their similar 
mechanism of action with levosimendan.
The subjects should avoid starting supplements (such as creatine, N-acetyl-cysteine, coenzyme 
Q10) as well as off-label uses of drugs for ALS (such as memantine and tamoxifen) during the 
study.
Use of botulinum toxin is not allowed during the study.
If the permissibility of a specific drug/treatment is questionable, the medical monitor must be 
contacted.
5.7.2
Permitted treatments during the study
Commonly used supplements such as vitamin C or multivitamin tablets are permitted during the 
study. 
If using riluzole, 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 treatment(s) should not be started during the study. If riluzole and/or edaravone needs 
to be discontinued due to an AE, the medical monitor must be contacted.
If necessarily required, benzodiazepines can be started during the study to treat e.g. panic attacks 
or anxiety.
Any other treatments, with the exceptions noted in section 5.7.1, which are considered necessary 
for the subject’s welfare, and which will not interfere with the study treatment, may be given at 
the discretion of the investigator.
If the permissibility of a specific drug/treatment is questionable, the medical monitor must be 
contacted.
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5.8
Treatment compliance and exposure
Treatment compliance will be assessed by study treatment accountability. The morning dose of 
study treatment will be administered at the study centre during the visit days. Treatment 
deviations must be recorded. Subjects should be asked about the reason for non-compliance.
Drug accountability records will be kept. The investigator must maintain accurate records 
demonstrating the date and amount of study treatments received, to whom and by whom 
dispensed (drug dispensing list) and accounts of study treatments accidentally or deliberately 
destroyed. 
At the end of the study, any remaining study treatments will be collected and returned to the 
sponsor. Any discrepancies between the returned and expected returned study treatments should 
be explained.
5.9
Availability of investigational medicinal product after termination of 
study
There is an option to continue levosimendan treatment once the study subject has completed 48 
weeks of treatment and the end-of-study visit of the current study, either in the form of an open-
label extension study or compassionate use program.
6.
STUDY PROCEDURES AND ASSESSMENTS
6.1
Study procedures
Table 1 lists all study procedures and indicates with an ‘x’ during which visit a particular 
procedure is performed.
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Table 1.
Schedule of study events
Protocol activities
Screening 
period
Baseline
Treatment period
Post-
treatment 
period
Scr. visit
4-14 d 
before V1
V1
Baseline D1
V2
Week 2
D15 ± 3 d
V3
Week 4
D29 ± 3 d
V4
Week 8
D57 ± 5 d
V5
Week 12
D85 ± 5 d
TC 
Week 
18
V6
Week 24
D169 ± 5 d
TC 
Week 
30
V7
Week 36
D253 ± 5 d
TC 
Week 
42
V8
Week 48
D337 ± 5 d
End-of-
study visit 
14-25 d 
after V81
IC
x
Demography
x
Physical examination
x
x
Weight
x
x
x
x
x
x
x
x
x
Height and BMI
x
HR and BP
x
x
x
x
x
x
x
x
x
x
12-lead ECG
x
x2
x
x
x
x
x
x
x
x
Laboratory safety assessments
Haematology
x
x
x
x
x
x
x
x
x
x
Chemistry
x
x3
x3
x3
x3
x3
x3
x3
x3
x3
Urinalysis
x
x
x
x
x
x
x
x
Serology
x
Pregnancy test for females of 
childbearing potential
x
x
x
x
x
x
x
x
x
Testing ability to swallow 
capsules
x
SVC sitting
x
SVC supine
x
x
x
x
x
x
x
x
x
x
Eligibility criteria and decision 
of entry
x
Study treatment
x
ALSFRS-R
x
x
x
x
x
x
x
x
x
x
CGI
x
x
x
x
x
x
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Protocol activities
Screening 
period
Baseline
Treatment period
Post-
treatment 
period
Scr. visit
4-14 d 
before V1
V1
Baseline D1
V2
Week 2
D15 ± 3 d
V3
Week 4
D29 ± 3 d
V4
Week 8
D57 ± 5 d
V5
Week 12
D85 ± 5 d
TC 
Week 
18
V6
Week 24
D169 ± 5 d
TC 
Week 
30
V7
Week 36
D253 ± 5 d
TC 
Week 
42
V8
Week 48
D337 ± 5 d
End-of-
study visit 
14-25 d 
after V81
Borg CR10 scale
x
x
x
x
x
x
x
x
x
Epworth Sleepiness Scale (ESS)
x
x
x
x
x
x
Pittsburgh Sleep Quality Index 
(PSQI)
x
x
x
x
x
x
Use of health care and home 
care resources and non-medical 
assistive devices
x4
x
x
x
x
x
x
x
Blood sampling for 
levosimendan, OR-1855 and 
OR-1896 PK
x
x
x
x
x
x
x
Blood sampling for riluzole PK
x
x
x
x
Blood sampling for exploratory 
biomarkers
x
x
x
x
x
x
x
Assessment of suicidality
x
x
x
x
x
x
x
x
x
x
Blood sampling for PG
x5
Status for NIV support, invasive 
mechanical ventilation by 
intubation or tracheostomy and 
survival
x
AEs and SAEs
x
Medical history and current 
medical conditions
x
Concomitant treatments
x
1 Also for subjects who discontinue treatment but continue in the study, end-of-study visit assessments will be performed 14-25 d after the last study treatment administration
2 3 baseline recordings pre-dose
3 Except thyroid-stimulating hormone (TSH)
4 Data requested for the past 7 days prior to baseline visit 
5 One sample during the study preferably at visit 1 (baseline)
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6.1.1
Procedures during the screening period
A screening visit will take place 4-14 days before the first study treatment administration. A 
prospective subject will receive both written and verbal information about the study, and will 
have an opportunity to ask questions and sufficient time to decide whether or not to participate 
in the study. A signed and dated written IC will be obtained (a witness may sign the consent 
form to indicate that the subject has given verbal consent).
Re-screening (one occasion, unless otherwise authorised by the Medical Monitor) is allowed for 
example in case the patient has been taking prohibited treatment within 3 months before the 
screening visit or the sitting SVC is not within the inclusion criterion limits (60-90%).
The following procedures will be performed at the screening visit to ensure fulfilling the 
inclusion/exclusion criteria:

Demographic data (birth year, age, sex, race, geographic region) and weight and height 
will be recorded. BMI will be derived from weight and height automatically in electronic 
case report form (eCRF).

ALS history (date of diagnosis, ALS family history, site of onset [spinal/bulbar] and start 
date of ALS symptoms) will be recorded.

HR and BP will be recorded in supine position.

12-lead ECG will be recorded in supine position.

Physical examination will be performed.

A blood sample for haematology, clinical chemistry and serology will be collected and 
a urine sample will be collected for urinalysis. A pregnancy test will be performed for 
females of childbearing potential.

Ability to swallow capsules will be tested with a placebo capsule.

SVC will be measured in the sitting and supine positions. Sitting SVC% will be assessed 
first and used for inclusion criterion. Thereafter, SVC supine will be assessed only to 
ensure successful assessment.

Status for NIV support, invasive mechanical ventilation by intubation or tracheostomy 
and survival will be recorded.

AEs will be inquired.

Medical history, current medical conditions and concomitant treatments will be recorded.

Suicidality will be assessed.
6.1.2
Procedures during the treatment period
Procedures during visit 1 (baseline) are presented in Table 2 and procedures during visits 2-8 in 
Table 3. The morning dose of study treatment will be administered at the study centre during the 
visit days.
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Table 2.
Procedures at visit 1 (baseline)
Time
Pre-dose
0 h
45-120 min
Weight
x
HR and BP 
x
x
12-lead ECG
x1
x
Laboratory safety assessments
Haematology
x
Chemistry
x2
Urinalysis
x
Pregnancy test for females of childbearing potential
x
SVC supine
x
Study treatment
x
ALSFRS-R
x
CGI
x
Borg CR10 scale
x
ESS
x
PSQI
x
Use of health care and home care resources and non-medical 
assistive devices
x3
Blood sampling for riluzole PK
x
Blood sampling for exploratory biomarkers
x
Blood sampling for PG
x4
Assessment of suicidality
x
Status for NIV support, invasive mechanical ventilation by 
intubation or tracheostomy and survival
x
AEs and SAEs
x
Medical history and current medical conditions
x
Concomitant treatments
x
1 3 baseline recordings
2 Except TSH
3 Data requested for the past 7 days prior to baseline visit
4 One sample during the study preferably at visit 1
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Table 3.
Procedures at visits 2-8
Time
Pre-
dose
0 h
30-90 
min
120-240 
min
Weight
x1
HR and BP 
x
x
12-lead ECG
x
x
Laboratory safety assessments
Haematology
x
Chemistry
x2
Urinalysis
x3
Pregnancy test for females of childbearing potential
x4
SVC supine
x
Study treatment
x
ALSFRS-R
x1
CGI
x3
Borg CR10 scale
x
ESS
x3
PSQI
x3
Use of health care and home care resources use and non-medical 
assistive devices
x
Blood sampling for levosimendan, OR-1855 and OR-1896 PK
x
x5
Blood sampling for riluzole concentration
x5
Blood sampling for exploratory biomarkers
x1
Assessment of suicidality
x
Status for NIV support, invasive mechanical ventilation by intubation 
or tracheostomy and survival
x
AEs and SAEs
x
Medical history and current medical conditions
x
Concomitant treatments
x
1 Not at visit 2
2 Except TSH
3 Not at visits 2 and 4
4 Not at visit 2
5 Not at visits 4, 5, 6 and 7
6.1.3
Telephone contacts
The study centre personnel will phone the subjects during weeks 18, 30 and 42. During the phone 
call ALSFRS-R will be assessed and AEs inquired.
6.1.4
Additional visits
Additional visits will be performed in case dose decreases were triggered by predefined HR 
increase criteria (see section 5.3.2). Additional visits may take place approximately 2 weeks after 
the dose decrease. Procedures during additional visits are presented in Table 4.
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Table 4.
Procedures during additional visits
Time
Pre-dose
0
HR and BP 
x
12-lead ECG
x
Study treatment
x
AEs and SAEs
x
6.1.5
Procedures during the post-treatment period
An end-of-study visit will take place 14-25 days after the last study treatment administration for 
each subject. The following procedures will be performed:

HR and BP will be recorded.

12-lead ECG will be recorded.

SVC supine will be assessed.

The Borg CR10 scale to assess the intensity of dyspnoea will be completed at rest in 
sitting and supine positions (immediately before SVC measurement).

Physical examination will be performed.

Weight will be recorded.

A blood sample for haematology and clinical chemistry and a urine sample for urinalysis 
will be collected. A pregnancy test will be performed for females of childbearing 
potential.

AEs, current medical conditions and concomitant treatments will be recorded.

Status for NIV support, invasive mechanical ventilation by intubation or tracheostomy 
and survival will be recorded

Suicidality will be assessed.
6.1.6
Follow-up period for subjects who have discontinued the study medication
The subjects who have discontinued the study medication, but continue in the study, are 
encouraged to follow the study visit and phone call schedule according to the study protocol for 
recording ALSFRS-R, ventilatory support and survival status.
6.2
Efficacy assessments
6.2.1
Slow Vital Capacity
The primary efficacy variable will be the change from baseline at 12 weeks in SVC measured in 
the supine position, SVC (supine). All SVC measurements prior to 12 weeks will be included in 
the statistical model. SVC is the maximum volume of air that can be exhaled slowly after slow 
maximum inhalation. The best read from 3 attempts will be chosen. The volume is measured in 
litres and the SVC variable will be % of predicted (normal) value for age, height and sex. In 
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addition, time to decline in supine from baseline SVC by ≥20% and time to supine SVC ≤ 50%
of predicted will be assessed. 
SVC (supine) will be assessed once at each visit during the study including the baseline (visit 1), 
i.e. in the morning before the study treatment administration.
SVC will be assessed in the sitting and supine position at screening visit. Sitting SVC will be 
one of the inclusion criteria. Supine SVC is assessed at screening and baseline to ensure that the 
subject is able to perform it successfully when entering the study.
6.2.2
Revised ALS Functional Rating Scale
ALSFRS-R (Cedarbaum JM et al., 1999) will be assessed. This scale includes 12 items: speech, 
salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, 
turning in bed and adjusting sheets, walking, climbing stairs, dyspnea, orthopnea, and respiratory 
insufficiency. Each item will be scored from 0 to 4. The variables derived will be the scores of 
the 12 separate items, the total scores of each subdomain (bulbar, fine motor, gross motor and 
respiratory) and the total score of ALSFRS-R. 
In addition the following variables will be assessed:

Combined assessment of function and survival (CAFS)

Change from baseline in ALSFRS-R total score

Time to decline from baseline in ALSFRS-R total score by ≥ 20% 

Time to decline from baseline in the respiratory domain of ALSFRS-R (items 10, 11, and 
12).
6.2.3
Time to respiratory event
The ‘Time to respiratory event’ composite endpoint will be used to validate the changes seen in 
supine SVC. This variable consists of the following events:

At least 1 point decrease in ALSFRS-R respiratory function score 10, 11 or 12

Meeting ‘protocolised’ criteria for NIV: supine SVC ≤ 50% predicted

Starting NIV (actual start or attempt to start NIV)

Invasive mechanical ventilation by intubation or tracheostomy or death.
Time to respiratory event will be reached whenever any of the 4 criteria listed above has been 
first met.
6.2.4
Clinical Global Impression
CGI is used to rate the severity of subjects’ clinical condition. Clinical condition is assessed by 
the subjects themselves with a VAS. Score of 0 indicates (in the 100 millimetre scale) that the 
subject is completely well without any disability and score of 100 indicates the worst possible 
severity of the condition. This rating is based on symptoms and function during the past 1 week 
and the score should reflect the average clinical condition during the week.
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6.2.5
Borg Category Ratio 10 Scale
Borg Category Ratio 10 (CR10) scale will be used in the assessment of dyspnoea (Borg GA, 
1982). The subjects will be asked to point out a score quantifying their perception on the intensity
of dyspnoea on the CR10 scale at rest in sitting and supine positions (immediately before SVC 
measurements). Orthostatic changes between sitting and supine positions will be calculated.
6.2.6
Epworth Sleepiness Scale
Daytime somnolence will be assessed by the ESS (Johns MW, 1991). The ESS is a self-
administered questionnaire with 8 questions. Subjects are asked to rate, on a 4-point scale (0-3), 
their usual chances of dozing off or falling asleep while engaged in eight different activities. 
Score 0 indicates ‘no chance of dozing’ and 3 indicates ‘high chance of dozing’. Most people 
engage in those activities at least occasionally, although not necessarily every day. If one has
not engaged recently in a certain activity, the subject will estimate how sleepy he/she would 
have been during that activity. The ESS score (the sum of 8 item scores, 0-3) can range from 0 
to 24. The higher the ESS score, the more pronounced the subject’s average daytime sleepiness.
The sum score 10 or more suggests medical attention may be required.
6.2.7
Pittsburgh Sleep Quality Index
PSQI is a self-rated questionnaire which assesses sleep quality and disturbances over a preceding 
1 month period (Buysse DJ et al., 1989). There are a total of 19 self-rated questions/items which 
are included in the scoring. These 19 items are combined to form seven component scores 
(subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleeping medication, daytime dysfunction) each of which has a range of 0-
3 points. In all components, a score of 0 indicates no difficulty, while a score of 3 indicates 
severe difficulty. The seven component scores are then added to yield one global score, with a 
range of 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all items.
The derived variable will be the PSQI global score. Global score of >5 indicates poor sleep 
quality.
6.2.8
Health care and home care resource use
For possible later use in pharmacoeconomic analysis, the subjects will be given a home diary for 
recording their use of health and home care resources. The diary will be filled in on a weekly 
basis. Any hospital inpatient days, other institutional care, any additional hospital emergency 
unit visits, days in other institutional care, and any outpatient visits to physicians or other 
relevant service providers will be recorded. In addition, all non-medical assistive devices which 
the subjects have in use at baseline, are recorded and thereafter all new devices that they start 
using due to ALS will be recorded in the diary each week. Regarding home care, the diary will 
contain information of the number of formal (paid/public services) and informal (unpaid e.g. by
spouse, other family members, friends or other volunteers) home care hours received. 
Additionally, information will be collected about the number of times such home care has been 
received during the night time. Details of the home diary will be described in a separate 
document.
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6.2.9
Other assessments
Subject’s status for NIV support, invasive mechanical ventilation by intubation or tracheostomy 
and survival will be recorded at all visits.
6.3
Pharmacokinetic assessments
6.3.1
Blood sampling
Blood samples for the determination of levosimendan and its metabolites OR-1855 and OR-1896 
will be collected. Blood samples will be drawn for the first time at visit 2 (2 weeks) and thereafter 
during all consecutive visits (except at end-of-study visit and possible additional visits). The 
samples will be collected in the morning after study drug intake (Table 5).
Table 5. 
Blood sampling for the determination of levosimendan and its metabolites 
concentrations
Blood sampling
Visit
V2
Week 2
V3
Week 4
V4
Week 8
V5
Week 12
V6
Week 24
V7
Week 36
V8
Week 48
First sample after dosing 
(min) 
30-90
30-90
30-90
30-90
30-90
30-90
30-90
Second sample after 
dosing (min)
120-240
120-240
-
-
-
-
120-240
Blood samples will be collected also to measure trough concentrations of riluzole before study 
treatment dosing at baseline and at visits 2, 3 and 8.
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study.
6.3.2
Determination of levosimendan, OR-1855 and OR-1896 concentrations in plasma
The concentrations of levosimendan, OR-1855 and OR-1896 in plasma will be determined with 
a validated liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method.
Bioanalytical details and criteria for acceptance of the results will be described in the 
bioanalytical plan and reported in the bioanalytical report.
6.3.3
Determination of riluzole concentrations in plasma
The concentrations of riluzole in plasma will be determined with a validated LC-MS/MS
method.
Bioanalytical details and criteria for acceptance of the results will be described in the 
bioanalytical plan and reported in the bioanalytical report.
6.3.4
Calculation of pharmacokinetic variables
Due to the sparse blood sampling, no PK variables will be calculated. However, plasma 
concentrations of levosimendan, OR-1855 and OR-1896 after the morning dose of the study 
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treatment at visit 2 (2 weeks) and thereafter during all consecutive visits (excluding the end-of-
study visit) and plasma concentrations of riluzole before study treatment dosing at baseline (visit 
1) and at visit 2, visit 3 and visit 8 will be collected.
6.4
Biomarker, pharmacogenomic and other specific biological 
variables
6.4.1
Biomarkers
Spare plasma taken originally for the analysis of levosimendan and its metabolites may be used
for exploratory research purposes. The plasma samples will be stored in the sponsor’s sample 
repository to allow possible exploratory biomarker analyses related to the disease state of the 
subjects and the pharmacodynamics of levosimendan.
A 5 ml blood samples will be collected before dosing at visits 1, 3, 4, 5, 6, 7 and 8. The samples 
may be used for exploratory biomarker analyses that may give supportive data related to the 
disease state of the subjects.
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study. The plasma samples will be stored in the sponsor’s sample 
repository until analysis.
6.4.2
Pharmacogenomics
A 5 ml blood sample for DNA extraction will be taken once during the study preferably at visit 1
(baseline).
Uses of the extracted DNA sample are:
1. Determination of subject’s acetylation status (NAT polymorphisms). This will be 
determined from all subjects participating in the study and the results will be source data. 
The samples will be destroyed 6 months after the sponsor has received analysis results.
2. PG assessment, but only if the subject has signed the PG IC.
The PG assessment is done as exploratory research. The objective of the PG research is to assess 
whether genetic polymorphisms relate to the absorption, distribution, metabolism, excretion, 
pharmacodynamics or safety of levosimendan. The extracted DNA will be stored in the 
sponsor’s DNA repository for future use. 
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study.
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6.5
Safety assessments
6.5.1
Adverse events
6.5.1.1
Definitions
An AE is any untoward medical occurrence in a study subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational medicinal 
product, whether or not related to the investigational medicinal product. The definition also 
covers medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product.
Thus, an AE may be an appearance or worsening of any undesirable sign or symptom, any 
worsening of the current medical conditions or onset of a new disease, compared with the 
previous observations or a clinically significant adverse change in a laboratory variable or other 
diagnostic finding (e.g. ECG).
In this study, day-to-day fluctuation in ALS signs/symptoms (e.g. dysphagia, muscular 
weakness) not indicating clinically significant progression of the disease should not be reported 
as an AE.
An SAE is any untoward medical occurrences that at any dose

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation (see section 
6.5.1.3 for exclusions)

results in persistent or significant disability/incapacity 

is a congenital anomaly/birth defect, or

is an important medical event jeopardizing the patient or requiring intervention to prevent 
a serious outcome (examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalisation; development of drug dependency or drug abuse; overdose or 
interaction).
Other significant AEs are AEs (other than those meeting the definition of serious) that are of 
clinical importance and lead to:

a diagnostic or therapeutic intervention

discontinuation of the investigational medicinal product

reduction of its dose

significant additional concomitant treatment, or
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
marked haematological and other laboratory abnormalities
6.5.1.2
Assessment of adverse events
All AEs must be elicited, documented and reported by the investigator to the sponsor from the 
time that a study subject signs the IC form until the end-of-study visit (14-25 days after the last 
study treatment administration). 
SAEs and other significant AEs should be followed up until resolved or until the event is 
considered a chronic or stable outcome, or both.
An AE may be notified to the investigator by the study subject (or his/her caregiver) or observed 
by the investigator clinically, or be an adverse change in laboratory assessment results. The 
investigator will evaluate the subject’s AEs at each visit by asking a standard question such as 
“Since you were last asked, have you felt unwell or different from the usual in any way?”
The investigator will assess and record the causality and severity of the AEs. Causality should 
be assessed in relation to the investigational medicinal product (see criteria for causality and 
severity below).
Causality criteria:
Related: The temporal relationship of the AE/SAE onset to the administration of the 
investigational medicinal product makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a sufficient explanation for the 
AE/SAE.
Not related: The temporal relationship of the AE/SAE onset to the administration of the 
investigational medicinal product makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient explanation for the 
AE/SAE.
Severity criteria:
Mild: Discomfort noticed, but it does not affect normal activity.
Moderate: Discomfort sufficient to reduce or affect normal daily activity.
Severe: Incapacitating with inability to work or perform normal daily activity.
From the time that a study subject candidate signs the IC form, newly appearing diagnosed 
diseases will be recorded on the AE CRF.
Investigators must report all AEs to the sponsor on a specific AE CRF irrespective of their 
assessment of the causal relationship of the investigational medicinal product to the event.
6.5.1.3
Reporting of serious adverse events by the investigator
The investigator must report all SAEs within 24 hours of becoming aware of an SAE. SAEs 
must be reported within 24 hours regardless of the time that may have elapsed since the time the 
event occurred and regardless of the causal relationship of investigational medicinal product to 
the event.
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In this study, the following events will not be reported as SAEs:

hospitalisation and elective surgery for treatment of pre-existing condition that has not 
exacerbated during the study

hospitalisation for procedures and/or evaluations in connection with ALS such as 
evaluation for the need or initiation of ventilatory support (e.g. NIV) or gastrostomy.
All SAEs should be reported electronically by the investigator or other relevant study centre 
personnel and submitted by the investigator. Optionally, if the investigator is not able to submit
the SAE electronically, a paper version of the SAE form can be completed and sent by e-mail or 
fax. The SAE reporting contact information can be found on the SAE form and will be filed in 
the investigator’s study file.
If the initial report is reported by phone or e-mail to the study monitor or other contract research 
organisation (CRO) personnel and the study centre personnel are unable to fill in the SAE 
electronically within 24 hours, a paper SAE form will be initiated by the person receiving the 
report. The investigator must report the SAE electronically as soon as possible. 
The minimum criteria for SAE reporting are: the event or outcome meets the SAE definition, 
the event happens to an identifiable study subject, and the event is reported by an identifiable 
and qualified reporter (usually an investigator or other qualified study centre personnel)
A follow-up report to an SAE should be prepared if any relevant change in the condition of the 
study subject occurs after the initial report. The follow-up report should be documented as an 
update to the initial report.
SAEs that occur after the end-of-study visit (14-25 days after the last study treatment 
administration), should be reported if the investigator feels that there is a reasonable possibility 
for the event to have been caused by the study subject’s participation in the study. 
6.5.1.4
Reporting of serious adverse events to competent authorities and ethics committees
The sponsor is responsible for expediting all suspected unexpected serious adverse reactions 
(SUSARs) as well as other safety issues requiring expedited reporting to the relevant authorities 
within applicable timelines. These tasks can also be carried out by a delegate of the responsible 
sponsor.
Notification of the ethics committees (ECs) and institutional review boards (IRBs) about all 
relevant events (SUSARs, other relevant safety information) will be performed by the sponsor 
or delegate of the responsible sponsor and/or by the investigator according to applicable 
regulations.
The Sponsor will inform all investigational sites about suspected unexpected serious adverse 
reactions (SUSARs) as well as other safety issues according to all applicable regulations.
The expectedness evaluation is required for regulatory reporting and it is performed by the 
sponsor. The expectedness in this study is evaluated against the Reference safety information 
section in the current ODM-109: oral levosimendan capsule for treatment of ALS investigator’s 
brochure.
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6.5.2
Special situations
Special situations with study treatment are defined as: 

medication error

overdose

abuse

misuse

interaction
These special situations with study treatment are reported on the Special situations with study 
treatment CRF even if there is no accompanying AE. All clinical manifestations in relation to 
these special situations will be reported as AEs or SAEs at the same time using the corresponding 
section of the CRF.
6.5.3
Pregnancy during the study
Whenever it becomes known that a study subject or a partner of a study subject was pregnant 
during the exposure to study treatments, the outcome of the pregnancy, delivery, postpartum 
recovery and the clinical condition of the offspring during the neonatal period should be 
reported, subject to the study subject’s or the partner’s consent. A pregnancy follow-up form 
will be provided to the investigator for completion after the sponsor has received the initial 
report.
Any case of pregnancy during a clinical study should be reported by the investigator in the same 
way as an SAE.
6.5.4
Clinical safety assessments
Vital signs (HR, systolic and diastolic BP) and standard 12-lead ECG will be assessed at 
screening, at each visit during the treatment period before and 30-90 minutes after the morning 
dose of the study drug, and at the end-of-study visit. At baseline visit, vital signs and ECG will 
be assessed before and 45-120 minutes after the morning dose of the study drug.
At the screening visit, only supine HR and BP will be measured. At baseline visit, each visit 
during the treatment period and end-of-study visit, supine HR and BP will be assessed after a 5-
minute rest. Subjects will then be asked to stand up and after 3 minutes, standing HR and BP 
will be measured (orthostatic test). In case the subject is not able to stand, only supine HR and 
BP will be measured.
A standard 12-lead ECG (central reading) will be recorded with subject lying supine and after a 
5-minute rest. 3 baseline recordings of ECG in 1-3 minutes intervals will be done before dosing 
at visit 1 (baseline). The HR, RR, PR and QT intervals and QRS duration will be analysed in the 
central ECG laboratory. QTc will be calculated using both Bazett’s and Fridericia’s correction. 
Each ECG will be assessed as normal/abnormal by the central ECG laboratory. Clinical 
significance of the abnormalities will be assessed by the investigator.
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Additional 1-2 assessments of 12-lead ECG should be performed within 5-10 minutes from each 
other (all before the morning dose), if the HR in the first recording was increased from baseline 
(visit 1) as follows:

> 20 bpm if the subject is receiving the study treatment 1 mg b.i.d., to assess the need for 
dose reduction (see section 5.3.2)

> 30 bpm if the subject is receiving the study treatment 1 mg once daily, to assess the 
need for discontinuation (see section 4.5)
If the HR increase is not repeated in the second ECG, no further ECG recordings are needed.
Physical examination will be performed at screening and the end-of-study visit. Weight will be 
measured at screening, at visits 1, 3, 4, 5, 6, 7, 8 and at the end-of-study visit. Height will be 
recorded at screening only.
In case there are abnormal findings, control assessments can be performed according to the 
judgement of the investigator.
6.5.5
Assessment of suicidality
Suicidality will be assessed by asking the following standard questions at screening, at each visit 
during the treatment period before dosing, and at the end-of-study visit:
Screening:
1. During the past 3 months, have you wished you were not alive anymore or had any 
thoughts about ending your life?
2. During the past 3 months, have you done anything or prepared to do anything to end your 
life?
Treatment period and end-of-study: 
1. Since the last visit, have you wished you were not alive anymore or had any thoughts 
about ending your life?
2. Since the last visit, have you done anything or prepared to do anything to end your life?
The second question (2) will be asked only in cases where the answer to the first question (1) 
has been ‘yes’.
6.5.6
Laboratory safety assessments
The following laboratory tests will be taken at the screening visit after at least 10 hours of fasting:
Haematology: 

Haemoglobin

Haematocrit

Erythrocyte count

Leukocyte count

Platelet count

Differential count (lymphocytes, monocytes, eosinophils, neutrophils, basophiles)

Mean corpuscular volume
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
Mean corpuscular haemoglobin
Chemistry:

Albumin

Alkaline phosphatase (ALP)

Bilirubin total

Bilirubin conjugated

Calcium

Creatine kinase

Creatinine

Creatinine clearance

C-reactive protein

Gamma-glutamyl transferase (GGT)

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Glucose

Lactate dehydrogenase

Potassium

Sodium

Troponin T

TSH 
Urinalysis: 

Glucose

Protein

Erythrocytes

Leucocytes
Serology: 

Hepatitis B surface antigen (HBsAg)

Hepatitis C virus antibody (HCVAb)
Haematology, chemistry (except TSH) and urinalysis will be repeated at each visit during the 
treatment period and at the end-of-study visit.
A pregnancy test for female subjects of childbearing potential will be performed at screening 
and baseline and at each visit during the treatment period (except visit 2, i.e. 2 weeks after 
baseline) and at the end-of-study visit.
The investigator will review all laboratory results and assess them for clinical significance. In 
case there are abnormal findings, control assessments can be performed according to the 
judgement of the investigator.
Instructions for the collection, handling, storage and transportation of samples will be provided
before the start of the study.
6.6
Changes implemented due to COVID-19 pandemic
In case visits 7 (Week 36), 8 (Week 48) and/or end-of-study visit (14-25 days after visit 8) 
described in Table 1 and in sections 6.1.2 and 6.1.5 cannot be conducted at the study centre 
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within the visit window due to restrictions related to COVID-19, a telephone visit (could also be 
a home visit or video call) should be arranged. 
The telephone visit should include all protocol assessments that can be performed remotely (see
table below) and should take place within the original visit window. The decision to replace the 
study centre visit with a telephone contact will be made by the investigator case by case, and the 
sponsor should be informed of each case as early as possible.
In addition to the telephone visit, the investigator should make reasonable efforts to obtain 12-
lead ECG, laboratory safety assessments and vital signs for each visit. These measurements may 
include local practitioners and resources. In case these assessments, at least vital signs, cannot 
be obtained within a reasonable time after the visit 7 telephone contact, the benefit-risk ratio for 
the subject to continue in the study should be reassessed.
Visit 8 telephone contact should take place at the time of stopping study medication. All safety 
data which are possible to obtain locally should be collected prior (on treatment) or at the remote 
visit: the study treatment should be stopped at the time of the remote visit. 
The following assessments will not be performed at telephone visits: SVC supine, weight, sitting 
or orthostatic changes in vital signs, blood sampling for levosimendan, OR-1855 and OR-1896 
PK, for riluzole concentration and for exploratory biomarkers, and physical examination.
All arrangements described in this section apply only to the extent that protocol requirements 
cannot be met because of COVID-19 restrictions. Study centre visits should take place to the 
extent possible and usual protocol requirements adopted for all subjects as soon as COVID-19 
limitations permit.
Exceptional measures taken in response to COVID-19 and their impact on study results, such as 
tests done in a local laboratory, will be explained, assessed and reported in the clinical study 
report following ICH E3.
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Procedures at remote visits
Time
Visit 7
Week 36
Visit 8
Week 48
End-of-
study
HR and BP 
x1
x1
x1
12-lead ECG
x2
x2
x2
Laboratory safety assessments3
Haematology
x
x
x
Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy test for females of childbearing potential
x4
x4
x4
Study treatment
x
x
ALSFRS-R
x
x
CGI
x
x
Borg CR10 scale
x
x
x
ESS
x
x
PSQI
x
x
Use of health care and home care resources use and non-medical 
assistive devices
x
x
Assessment of suicidality
x
x
x
Status for NIV support, invasive mechanical ventilation by intubation or 
tracheostomy and survival
x
x
x
AEs and SAEs
x
x
x
Medical history and current medical conditions
x
x
x
Concomitant treatments
x
x
x
1 Only in supine position after at least 5 min rest before the morning dose of the study treatment. The assessment 
should preferably be done by a health care professional. The use of alternative methods, including home devices 
are subject to sponsor approval.
2 The measurement should be taken using the local ECG device, preferably before the morning dose of the study 
treatment, after at least 5 min rest. A copy of the trace (paper or electronic) should be provided.
3 Standard biochemical, electrolyte and haematological test panels of the local laboratory will be accepted. A copy 
of the laboratory report with local reference range should be provided.
4 Test kits for urine pregnancy test should be provided to the subject for testing at home (unless taken in a local 
laboratory).
7.
DATA COLLECTION AND MANAGEMENT
The investigators and study centre personnel will prepare and maintain accurate source data for 
each study subject about clinical findings specified in the protocol. Source data include patient 
records, laboratory results and questionnaires if not collected electronically. The data from 
source documents will be recorded into an electronic data capture (EDC) system, Medidata Rave 
(Medidata Inc), using eCRFs at the study centre. Safety laboratory, spirometry and ECG will be 
analysed centrally and results will be uploaded to the Rave system and electronically signed by 
the investigator. All data on the eCRFs must be verifiable in the source data or patient records 
unless eCRF data are declared as source data.
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Investigators and other relevant study centre personnel will be trained to use the eCRFs. After 
completion of training, they are provided with user names and authorised access to enter and 
correct data on the eCRFs.
Electronic queries about missing, misleading, incomplete or illogical data will appear in the EDC 
system. An audit trail within the system will track all changes/corrections made. The investigator 
has to confirm the content of the eCRF with an electronic signature.
Individual data fields in the EDC system may be locked on an ongoing basis during the study. 
The fields may be unlocked if further updates are needed. When all data have been entered and 
all queries resolved, the whole database will be locked. Only authorised and well-documented 
updates to the study data are possible after the database lock. 
Further details regarding data collection and management are presented in the data management 
plan.
8.
STATISTICAL METHODS
8.1
Statistical hypotheses
The main statistical hypothesis of the study is to show the superiority of levosimendan against 
matching placebo in SVC (supine) at 12 weeks. The statistical hypothesis will be two-sided 
comparing change from baseline to 12 week pre-dose sample using the mixed model for repeated 
measures (MMRM) at a nominal 5% significance level.
H0: ∆SVC% levosimendan = ∆SVC% placebo
H1: ∆SVC% levosimendan ≠ ∆SVC% placebo
8.2
Estimation of sample size
Sample size estimation is primarily based on the study 3119001 LEVALS SVC (supine) results 
(Table 6). The LEVALS study had placebo controlled data only up to 2 weeks and therefore 
extrapolation of the results is needed. The placebo effect from phase II tirasemtiv trial 
BENEFIT-ALS (Shefner JM et al., 2016) is also evaluated.
Assuming at least 3.6% difference between treatment arms and common standard deviation of 
10%, 164 evaluable subjects have 90% power to detect a statistically significant difference at 
two-sided 5% level using 1:1 allocation ratio and two group T-test. Randomisation of 
450 subjects to study using a 2:1 allocation ratio (approximately 300 levosimendan and 
150 placebo treated subjects) allows approximately 20% drop out rate.
Based on dexpramipexole phase III study EMPOWER (Cudkowicz ME et al., 2013) 12 point 
reduction in total ALSFRS-R score and a 15% mortality rate at 12 months can be assumed in 
placebo treated patients. Assuming 10 point decline, with 8 point standard deviation, in 
ALSFRS-R and 20% relative improvement in survival 450 patients provide approximately 80% 
simulated power to detect statistically significant difference using joint rank test. With 450 
subjects and assuming 48 week levosimendan event rate of 73% and hazard ratio of 0.70, time 
to respiratory event has approximately 70% power to detect statistically significant difference 
using log-rank test.
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Table 6.
Mean (SD) change from baseline SVC (supine)
Treatment
2 weeks
12 weeks
Levosimendan 1 mg x 2
+2.4 (8.3)
-4.9
Levosimendan 1 mg x 1
+0.8 (8.6)
Placebo
-3.6 (9.4)
-17.71
Placebo (BENEFIT-ALS)
-1.4
-8.5
1 Extrapolated from the data
SD = standard deviation
8.3
Analysis populations
Intent-to-treat (ITT) dataset, including all randomised subjects, will be used for the primary 
evaluation. Sensitivity analyses using full analysis set (FAS) and per-protocol (PP) dataset will 
be performed and described in the SAP. FAS includes all treated subjects with at least one post 
baseline SVC measurement. PP dataset includes all randomised subjects excluding subjects with 
relevant major protocol deviations. All subjects who received any study treatment will be 
included in the evaluation of safety. Subject classification will be completed during the blind 
review before the database lock and opening the treatment code.
8.4
Statistical analyses
Statistical analyses will be described in more detail in the SAP.
8.4.1
Demographic and other baseline characteristics
All relevant demographic and baseline characteristics will be summarised using descriptive 
statistics. The number and reasons for discontinuations will be listed and tabulated by treatment 
groups.
An authorised person will code medical history and concomitant diseases using standard coding 
dictionaries.
8.4.2
Treatment compliance and extent of exposure
The number of exposed subjects, the number of dispensed and returned study treatments and the 
duration of study treatment exposure will be tabulated with descriptive statistics.
8.4.3
Analysis of efficacy
The primary efficacy variable SVC (supine) will be compared between the treatment arms using 
the MMRM with between subject effects for treatment, centre and randomisation strata, time as 
within subject effect, and baseline value (visit 1) as a covariate. Primary efficacy will be 
evaluated at 12 weeks using contrasts to obtain estimates from the primary model including all 
SVC measurements prior to 12 weeks. Any missing data will be imputed using multiple 
imputation method. Effect of missing data imputation will be evaluated analysing observed data 
only and estimating the slope of decline using the random slope model. Several sensitivity 
subgroup analyses will be performed and defined in the SAP. Additional evaluations will be 
performed including all data through 48 weeks, using the MMRM.
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Secondary efficacy endpoints will be tested in following hierarchy to preserve the overall alpha 
level:
1. Combined assessment of ALSFRS-R function and survival through 48 weeks
2. Time to respiratory event through 48 weeks
3. CGI through 48 weeks
4. Supine Borg CR 10 scale at 12 weeks
5. Slope of decline in respiratory function of ALSFRS-R through 48 weeks
The efficacy variables time to respiratory event, time to NIV or death, time to SVC (supine) 
decline of 20%, time to SVC (supine) ≤ 50% of predicted, time to ALSFRS-R total score decline 
of 20% and time to decline in ALSFRS-R respiratory domain will be evaluated using the Cox’s 
proportional regression model. The model will include effect for treatment and will be adjusted 
for randomisation strata. Premature discontinuations will be censored from the analyses.
Censoring rules will be defined in the SAP.
The efficacy variables ALSFRS-R total score and its subdomain scores will be performed 
through 48 weeks. Primary analysis will combine change from baseline to 48 weeks and survival 
through 48 weeks in joint rank analysis (Berry JD et al., 2013) using Wilcoxon-Mann-Whitney 
test. Slope of decline will be estimated using the random slope model. Additional analyses will 
be conducted using the MMRM and estimates for individual time points will be done using 
contrasts. Imputation of missing data using the multiple imputation method will be considered.
CGI, Borg CR10 (sitting, supine and orthostatic changes), ESS and PSQI will be evaluated using 
the MMRM and estimates for individual time points will be done using contrasts. In addition 
categorical analyses for ESS and PSQI will be performed using repeated measures logistic 
regression using the generalised estimating equation (GEE) approach.
All efficacy data will be listed and summarised over the time and by treatment groups using 
appropriate descriptive statistics. Health and home care resource use data will be summarised in 
the study report, but any further analysis for potential pharmacoeconomic purposes will be 
reported separately.
8.4.4
Pharmacokinetic analysis
Levosimendan, OR-1855, OR-1896 and riluzole concentrations will be summarised using 
descriptive statistics. Metabolites OR-1855 and OR-1896 will be further summarised by subject 
acetylation status.
8.4.5
Population PK/PD modelling
A population pharmacokinetic/pharmacodynamic (PK/PD) model between OR-1896 and 
OR-1855 exposure and efficacy related endpoints will be explored. This will include building 
population PK model, and characterising the concentration effect relationship with PD
endpoints.
8.4.6
Evaluation of pharmacogenomics
Acetylation status will be determined from all subjects participating in the study and the results 
will be source data. Acetylation status will be summarised by treatments groups. The effects of 
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acetylation status on OR-1896 and OR-1855 pharmacokinetics and on SVC and HR will be 
evaluated using analysis of variance (ANOVA).
In the context of this study, genetic polymorphisms will be analysed in relation to significant 
variation or specific scientific questions in PK, PD or safety variables of levosimendan. These 
pharmacogenomic analyses apply only to those subjects who have signed a separate IC for PG. 
If such analysis is performed, the results will be reported in a separate report.
8.4.7
Evaluation of exploratory biomarkers
In the context of exploratory biomarker analyses, microRNA, proteins or biochemical 
metabolites may give supportive data related to the disease state of the patients and 
pharmacodynamics of levosimendan. If such analysis will be performed, the results will be 
reported in a separate report.
8.4.8
Safety analysis
An authorised person will code AEs, prior and concomitant medications using standard coding 
dictionaries.
8.4.8.1
Analysis of adverse events
AEs reported during the study will be classified by system organ classes and preferred terms 
using the Medical Dictionary for Regulatory Activities (MedDRA) coding system. The AEs will 
be displayed in a frequency table. The number and proportion (%) of subjects having each AE 
will be given, the severity of AEs (mild, moderate, severe) and causality to the study treatment 
will be evaluated. SAEs and other significant AEs will be evaluated case by case. AEs occurring 
before and after the start of study treatment will be reported separately.
8.4.8.2
Clinical safety analysis
Vital signs (supine and orthostatic HR, systolic and diastolic BP) as well as standard 12-lead 
ECG variables will be tabulated by treatment. Potential treatment effects will be analysed using 
the MMRM. The number of subjects with QTc interval prolongation will be classified and 
summarised. The details of the MMRM model and categorical analyses will be defined in the 
SAP. Abnormal ECG findings, special situations and physical examination findings will be 
summarised by treatment group using descriptive statistics.
8.4.8.3
Laboratory safety analysis
Safety laboratory results will be primarily evaluated using descriptive statistics and line plots
only. Potential treatment effects may be analysed using the MMRM, if deemed necessary. The 
frequencies of normal and abnormal safety laboratory findings will be summarised based on the 
provided reference ranges of the respective laboratory, and the clinical significance of the 
findings will be evaluated.
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8.4.8.4
Analysis of prior and concomitant treatments
Prior and concomitant treatments will be coded using the anatomical therapeutic chemical 
(ATC) classification system. The number and percentage of subjects using concomitant 
treatments will be summarised by pharmacological subgroup and chemical substance. 
8.4.8.5
Analysis of suicidality
Suicidality will be summarised by treatment group using descriptive statistics.
8.5
Interim analyses
Interim/futility analyses will be done when approximately 50% and 100% of the subjects have 
been treated for 12 weeks. Futility will be evaluated using SVC% response and time to 
respiratory event endpoint. Based on the estimation, approximately 35% and 75% of the 
respiratory events have cumulated at the time of planned analyses. Stopping criteria will be based 
on O’Brien-Fleming type of boundaries (O'Brien PC et al., 1979, Lan GKK et al., 1983). Exact 
alpha spending for futility analyses will be based on the actual amount of information used and 
are detailed in a DSMB charter. An independent DSMB will perform and evaluate the 
interim/futility analyses and make recommendations for the study conduct.
9.
DATA QUALITY ASSURANCE
9.1
Training
An investigators’ meeting will be arranged for the investigators and other relevant study centre 
personnel. This meeting will include a review of the protocol, CRF completion and study 
procedures as well as training on efficacy assessments like supine SVC and ALSFRS-R.
The investigators will ensure that appropriate training relevant to the study is given to the 
medical, nursing and other personnel involved in the study. The investigators will also ensure 
that any information relevant to the conduct of the study is forwarded to other relevant study 
centre personnel.
9.2
Case report forms
Electronic queries about missing, misleading, incomplete or illogical data will appear in the EDC 
system. An audit trail within the system will track all changes/corrections made. The investigator 
has to confirm the content of the eCRF with an electronic signature.
9.3
Monitoring, audits and inspections
The study monitor will visit the study centre regularly as agreed by the investigator and the 
sponsor. The study monitor will ensure that the study complies with good clinical practice (GCP) 
and applicable regulatory requirements and that the protocol is followed in all aspects, including 
the randomisation procedure, accurate recording of results, reporting of AEs, drug accountability 
and record keeping. Furthermore, it will be verified that the clinical facilities remain appropriate, 
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and that the CRFs correspond with source data. Further details regarding monitoring are 
presented in the monitoring manual.
The study may be audited by independent representative(s) of the sponsor or inspected by the 
competent authorities (CAs). For these purposes, the study monitor, auditors and inspectors will 
be allowed direct access to hospital or patient records/source data of the study subjects, original 
laboratory data etc., as far as they are related to the study.
It is essential that the investigator and other relevant members of the study centre team are 
available during the monitoring visits, audits and inspections, and that they devote sufficient 
time to these processes.
9.4
Laboratories and other vendors
A central laboratory will be used for laboratory safety measurements, ECG analyses and 
spirometry.
Details regarding laboratory safety measurements, ECG analyses and spirometry are presented
in the separate instructions. Quality certificates are required from all safety laboratories.
Bioanalytics will be performed using validated methods.
10. FURTHER REQUIREMENTS AND GENERAL INFORMATION
10.1 Investigators and study administrative structure
10.1.1
Investigators
Should the investigator transfer one of his/her responsibilities to other members of the study 
centre team, he/she must have this approved by the representative of the sponsor and 
documented.
In the event of changes in key study centre team members, the responsible investigator must 
ensure that the successor is fully informed and capable of following the procedures.
A curriculum vitae in English must be obtained from all investigators who sign the protocol, and 
from other relevant persons.
10.1.2
Data and safety monitoring board
An independent DSMB will be established for the study. The duty of the DSMB is to protect the 
ethical and safety interests of the study subjects and all others who may possibly be exposed to 
study treatments. The DSMB safety meetings will occur by approximately bimonthly frequency. 
The DSMB will also perform and evaluate formal futility/interim analyses and make 
recommendations for the study conduct. 
Further details regarding the composition and responsibility of the DSMB are presented in a
DSMB charter.
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10.2 Amendments to the study protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, and when required by the EC/IRB or CA. Only in the event 
of a need to eliminate an immediate hazard(s) to study subjects, the investigator may implement 
a deviation from the protocol without prior approval.
Any change or addition to the approved study protocol may lead to suspension of the study or 
its results.
Any changes to the study protocol are subject to prior discussion with, and approval by, the 
sponsor and the study coordinating investigator. As a general rule, protocol amendments should 
be approved according to the same procedures as the study protocol.
Amendments are regarded as substantial, where they are likely to have a significant impact on 
the safety, physical or mental integrity of the study subjects, or the scientific value of the study. 
An approval of the responsible EC/IRB or CA shall be obtained before substantial amendments 
may be implemented, unless local regulations are different.
If an amendment contains only minor changes (typically administrative) not affecting the safety, 
physical or mental integrity of the study subjects, or the scientific value of the study, the EC/IRB
or CA need not to be notified and in-house approval (including approval by the study 
coordinating investigator) is adequate.
10.3 Insurance
The sponsor will provide clinical trial liability insurance for study subjects in all participating 
countries according to local regulations.
10.4 Financial disclosure
The investigator will be required to disclose any financial arrangement whereby the value of the 
compensation for conducting the study could be influenced by the outcome of the study; any 
significant payments of other sorts from the sponsor, such as a grant to fund on-going research, 
compensation in the form of equipment, retainer for on-going consultation, or honoraria; any 
proprietary interest in oral levosimendan; any significant equity interest in the sponsor as defined 
in the US Code of Federal Regulations [21 CFR 54 2(b)].
In consideration of participation in the study, the sponsor will pay the investigator, or nominated 
payee the sums set out in the payment schedule attached to the Investigator Agreement.
10.5 Completion of the study
The end of the study is defined as the date of the last subject’s last visit or last contact with the 
study site.
Study centres will be closed upon study completion. A study centre is considered closed when 
all required documents and study supplies have been collected and a study 
completion/termination visit has been performed.
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The sponsor reserves the right to prematurely terminate the study, or recruitment to the study,
for valid scientific or administrative reasons. After decision to prematurely terminate the study, 
the investigator must contact all participating study subjects within 7 days, and invite them for 
an end-of-study visit.
10.6 Reports, publications and communication of results
Orion wishes to collaborate with the investigators to publish the results as timely as possible, 
without compromising accuracy or industrial property rights. The preparation, submission and 
authorship for publications containing the study results shall be in accordance with a process 
determined by mutual written agreement among the sponsor and participating 
investigators/institutions, and in accordance with international criteria for authorship; see 
International Committee of Medical Journal Editors recommendations, available at 
http://www.icmje.org.
Orion remains the exclusive owner of the study data defined by the protocol.
This study will be registered in one of the acceptable registries before the enrolment of the first 
subject.
10.7 Retention of records
The investigator agrees to keep the following documentation in the investigator’s study file: 
study subject records, including a subject screening log, a subject identification list, all original 
signed IC forms, a copy of CRFs and records of drug dispensing. 
The study files at the study centres will be stored in the respective archives for 15 years, after 
which the sponsor will be contacted and the possibility of future archiving will be mutually 
agreed upon.
11. ETHICS
11.1 Ethics committee
The study protocol, subject information sheet, IC form, and all other necessary documents will 
be submitted to an independent EC/IRB for review according to local regulations.
The investigator is responsible for obtaining a favourable opinion from the EC/IRB for the study, 
submitting any amendment(s), and communicating study-related safety issues as requested by 
the EC/IRB. The investigator should file all correspondence with the EC/IRB in the 
investigator’s study file. Relevant copies of this correspondence should be forwarded to the 
sponsor.
11.2 Ethical conduct of the study
The study will be conducted in accordance with the Declaration of Helsinki guiding physicians 
in biomedical research involving human subjects.
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The study shall not be initiated before favourable opinion from the EC/IRB and approval from 
the CA has been obtained for the protocol, including its appendices.
The study will be conducted in compliance with the protocol, GCP (ICH/135/95) and applicable 
regulatory requirements. A substantial amendment shall not be implemented until the protocol 
amendment has received favourable opinion from the EC and approval from the CA. Only in 
case of the need to eliminate an immediate hazard(s) to study subjects, the investigator may 
implement deviation from the protocol without prior favourable opinion from the EC and 
approval from the CA for the protocol amendment.
In case of serious breaches, the Medicines and Healthcare Products Regulatory Agency (MHRA)
GCP Inspectorate must be notified according to MHRA Guidance for the notification of serious 
breaches of GCP or the study protocol (see http://www.mhra.gov.uk).
11.3 Subject information and informed consent
The investigator will ensure that each subject candidate is fully informed about the objectives 
and procedures of the study. The investigator will also explain any possible risks with 
participating in the study and answer all questions regarding the study. In the case that the subject 
is unable to sign the consent form due to muscular weakness, a witness may sign the form to 
indicate that the subject has given oral consent to participate in the study. In such cases, the 
investigator must also explain the study to the witness at the same time as they explain the study 
to the participant. After this, the subject will be given sufficient time to make a decision 
regarding participation in the study.
Subjects will be informed of their right to discontinue the study at any time without their medical 
care or legal rights being affected. Subjects will also be informed that representatives of the 
sponsor or CA may inspect relevant parts of their medical records and study data.
The investigator will obtain a signed and dated consent from each subject before any study 
related procedures are performed. A copy of each signed and dated IC will be given to the 
subject. The investigator should confirm the receipt of every IC by entering the date of the 
consent both on the subject’s CRF and also on the subject screening log and identification list.
11.4 Subject data protection
Information collected during the course of the study will be stored in a database and used in the 
further development of oral levosimendan and thereafter for as long as the information is 
relevant to patient care. The use includes the transfer of data to CAs in the European Union, the 
USA or other countries for the purpose of obtaining and maintaining marketing authorisations. 
All information is handled confidentially and according to local laws and regulations.
The study subjects can be identified in the CRFs only by study subject number, birth year and 
sex.
The confidentiality of PG data will be protected according to local laws and regulations.
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12. REFERENCE LIST
Andersen PM et al. (2012) EFNS guidelines on the clinical management of amyotrophic lateral 
sclerosis (MALS)--revised report of an EFNS task force. Eur J Neurol. 19 (3): 360-75.
Baumann F et al. (2010) Use of respiratory function tests to predict survival in amyotrophic 
lateral sclerosis. Amyotrophic lateral sclerosis : official publication of the World 
Federation of Neurology Research Group on Motor Neuron Diseases. 11 (1-2): 194-202.
Bensimon G et al. (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. 
ALS/Riluzole Study Group. N Engl J Med. 330 (9): 585-91.
Berry JD et al. (2013) The Combined Assessment of Function and Survival (CAFS): a new 
endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 14 
(3): 162-8.
Borg GA (1982) Psychophysical bases of perceived exertion. Medicine and science in sports 
and exercise. 14 (5): 377-81.
Brooks BR et al. (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic 
lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 1 (5): 293-9.
Buysse DJ et al. (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric 
practice and research. Psychiatry research. 28 (2): 193-213.
Cedarbaum JM et al. (1999) The ALSFRS-R: a revised ALS functional rating scale that 
incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J 
Neurol Sci. 169 (1-2): 13-21.
Cudkowicz ME et al. (2013) Dexpramipexole versus placebo for patients with amyotrophic 
lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 
12 (11): 1059-67.
Deschodt-Arsac V et al. (2010) Absence of mitochondrial activation during levosimendan 
inotropic action in perfused paced guinea pig hearts as demonstrated by modular control 
analysis. Am J Physiol Regul Integr Comp Physiol. 299 (Copyright (C) 2015 U.S. 
National Library of Medicine.): R786-92.
Doorduin J et al. (2012) The calcium sensitizer levosimendan improves human diaphragm 
function. Am J Respir Crit Care Med. 185 (1): 90-5.
Haikala H et al. (1995) Troponin C-mediated calcium sensitization by levosimendan accelerates 
the proportional development of isometric tension. J Mol Cell Cardiol. 27 (10): 2155-65.
Hewitt CE et al. (2006) Is restricted randomisation necessary? BMJ (Clinical research ed). 332 
(7556): 1506-8.
Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep. 14 (6): 540-5.
Kivikko M et al. (2015) Oral Levosimendan Increases Cerebral Blood Flow Velocities in 
Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study. 
Current therapeutic research, clinical and experimental. 77: 46-51.
Lan GKK et al. (1983) Discrete sequential boundaries for clinical trials. Biometrika. 70 (3): 659-
663.
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Lechtzin N et al. (2002) Spirometry in the supine position improves the detection of 
diaphragmatic weakness in patients with amyotrophic lateral sclerosis. Chest. 121 (2): 
436-42.
NICE guideline [NG42]. Motor neurone disease: assessment and management. Last updated 
February 2016. https://www.nice.org.uk/guidance/NG42
Nieminen MS et al. (2008) Oral levosimendan in patients with severe chronic heart failure --the 
PERSIST study. Eur J Heart Fail. 10 (12): 1246-54.
O'Brien PC et al. (1979) A multiple testing procedure for clinical trials. Biometrics. 35 (3): 549-
56.
Press release (2017) http://markets.businessinsider.com/news/stocks/Cytokinetics-Announces-
Presentation-of-Results-From-VITALITY-ALS-at-28th-International-Symposium-on-
ALS-MND-1010634758, Markets Insider.
Schmidt EP et al. (2006) Pulmonary predictors of survival in amyotrophic lateral sclerosis: use 
in clinical trial design. Muscle & nerve. 33 (1): 127-32.
Shefner JM et al. (2016) A randomized, placebo-controlled, double-blind phase IIb trial 
evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral 
sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 17 (5-6): 426-35.
Turner MR et al. (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet 
Neurol. 12 (3): 310-22.
van Hees HW et al. (2011) Levosimendan improves calcium sensitivity of diaphragm muscle 
fibres from a rat model of heart failure. Br J Pharmacol. 162 (3): 566-73.
van Hees HW et al. (2009) Levosimendan enhances force generation of diaphragm muscle from 
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 179 
(1): 41-7.
Zinman L et al. (2011) Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet 
Neurol. 10 (5): 481-90.
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13. SUMMARY OF CHANGES TO AMENDMENT 2
13.1 Revision history
Protocol and amended protocols
Date
Applies to
Clinical study protocol
20 October 2017
Global
Amendment 1 - Amended clinical study protocol
05 January 2018
Global
Amendment 2 - Amended clinical study protocol
17 April 2018
Global
Amendment 3 - Amended clinical study protocol
26 March 2020
Global
Country specific amendments
Date
Applies to
Amendment 1
27 Mar 2018
Sweden
Amendment 1
06 Apr 2018
The United Kingdom
Amendment 1 
16 Apr 2018
Belgium
13.2 Summary of changes
The changes incorporated in this amended protocol from the Amendment 2 – Amended clinical study protocol dated 17 April 2018
are described in the following. The modifications of the text are indicated by strikethrough (for deletions) and underline (for additions).
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The following changes were made due to COVID-19 pandemic:
Section
Previous text
New text
Rationale for the change
6.6 Changes 
implemented due 
to COVID-19 
pandemic
-
Whole text is new, see the section 6.6.
New section describing 
changes due to COVID-19 
pandemic added
In addition,

the table of contents was updated to reflect the headings and pagination of the current document.

the title page and header and footer sections were updated to reflect the version details of the current document.

the approver information was updated.
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14. APPENDICES
Appendix 1.
Investigator signature
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SAP_001.pdf: 
 
 
Document type: 
Statistical Analysis Plan 
Title: 
Effects of oral levosimendan (ODM-109) on respiratory function in 
patients with ALS 
NCT Number: 
NCT03505021 
Document date: 
18 June 2020 
 




Orion Corporation
ORION PHARMA
Statistical analysis plan 3119002
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................... 2
ABBREVIATIONS.......................................................................................................................... 5
1.
GENERAL REMARKS........................................................................................................... 7
2.
OVERALL STUDY DESIGN AND PLAN................................................................................... 7
3.
STUDY OBJECTIVES............................................................................................................ 8
3.1
Primary objective......................................................................................................... 8
3.2
Secondary objectives ................................................................................................... 8
3.2.1
Other objectives....................................................................................................... 8
3.2.2
Exploratory objectives............................................................................................. 8
4.
STATISTICAL HYPOTHESES................................................................................................. 9
5.
DETERMINATION OF SAMPLE SIZE...................................................................................... 9
6.
GENERAL STATISTICAL CONSIDERATIONS........................................................................ 10
6.1
Data sets to be analysed ............................................................................................. 10
6.2
Statistical issues ......................................................................................................... 10
6.2.1
Randomization ...................................................................................................... 10
6.2.2
Significance level and confidence intervals.......................................................... 11
6.2.3
Multiplicity............................................................................................................ 11
6.2.4
Intercurrent events................................................................................................. 11
6.2.5
Dropouts and missing data.................................................................................... 12
6.2.6
Outliers.................................................................................................................. 14
6.2.7
Baseline values...................................................................................................... 14
6.2.8
Multiple measurements ......................................................................................... 14
6.2.9
Multiple timepoints ............................................................................................... 14
6.2.10
Checking model assumptions................................................................................ 14
6.2.11
Transformations .................................................................................................... 15
6.2.12
Multicentre studies................................................................................................ 15
6.2.13
Interim analyses and data monitoring ................................................................... 15
6.2.14
Subgroups.............................................................................................................. 15
6.2.15
Descriptive statistics.............................................................................................. 16
7.
STATISTICAL ANALYSES................................................................................................... 17
7.1
Disposition of subjects............................................................................................... 17
7.2
Demographic and other baseline characteristics........................................................ 17
7.3
Medical history .......................................................................................................... 18
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Statistical analysis plan 3119002
7.4
Extent of exposure and treatment compliance........................................................... 19
7.5
Efficacy...................................................................................................................... 19
7.5.1
Primary efficacy variable(s).................................................................................. 19
7.5.1.1
Slow Vital Capacity.......................................................................................... 19
7.5.2
Secondary efficacy variables................................................................................. 21
7.5.2.1
Revised ALS Functional Rating Scale ............................................................. 21
7.5.2.2
Combined assessment of function and survival ............................................... 22
7.5.2.3
Respiratory event and other time-to-event endpoints....................................... 23
7.5.2.4
Clinical Global Impression............................................................................... 24
7.5.2.5
Borg Category Ratio 10 Scale .......................................................................... 25
7.5.2.6
Epworth Sleepiness Scale................................................................................. 25
7.5.2.7
Pittsburgh Sleep Quality Index......................................................................... 25
7.5.3
Additional variables .............................................................................................. 26
7.5.3.1
Health care and home care resource use........................................................... 26
7.5.4
Sensitivity analyses ............................................................................................... 26
7.5.4.1
Full analysis set ................................................................................................ 26
7.5.4.2
Per-protocol population.................................................................................... 27
7.5.4.3
Use randomisation strata from CRF data ......................................................... 27
7.5.4.4
Analyses without missing data imputation....................................................... 27
7.5.4.5
Include unacceptable quality SVC measurements ........................................... 27
7.5.4.6
Exclude subjects that changed SVC supine angle during the study................. 28
7.5.4.7
Exclude SVC supine measurements performed with > 15 degree angle.......... 28
7.5.4.8
Combined impact of position and angle on SVC supine results ...................... 28
7.5.4.9
Adjust for riluzole use at baseline .................................................................... 28
7.5.4.10
Adjust for effect of paper questionnaire collection .......................................... 29
7.5.4.11
Exclude efficacy data after initiation of NIV ................................................... 29
7.6
Pharmacokinetics and pharmacodynamics ................................................................ 29
7.7
Pharmacogenomics .................................................................................................... 30
7.8
Exploratory biomarkers ............................................................................................. 30
7.9
Safety ......................................................................................................................... 30
7.9.1
Deaths.................................................................................................................... 30
7.9.2
Adverse events ...................................................................................................... 30
7.9.3
Laboratory values.................................................................................................. 32
7.9.4
12-lead ECG.......................................................................................................... 34
7.9.5
Vitals signs ............................................................................................................ 34
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Statistical analysis plan 3119002
7.9.6
Physical findings and other observations.............................................................. 35
7.10
Additional analyses.................................................................................................... 35
7.10.1
Prior and concomitant treatments.......................................................................... 35
7.10.2
Suicidality.............................................................................................................. 36
7.10.3
COVID-19............................................................................................................. 36
7.11
Changes from the clinical study protocol .................................................................. 36
7.12
Execution of statistical analyses ................................................................................ 38
7.13
Software ..................................................................................................................... 38
8.
REFERENCES.................................................................................................................... 38
9.
REVISION HISTORY........................................................................................................... 39
10.
APPENDICES..................................................................................................................... 40
10.1
Medical history groups of interest ............................................................................. 40
10.2
Adverse events of special interest.............................................................................. 40
10.3
Concomitant treatment groups of interest.................................................................. 40
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Statistical analysis plan 3119002
ABBREVIATIONS
AE 
Adverse event
AESI
Treatment-emergent adverse event of special interest
ALS
Amyotrophic lateral sclerosis
ALSFRS-R
Revised ALS Functional Rating Scale
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Asparate transaminase
ATC
Anatomical therapeutic chemical
BMI
Body mass index
BP
Blood pressure
CAFS
Combined assessment of function and survival
CGI
Clinical Global Impression
CI
Confidence interval
CR10
Category Ratio 10
CRF
Case report form
DSMB
Data and safety monitoring board
ECG
Electrocardiogram
eGFR
Creatinine clearance
ESS
Epworth Sleepiness Scale
FAS
Full analysis set
FCS
Fully conditional specification
GEE
Generalised estimating equation
HR
Heart rate
IHSC
In-house search category
ITT
Intent-to-treat
KM
Kaplan-Meier
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MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
NIV
Non-invasive mask ventilation
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per-protocol
PR
Pulse rate
PSQI
Pittsburgh Sleep Quality Index
PT
Preferred term
RMST
Restricted mean survival time
RTSM
Randomization and trial supply management
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMQ
Standardised MedDRA Query
SOC
System organ class
SVC
Slow vital capacity
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
ULN
Upper limit of normal
VAS
Visual analogue scale
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Statistical analysis plan 3119002
1.
GENERAL REMARKS
The purpose of this document is to describe the statistical methodology for this clinical study, 
including also plans of analysis datasets to be used and the plans how the results will be 
presented. 
2.
OVERALL STUDY DESIGN AND PLAN
This is a randomised, double-blind, placebo-controlled, parallel-group, multinational, 
multicentre phase III study. The subjects will be allocated to 2 parallel groups receiving either 
levosimendan 1-2 mg daily or placebo in 2:1 ratio. The study will be conducted globally. The 
estimated number of sites is approximately 100.
The total duration for double-blind comparison will be 48 weeks. The primary efficacy analysis 
will be based on data collected from the first 12 weeks of the study. Two futility/interim analyses 
will be conducted: the first when approximately 50%, and the second when all of the subjects 
have been treated for 12 weeks. An independent data and safety monitoring board (DSMB) will 
be established for this and for safety monitoring purposes.
There will be a screening visit, a baseline visit (V1) followed by visits at 2 weeks (V2), 4 weeks 
(V3), 8 weeks (V4), 12 weeks (V5), 24 weeks (V6), 36 weeks (V7) and 48 weeks (V8), and 
telephone contacts during weeks 18, 30 and 42. An end-of-study visit will take place 14-25 days 
after the last study treatment administration for each subject. Additional visits may take place 
after visit 3 and after later visits. The total study duration for each subject will be about 51-52 
weeks, including the end-of-study visit. The study design is presented in Figure 1.
Figure 1. Study design
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3.
STUDY OBJECTIVES
3.1
Primary objective
The primary objective of this study is to confirm that levosimendan can significantly improve 
respiratory function measured by supine slow vital capacity (SVC) in amyotrophic lateral 
sclerosis (ALS) patients.
3.2
Secondary objectives
The secondary objective is to confirm that levosimendan improves the functionality of subjects 
measured by Revised ALS Functional Rating Scale (ALSFRS-R), Clinical Global Impression 
(CGI), Borg Category Ratio 10 (CR10) scale on the intensity of dyspnoea, Epworth Sleepiness 
Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). The latter two are sleep scales assessing 
daytime somnolence and sleep quality, respectively. In addition, the long-term tolerability and 
safety of levosimendan in ALS patients will be evaluated, assessing up to 48 weeks of exposure.
3.2.1
Other objectives
For the purposes of potential later pharmacoeconomic analysis, the use of specific health care 
resources will be quantified on weekly basis, including:

The number of days spent in hospital care.

The number of additional visits to a hospital emergency unit.

The average number of formal home care hours per day on the given week (paid/public 
services obtained) and the number of times such care was received during a usual night. 

The average number of informal home care hours per day on the given week (unpaid; by 
family, other relative, friend or volunteer) and the number of times such care was 
received during a usual night. 

The number of days spent in institutional care other than hospital (e.g. 
respite/hospice/nursing home/rehabilitative care).

Receipt of new, non-medicinal assistive devices and other aids.
3.2.2
Exploratory objectives
The plasma concentrations of levosimendan and the metabolites OR-1855 and OR-1896 will be 
determined. In addition, a population pharmacokinetic/pharmacodynamic (PK/PD) model 
between OR-1855 and OR-1896 exposure and efficacy related endpoints and HR will be 
explored. Plasma concentrations of riluzole will also be determined. The effects of 
levosimendan, OR-1855 and OR-1896 on plasma trough concentrations of riluzole will be 
evaluated.
The acetylation status will be determined for all subjects to assess whether it affects the PD
responses of levosimendan in patients with ALS.
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4.
STATISTICAL HYPOTHESES
A mixed model for repeated measures (MMRM) will be fitted for the change from baseline in 
supine slow vital capacity. The model will include data from all visit up to Week 12.
The difference between treatment groups at Week 12 is estimated from the MMRM with the use 
of contrasts, such that the quantity of interest is given by
 = 	
	 + 	
	×		
The following null () and alternative () hypotheses will be used for testing the statistical 
significance of :
:  = 0
:  ≠0
5.
DETERMINATION OF SAMPLE SIZE
Sample size estimation is based primarily on supine SVC results from the study 3119001 
LEVALS (Table 1). LEVALS had placebo-controlled data only up to 2 weeks, and therefore 
extrapolation of the results was needed. The placebo effect from phase II tirasemtiv trial 
BENEFIT-ALS (Shefner JM et al., 2016) was also evaluated.
Assuming a difference of at least 3.6% in change from baseline supine SVC between treatment 
groups and a common standard deviation of 10%, 164 evaluable subjects per group in a 1:1 
allocation ratio have 90% power to detect a statistically significant difference in a two-sided, 5% 
-level, two group T-test. Using a 2:1 allocation ratio, randomisation of 450 subjects to the study 
(approximately 300 levosimendan and 150 placebo treated subjects) allows for a total dropout 
rate of approximately 20%.
Table 1.
Mean (SD) change from baseline SVC (supine) %-predicted in LEVALS
Treatment
2 weeks
12 weeks
Levosimendan 1 mg x 2
+2.4 (8.3)
-4.9
Levosimendan 1 mg x 1
+0.8 (8.6)
Placebo
-3.6 (9.4)
-17.71
Placebo (BENEFIT-ALS)
-1.4
-8.5
1 Extrapolated from the data
SD = standard deviation
Based on the dexpramipexole phase III study EMPOWER (Cudkowicz ME et al., 2013), a 12 
point reduction in total ALSFRS-R score and a 15% mortality rate at 12 months can be assumed 
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in placebo treated patients. Assuming a 10 point decline in ALSFRS-R, with a standard deviation 
of 8 points, and a 20% relative improvement in survival, 450 patients provide approximately 
80% simulated power to detect a statistically significant difference using a joint rank test. With 
450 subjects and assuming a 48-week levosimendan event rate of 73% and hazard ratio of 0.70, 
time to respiratory event has approximately 70% power to detect a statistically significant 
difference using a log-rank test.
6.
GENERAL STATISTICAL CONSIDERATIONS
6.1
Data sets to be analysed
The intent-to-treat (ITT) population, including all randomized subjects, will be used for the 
primary evaluation. All subjects who received any study treatment will be included in the 
evaluation of safety. Sensitivity analyses will include evaluations of key endpoints in the in the 
full analysis set (FAS), including all treated subjects with at least a baseline and one post-
baseline SVC measurement, and in the per-protocol (PP) population.
The PP population includes all randomized subjects, excluding subjects with important protocol 
deviations affecting the evaluation of efficacy. The study has two key intervals at which efficacy 
endpoints are generally evaluated: up to week 12, and up to week 48. For endpoints evaluated at 
week 12, it would not be desirable to exclude subjects from the PP analyses due to important 
protocol deviations occurring only after the endpoint has already been assessed. To address this, 
two separate PP populations will be created: PP up to week 12 (PP1) and PP up to week 48 
(PP2). Important protocol deviations occurring before week 12 will lead to exclusion from both 
populations, while deviations occurring only after the week 12 visit has already been completed 
will only exclude the subject from PP2. The appropriate PP population will then be chosen for 
the analyses, according to the endpoint.
The importance of protocol deviations with respect to leading to exclusion from the PP 
populations will be evaluated during subject classification review mettings with the clinical 
study team. General principles that lead to exclusion contain: inclusion and exclusion criteria 
deviatiotions, completeness of key efficacy assessments, use of prohibited medications, 
compliance and other important protocol deviations; and are detailed in a separate subject 
classification document.
Subject classification will be completed during the blind review before the database lock and 
opening of the treatment code.
Analyses of the effects of the COVID-19 pandemic are detailed in section 7.10.3.
6.2
Statistical issues
6.2.1
Randomization
Randomization will be conducted centrally using Medidata Rave RTSM. The subjects will be 
allocated to 2 parallel groups receiving either levosimendan 1-2 mg daily or placebo in 2:1 ratio. 
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The estimated number of sites is approximately 100 and randomization will not be stratified by 
centre. Randomization will be stratified by the following factors:
1. Bulbar onset
2. Edaravone use
3. North American region
The stratification variable used to adjust the statistical models will combine all three 
randomization factors into a single factor with 2 = 8 distinct levels.
Due to data entry errors at randomization, levels of the stratification factors used for 
randomization may differ from final CRF data. Primary analyses will be conducted with the 
levels of stratification factors used for randomization (STRATAR in ADSL), while final CRF 
data will be used in a sensitivity analysis (STRATAV in ADSL; see 7.5.4).
6.2.2
Significance level and confidence intervals
Two-sided tests with a significance level of 5% will be used throughout the analyses. 
Corresponding 95% confidence intervals will be calculated for model-based contrasts, 
comparing the active treatment to placebo, using model-based standard error estimates.
The study has interim analyses that allow early stopping for futility, but not for efficacy.
Therefore, we do not make adjustments to the significance levels in the final analyses.
6.2.3
Multiplicity
No adjustment for multiplicity is planned.
Secondary endpoints will be tested hierarchically, in the following order:
1. Combined assessment of function and survival (CAFS) through 48 weeks
2. Time to respiratory event
3. Clinical Global Impression (CGI) through 48 weeks
4. Supine Borg CR 10 scale at 12 weeks
5. Slope of change in the ALSFRS-R respiratory domain through 48 weeks
See section 7.5.2 for more detailed descriptions of the endpoints and their methods of analysis.
6.2.4
Intercurrent events
Intercurrent events refer to events occurring after the start of study treatment that have an impact 
on the interpretation of or ability to collect measurements used to evaluate efficacy. For example, 
deaths and study discontinuations lead to missing data, study treatment discontinuation can cause 
a treatment effect to cease, or concomitant use of efficacious emergency medication can lead to 
misperceived efficacy of the investigational product.
In the primary efficacy analyses, missing data due to study discontinuations or deaths will be 
imputed following the procedure described in section 6.2.5 below. As specified in the study 
protocol, many endpoints are no longer collected after the end of study treatment. These missing 
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data points will also be handled following section 6.2.5. In these cases, missing data imputation 
attempts to estimate what could have happened, had the intercurrent event not occurred.
We do not consider there to be any relevant rescue medications to account for in the analyses. 
Baseline therapies of riluzole and edaravone are assumed to be stable for the course of the study, 
as required by the study protocol.
6.2.5
Dropouts and missing data
If a subject’s data for a given planned visit is missing due to the actual visit having occurred 
outside the specified visit interval, data from the actual visit will be used for imputing data for 
the planned visit, if the time difference between the planned and actual visit no more than twice 
the tolerance for that visit. Otherwise, data will be imputed following the process for other types 
of missing data. See Figure 1 in section 2 for the visit timings and tolerance intervals.
In the primary evaluation, the flowing efficacy analyses will be conducted with missing data 
imputed using multiple imputation:
1. Supine slow vital capacity (SVC) through 12 weeks
2. Combined assessment of function and survival (CAFS) through 48 weeks
3. Time to respiratory event
4. Clinical Global Impression (CGI) through 48 weeks
5. Supine Borg CR 10 scale at 12 weeks
6. Slope of change in the ALSFRS-R respiratory domain through 48 weeks
For each imputed endpoint, 10 independent imputed data sets will be generated using the fully 
conditional specification (FCS) method. Predictive mean meatching will be used to impute 
continuous variables, and logistic regression methods for classification variables, as appropriate.
The imputation models will include measurements of the endpoint being imputed from all 
planned visits at which it should be collected, from the baseline visit up to the week 48 visit. The 
measurements are used in a one-row-per-subject format, by which all other visits’ data are used 
to impute missing data at all visits. Further, the imputation model will also include time-invariant 
variables used in the statistical models or potentially associated with the missing outcome: 
treatment group, randomisation strata (site of onset, edaravone use, and region; as collected on 
the CRFs), sex, age group (< 65, 65–74, ≥75), and riluzole use status.
SAS code in the following fashion will be used to perform the imputation process:
proc mi nimpute = 10 seed = 270815;
  class ARM STRATAV SEX AGEGR1 RILUZUSE;
  var ARM STRATAV SEX AGEGR1 RILUZUSE AVAL1-AVAL8;
  fcs regpmm (/ k = 5) logistic;
run;
To ensure reproducibility of the imputation results, the randomly chosen seed value of 270815
will be used for all imputation procedures.
Imputation will be done directly based on the collected values, and derived quantities used for 
the analyses, like e.g. change from baseline, will be calculated after the imputation process,
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within each imputed data set. For questionnaires that consist of multiple sub-items, values for 
individual items will be imputed, and the summary scores that are used for analysis purposes 
will be re-calculated based on the imputed data. Imputation is not done directly on the summary 
scores—which will have missing values if even one of their sub-items has a missing value—in 
order to maximise the use of collected information.
Multiply-imputed data will be analysed according to the methods specified for each endpoint in 
section 7, with the addition of performing the analysis separately in each imputed data set with 
the use of a by-statement in the analysis procedure. Results of all the analyses are then saved, 
and pooled estimates are calculated for inference purposes.
Pooled estimates of model parameters are be obtained, depending on the analysis method, with 
SAS code in the following fashion:
proc mianalyze parms = parms covb(effectvar = rowcol) = covb;
  class TRTP VISIT;
  modeleffects TRTP VISIT TRTP * VISIT;
run;
Above, the parms and covb data sets are obtained from the corresponding solution and covb
outputs from the proc mixed procedure. The exact statements and options used for the pooling 
procedure will vary based on the analysis model used.
Model-based contrasts obtained with estimate statements will also be pooled, however the 
method used differs slightly from the one used for model parameters:
proc mianalyze data = estimates;
  modeleffects estimate;
  stderr stderr;
  by label;
run;
The method above will also be used to analyse hazard ratios from Cox models for time-to-event 
endpoints, with parameterestimates from proc phreg as the estimates data. For CAFS, Hodges-
Lehmann estimates for median difference will be pooled in the same manner.
A complete-case analysis will be performed as a sensitivity analysis, using observed data only. 
There, listwise deletion will be used to select subject-visit records for fitting the model, removing 
subject-visits records from the analysis if any of the variables used contains a missing value.
Tipping point analyses will be considered for further evaluating sensitivity of the results with 
respect to missing data. In such an analysis, the distribution of missing data in the active 
treatment group would be shifted by varying amounts, until a point is found where the results of 
the analysis cross the threshold of statistical significance specified in section 6.2.2. The 
plausibility of a shift of the found size is then used to assess the robustness of results to 
unobserved differences due to missing data.
Subjects who discontinue study treatment but remain in the study can continue to contribute 
ALSFRS-R data, which will be included in the analyses where applicable. However, in time-to-
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event analyses subjects will be censored from follow-up one day after study treatment 
discontinuation.
6.2.6
Outliers
Detection of outliers will be done via visual inspection. If outliers are detected, a sensitivity 
analysis excluding the outliers may be performed to evaluate their impact to the results.
SVC efforts that are judged by a central analyst to be of unacceptable quality (BTRGRCD = 
“U”) will be treated as missing data in the primary analyses.
6.2.7
Baseline values
Planned Visit 1 pre-dose measurements will be used as baseline values for all variables. Should 
the baseline measurement be missing, the corresponding measurement from the Screening visit 
will be used as baseline instead, before any missing data imputation.
For 12-lead ECG measurements, which are repeated three times before dosing at Visit 1, the 
mean of all successful measurements will be used as the baseline value. The most severe 
interpretation of the baseline contributing measurements will be chosen as the baseline 
interpretation.
6.2.8
Multiple measurements
Here, a multiple measurement refers to a combination of analysis visit and timepoint where there 
are more than one value recorded for a given parameter.
Unless otherwise specified, if there are multiple measurements for a given parameter-visit-
timepoint combination, values from the measurement that was performed last will be used.
For 12-lead ECG parameters (specifically, all parameters in the ADEG dataset), the mean value 
of all multiple measurements will be used for parameters measured quantitatively. For 
parameters measured qualitatively, the most severe value will be used.
6.2.9
Multiple timepoints
The primary efficacy model will include all planned post-baseline visits up to the Week 12 visit. 
Additional analyses of primary efficacy will include all planned study visits. Included timepoints 
for other endpoints will be described separately. Baseline measurements of outcome variables 
will be included as covariates in the models. The MMRM will be used to estimate the covariance 
between measurements for a given subject, without assuming any specific structure a priori. 
Planned visit will be included as a factor in the model. For slope analyses, the actual study day 
of the visit will be used. All time-to-event analyses will be performed up to the first event only.
6.2.10 Checking model assumptions
Assumptions for parametric testing will be checked by visual inspection of residuals. If the 
residuals do not sufficiently closely follow the distribution assumed by the model in question, 
non-parametric comparison methods or use of transformation will be considered.
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6.2.11 Transformations
No data transformations are planned.
6.2.12 Multicentre studies
The study activated a total of 104 centres for recruitment in 14 countries.
Subject disposition will be tabulated by centre and by country of randomization. A summary 
table showing the number of patients screened, randomized, discontinued, and completed for 
each centre will be provided.
For statistical models, centre will be included as a random effect, where applicable. A treatment 
by centre interaction will be investigated in the primary efficacy analysis, if feasible. Pooling 
small centres will be considered if there is reason to suspect impactful centre differences. 
However, the primary analysis will drop the centre random effect, if it leads to convergence 
issues.
6.2.13 Interim analyses and data monitoring
Two interim analyses will be conducted: first when approximately 50% of the subjects, and 
second when all of the subjects have completed their Week 12 study visit (Visit 5).
An independent DSMB will perform and evaluate the interim/futility analyses and make 
recommendations for the study conduct. The DSMB will have access to the treatment code 
through an independent reporting statistician, and the DSMB will have a possibility review any 
unblinded information in a separate closed session. Details on the composition and responsibility 
of the DSMB are outlined in a DSMB charter. Based on the futility analyses the DSMB will give 
its recommendation “continue” or “not continue” the study to the Orion Executive Committee 
(OEC).
Futility will be evaluated in the primary efficacy endpoint, and the time to respiratory event 
endpoint. We estimate that approximately 40% and 85% of the respiratory events will have 
accumulated at the time of the planned interim analyses.
In addition the SVC and respiratory event endpoints, accumulated data for the ALSFRS-R, CGI 
and Borg CR 10 will be summarized at the interim analyses.
Non-binding stopping criteria will be based on O’Brien-Fleming type boundaries (Lan GKK et 
al., 1983, O'Brien PC et al., 1979) and are detailed in the DSMB SAP.
As the interim analyses only allow early stopping for futility, not for efficacy or sample size re-
estimation, adjustments to significance levels are not made in the final analyses.
6.2.14 Subgroups
Subgroups will be analysed for evidence of a differential treatment effect. A treatment-by-
subgroup interaction term will be added to the statistical model, and the stratification factor, if 
present, will be removed. Subgroups defined by the following variables will be investigated:
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1. Age (< 65, 65–74, ≥75)
2. Sex (male, female)
3. Race (white, non-white)
4. Country
5. Region (North America, rest of the world)
6. Site of onset (bulbar, spinal)
7. Edaravone use (yes, no)
8. Riluzole use (yes, no)
9. Combination of edaravone and riluzole use (4 groups)
10. Below median disease duration (time from symptom onset to randomization)
11. Above median time from symptom onset to diagnosis
12. Acetylation status (slow, fast; see 7.7)
13. Renal impairment status (see 7.9.3)
14. Hepatic impairment status (see 7.9.3)
15. Below median SVC (sitting) at screening
16. Below median SVC (supine) at baseline
17. King’s clinical stage at baseline (see 7.5.2.1)
18. Below median ALSFRS-R at baseline
19. ALS progression rate at baseline (< 1 point/month, ≥1 point/month)
20. ALS progression rate at baseline (observed tertiles)
21. Dose change category (see section 7.4)
Subgroup analyses will be performed for the primary efficacy endpoint, the time to respiratory 
event endpoint, and the slope of change in the ALSFRS-R total score endpoint. Ad-hoc analyses 
of other endpoints may also be performed, and included in the study report.
Summary of AEs and AESIs will be presented in the subgroups of: age; sex; race; BMI;
edaravone use; riluzole use; acetylation status; baseline medical history groups of interest (see 
7.3); baseline renal and hepatic impairment status; and baseline King’s clinical stage.
Adverse events will be summarised by patients having heart rate increase related dose changes. 
Drug-drug-interactions with medication groups of interest (see 7.10.1) will be evaluated for
blood pressure, pulse rate, and QT interval. Dose changes will be further presented by acetylation 
status.
6.2.15 Descriptive statistics
The following statistics will be provided for continuous variables: number of observations, 
mean, standard deviation (SD), minimum, median and maximum. For categorical variables,
frequency counts and percentages will be presented.
Mean, median and SD values will be presented to one more decimal place than the raw values. 
Minima and maxima will be presented as they appear. Percentages will be rounded to the nearest 
single decimal place, with the exception of 0 and 100, which will be presented as integers.
When descriptive statistics are reported by treatment group, data for a pooled total arm will also 
be reported, unless otherwise specified.
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7.
STATISTICAL ANALYSES
7.1
Disposition of subjects
The number of subjects will be tabulated by treatment group for the following populations:
-
Screened population
-
Intention-to-treat (ITT)
-
Full analysis set (FAS)
-
Per-protocol up to week 12 (PP1)
-
Per-protocol up to week 48 (PP2)
-
Safety population
-
Discontinued study treatment
-
Discontinued study
-
Completed study
Separate tables by treatment group will also be provided for each country, and each study centre.
The disposition and number of subjects, along with reasons for screening failure, study treatment 
withdrawal and study discontinuations, will be listed and tabulated by treatment group. Reasons 
for excluding subjects from the FAS and PP populations will be listed. Data from subjects who 
failed at screening will be included only in the disposition tabulations and data listings.
Time to study and study treatment discontinuation will be summarised with descriptive statistics 
by treatment group. They will be further broken down by discontinuation reason, and when 
reason for discontinuation is adverse event, the preferred term.
7.2
Demographic and other baseline characteristics
Descriptive statistics (see 6.2.15) of demographic and other baseline characteristics will be 
tabulated in the ITT, FAS, and Safety populations, stratified by treatment group. An authorised 
person will code medical history and concomitant diseases using standard coding dictionaries
(see 7.10.1).
The following variables will be summarized:
1. Age
2. Age (< 65, 65–74, ≥75)
3. Sex
4. Race
5. Ethnicity
6. Height
7. Weight
8. BMI
9. BMI (< 18.5, 18.5–24.9, 25.0–29.9, ≥ 30.0)
10. Country
11. Region (North America, rest of the world)
12. Site of onset (bulbar, spinal)
13. Edaravone use
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14. Riluzole use
15. Combination of edaravone and riluzole use
16. Combination of edaravone and riluzole use by region
17. Disease duration (time from symptom onset to randomization)
18. Below median disease duration (time from symptom onset to randomization)
19. Time from symptom onset to diagnosis
20. Above median time from symptom onset to diagnosis
21. El Escorial criteria for ALS diagnosis
22. Acetylation status (slow, fast; see 7.7)
23. Acetylation status (4 groups; see 7.7)
24. Medications associated with hypotension / decrease in BP (see 7.10.1)
25. Medications associated with hypertension / increase in BP (see 7.10.1)
26. Medications associated with tachycardia / increased pulse rate (see 7.10.1)
27. Medications associated with bradycardia / decreased pulse rate (see 7.10.1)
28. Medications known to affect QT interval (see 7.10.1)
29. Cardiac or vascular abnormality (see 7.3)
30. Ischaemic heart disease (see 7.3)
31. Cardiac arrhythmias (see 7.3)
32. Cardiac failure (see 7.3)
33. Renal impairment (see 7.9.3)
34. Hepatic impairment (see 7.9.3)
35. SVC (sitting) at screening
36. Below median SVC (sitting) at screening
37. SVC (supine) at screening
38. Below median SVC (supine) at screening
39. SVC (supine) at baseline
40. Below median SVC (supine) at baseline
41. King’s clinical stage at baseline (see 7.5.2.1)
42. ALSFRS-R at baseline
43. Below median ALSFRS-R at baseline
44. ALSFRS-R bulbar subdomain at baseline
45. ALSFRS-R fine motor subdomain at baseline
46. ALSFRS-R gross motor subdomain at baseline
47. ALSFRS-R respiratory subdomain at baseline
48. ALS progression rate at baseline
49. ALS progression rate at baseline (< 1 point/month, ≥1 point/month)
50. ALS progression rate at baseline (observed tertiles)
7.3
Medical history
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0. Descriptive statistics will be provided by body system organ class (SOC), and 
preferred term (PT) for the ITT population, by treatment group.
Past findings, where the subject reports the condition has ended prior to their start of the study, 
and present findings, those ongoing at the start of the study, will be reported separately.
The following categories define groups of interest used in safety subgroup analyses:
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1. Cardiac or vascular abnormality
2. Ischaemic heart disease (SMQ)
3. Cardiac arrhythmias (SMQ)
4. Cardiac failure (SMQ)
Both past and present findings the start of the study are included in forming these groups. See 
Appendix 10.1 for definitions of the search categories. If an SMQ has both a broad and a narrow 
definition, the narrow search will be used.
7.4
Extent of exposure and treatment compliance
The total number of exposed subjects, the total duration of study treatment exposure (continuous, 
and categorized both separately and cumulatively at the thresholds of ≤ 4, ≤ 8, ≤ 12, ≤ 24, and ≤ 
48 weeks), and dose levels (in milligrams), averaged over the course of the study as well as at 
each study visit, will be reported as measures of extent of exposure.
Dose changes will be described by reporting the subject counts in the following categories:
1) remained at 1 mg for the entire study (“never increased”)
2) uptitrated to 2 mg and remained for the rest of the study (“increased and remained”)
3) uptitrated to 2 mg and later downtitrated to 1 mg (“increased, then decreased”).
Dose changes will also be reported by acetylation status.
Treatment compliance will be described by reporting the number of dispensed and returned study 
treatment capsules at each study visit. The number of subjects with treatment interruptions 
longer than 7 days will be reported with descriptive statistics.
Both extent of exposure and treatment compliance will be tabulated with descriptive statistics.
7.5
Efficacy
All efficacy data will be listed and tabulated by treatment group for each visit.
7.5.1
Primary efficacy variable(s)
7.5.1.1
Slow Vital Capacity
The primary efficacy variable will be change from baseline SVC, measured in the supine 
position (SVC [supine]), through the Week 12 visit (Visit 5). SVC is defined as the maximum 
volume of air that the subject can exhale slowly after slow maximum inhalation. The raw SVC 
volume is measured in litres. The SVC variable used in the analyses is derived from the raw 
SVC volume, and measured as a percentage of the predicted (normal) volume for age, height 
and sex. Predicted values used for the calculation are derived based on the global lung function 
2012 equations (Quanjer PH et al., 2012).
SVC will be assessed in both the sitting and supine position at the screening visit. Sitting SVC 
is used for an inclusion criterion (sitting SVC between 60–90% of the predicted value), and 
supine SVC is assessed to ensure that the subject is able to perform it successfully when entering 
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the study. At further study visits, SVC (supine) will be assessed in the morning, before 
administration of the study treatment. The analysis will use the best read from up to 8 attempts, 
as determined by the central analysts’ assessment. Only the value from the best read will be 
included in the study’s database. If even the best read is determined to be of unacceptable quality 
(BTRGRCD = “U”), it will be treated as missing data in the statistical analysis.
A mixed model for repeated measures (MMRM) will be used to evaluate the change from 
baseline SVC (supine) in the primary efficacy analysis. The model will include: fixed effects for 
planned treatment, randomization stratum, study visit and a visit by treatment interaction;
random effects for subject and centre; and the baseline SVC (supine) value as a covariate.
Should the model estimation fail to converge, the following steps will be taken sequentially to 
simplify the model structure until convergence is achieved:
1. The random effect for centre will be dropped.
2. The structure of the covariance matrix for the subject effect will be changed from 
unstructured to: 1) Toeplitz (TOEP); 2) first-order autoregressive (AR(1)); 3) compound 
symmetry (CS).
Primary efficacy will be evaluated based on the fitted model, using contrasts to obtain an 
estimate of the difference between the treatment and placebo at the Week 12 visit (Visit 5). 
Statistical significance of the Week 12 treatment difference will be tested. All SVC 
measurements from planned study visits prior to the Week 12 visit will be included in the 
estimation of the model.
SAS code in the following fashion will be used to perform the computations:
proc mixed data = ADEFF order = data alpha = 0.05 covtest;
  where ITTFL = "Y" and PARAMCD = "SVCPPSUP" and
    AVISIT in ("Week 2", "Week 4", "Week 8", "Week 12");
  class TRTP(ref = "PLACEBO") AVISIT STRATAR USUBJID SITEID;
  model CHG = BASE STRATAR TRTP AVISIT TRTP * AVISIT / ddfm = KR;
  repeated AVISIT / subject = USUBJID type = UN R;
  random SITEID / type = VC;
  estimate "Treatment Difference at Week 12"
    TRTP 1 -1 TRTP * AVISIT 0 0 0 1  0 0 0 -1 / cl;
run;
In the primary analysis, missing data are imputed using multiple imputation. As a result, the 
analysis above is repeated for each of the imputed data sets with the use of a by-statement. The 
anayliss results are then pooled for inference according to the methods described in 6.2.5.
In additional analyses, data from all planned visits through 48 weeks will be included in the 
MMRM, and the treatment effect will be estimated with contrasts at each study visit. Further, a
random slope model will be fitted, with visits’ actual study days replacing the visit factor.
Changes in SVC (supine) between the last measurement while on treatment and the post-
treatment measurement from their End of Study visit will be described.
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Subgroup analyses will be conducted by removing the randomization stratum effect from the 
primary analysis model, and including the subgroup term and its interaction with treatment.
Descriptive statistics of SVC (supine) will also be presented by visit, treatment group, and angle 
of measurement position. The angle is categorised into three groups: 1) completely flat (0 
degrees); 2) slightly elevated (up to 15 degrees); 3) unable to perform supine (> 15 degrees).
The effect of angle of measurement will also be explored in an additional analysis, where the 
angle will be included as a factor in the primary analysis MMRM.
Time to decline from baseline SVC (supine) by ≥20% and time to SVC (supine) ≤ 50% of 
predicted will be assessed as secondary endpoints. Their method of analysis is described among 
other time-to-event endpoints in section 7.5.2.3.
7.5.2
Secondary efficacy variables
The following secondary efficacy endpoints will be tested in the hierarchy below in order to 
preserve the overall alpha level:
1. Combined assessment of function and survival (CAFS) through 48 weeks
2. Time to respiratory event
3. Clinical Global Impression (CGI) through 48 weeks
4. Supine Borg CR 10 scale at 12 weeks
5. Slope of change in the ALSFRS-R respiratory domain through 48 weeks
The endpoints and their methods of analysis are described in the following sections. Endpoints 
and analyses that are not listed in the testing hierarchy are included for supportive purposes only.
7.5.2.1
Revised ALS Functional Rating Scale
The ALSFRS-R (Cedarbaum JM et al., 1999) includes 12 items: speech, salivation, swallowing, 
handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and 
adjusting sheets, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. 
Each item will be scored from 0 to 4, with lower values indicating worse function. The variables 
derived will be the scores of the 12 separate items, the total scores of each subdomain (bulbar
[items 1-3], fine motor [4-6], gross motor [7-9] and respiratory [10-12]) and the total score of 
ALSFRS-R.
The ALSFRS-R and its subdomains will be analysed through 48 weeks. The slope of decline for 
ALSFRS-R will be estimated using a random slope model. Statistical significance of the 
difference in slopes between the treatment groups will be tested. Additional analyses of the 
ALSFRS-R and its subdomains will be conducted using the MMRM and estimates for the 
treatment effect at each study visit will be obtained with model-based contrasts. Descriptive 
statistics over the course of the study will be reported for all items in the scale, as well as each 
subdomain and the total scale.
The following efficacy variables derived from the ALSFRS-R scores will also be assessed:

Combined assessment of function and survival (CAFS; see 7.5.2.2).

Time to decline from baseline in ALSFRS-R total score by ≥ 20%.

Time to decline from baseline in an ALSFRS-R respiratory domain score (items 10–12).
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
Time to continuous ventilator dependence (item 12 ≤ 1).
The methods of analysis for the time-to-event endpoints are described in 7.5.2.3. CAFS and its 
analysis are described further in section 7.5.2.2 below.
For use in subgroup analyses, two additional variables will be derived from the ALSFRS-R:
King’s clinical stage is a staging system used to measure the clinical progression of the ALS 
disease across body system regions. Staging is not directly collected as part of the study. Instead, 
King’s clinical stage will be estimated from the ALSFRS-R as follows (Balendra, 2014):
1. Respiratory failure (Item 10 = 0 or Item 12 < 4) ⇒Stage 4b
2. Nutritional failure (answered item 5b) ⇒Stage 4a
3. For lower stages, count the number of regions involved:
a.
Bulbar (any of items 1–3 < 4)
b. Upper limbs (either of items 4 and 5a < 4)
c.
Lower limbs (item 8 < 4)
King’s stage is used to describe disease progression, and will be reported with descriptive 
statistics over the course of the study.
ALS progression rate at baseline will be calculated as the number of points missing from a full 
ALSFRS-R score (48) at baseline divided by the time (in months) between symptom onset and 
the baseline ALSFRS-R measurement.
7.5.2.2
Combined assessment of function and survival
Combined assessment of function and survival (CAFS) is a rank score based on the subject’s 
survival time and change in ALSFRS-R score (Berry JD et al., 2013). A higher CAFS score for 
a subject indicates a better outcome relative to other subjects in the study.
To find the CAFS score, a sum score is calculated for each subject by comparing their status to 
all other subjects. In each individual comparison, the subject’s score is incremented if they fared 
better than the other, and decremented if they fared worse. If their outcomes are equal, the score 
remains unchanged. This process produces an equivalent ordering to simply ranking the subjects 
based on their outcomes, and breaking ties with the given hirerarchy of outcomes. The ordering 
between the subjects’ outcomes is determined first by survival status: if both subjects died, then 
by survival time; and if both subjects survived, finally by the change from baseline ALSFRS-R 
score. Once these scores have been calculated for all subjects, they are ranked, from lowest (died 
first) to highest (best ALSFRS-R outcome among those who survived), yielding the final CAFS 
score used as the endpoint.
CAFS is analysed using the Wilcoxon-Mann-Whitney test to compare mean scores between the 
treatment groups at the Week 48 study visit. Statistical significance will be assessed based on 
the confidence interval derived for the Hodges-Lehmann estimator. In additional analyses, 
CAFS will also be assessed at the Week 12 and Week 24 study visits.
SAS code in the following fashion will be used to conduct the analysis:
proc npar1way data = ADEFF wilcoxon hl;
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  where ITTFL = "Y" and PARAMCD = "CAFS" and AVISIT = "Week 48";
  class TRTP;
  var AVAL;
run;
7.5.2.3
Respiratory event and other time-to-event endpoints
A ‘time to respiratory event’ composite endpoint consists of the following events:

A decrease of one or more points from baseline in any of the ALSFRS-R respiratory 
function subdomain scores (items 10–12).

Starting non-invasive mask ventilation (NIV).

Meeting ‘protocolised’ criteria for NIV: SVC (supine) ≤ 50% predicted.

Invasive mechanical ventilation by intubation.

Invasive mechanical ventilation by tracheostomy.

Death.
Time to respiratory event is reached whenever any of the criteria has first been met.
The following time-to-event secondary efficacy variables will be evaluated using Cox’s 
proportional hazards regression:
1. Time to tracheostomy, continuous ventilator dependence, or death (TRCVDDTH)
2. Time to NIV or death (NIVDEATH)
3. Time to respiratory event (RESPEVNT)
Individual components of all the composite endpoints will be analysed in the same fashion:
1. Time to continuous ventilator dependence (ALSFRS-R item 12 ≤ 1; CVD)
2. Time to decline from baseline in any ALSFRS-R respiratory domain score (FRSBR1D)
3. Time to SVC (supine) ≤ 50% of predicted (SVC50PP)
4. Time to non-invasive mask ventilation (NIV)
5. Time to intubation (INTUB)
6. Time to tracheostomy (TRACH)
7. Time to death (DEATH)
As will these additional endpoints derived from the SVC and ALSFRS-R values:
1. Time to decline from baseline SVC (supine) by ≥20% (SVC20PD)
2. Time to decline from baseline ALSFRS-R total score by ≥ 20% (FRS20PD)
3. Time to continuous use of NIV during the night (ALSFRS-R item 12 ≤ 2)
The data for the time-to-event variables will be stored in the ADTTE dataset with parameter 
names corresponding to those in parentheses above.
The analysis model will include an effect for treatment, and will be adjusted for randomization 
strata. Premature discontinuations will be treated as right-censored in the analyses. Censoring 
rules for different scenarios are described in Error! Reference source not found.. For the p
urpose of determining the end date, survival and ventilation status are considered to be assessed 
daily; ALSFRS-R and SVC measurements are assessed only on study visits. For composite 
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CGI through Week 48 will be evaluated using the MMRM and estimates for the treatment effect 
at each study visit will be obtained using contrasts. Statistical significance of the treatment 
difference at Week 48 will be tested. Descriptive statistics will be reported by treatment group
for each study visit.
7.5.2.5
Borg Category Ratio 10 Scale
The Borg Category Ratio 10 (CR10) scale will be used in the assessment of dyspnoea (Borg GA, 
1982). The subjects will be asked to point out a score quantifying their perception on the intensity 
of dyspnoea on the CR10 scale at rest in sitting and supine positions (immediately before SVC 
measurements). Orthostatic changes between sitting and supine positions will be calculated.
Borg CR10 in the supine position will be evaluated through Week 12 using the MMRM. 
Estimates for the treatment effect at Week 12 will be derived from model-based contrasts, along 
with a test result for it’s statistical significance. Additionally, sitting, supine and orthostatic 
changes will be evaluated in a similar fashion through Week 48, with estimates for the treatment 
effect obtained at each study visit. Descriptive statistics for all Borg CR10 variables will be 
reported by treatment group for each study visit.
7.5.2.6
Epworth Sleepiness Scale
Daytime somnolence will be assessed by the Epworth Sleepiness Scale (ESS) (Johns MW, 
1991). The ESS is a self-administered questionnaire with 8 questions. Subjects are asked to rate, 
on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight 
different activities. Score 0 indicates ‘no chance of dozing’ and 3 indicates ‘high chance of 
dozing’. Most people engage in those activities at least occasionally, although not necessarily 
every day. If one has not engaged recently in a certain activity, the subject will estimate how 
sleepy he/she would have been during that activity. The ESS score (the sum of 8 item scores, 0-
3) can range from 0 to 24. The higher the ESS score, the more pronounced the subject’s average 
daytime sleepiness. A sum score of 10 or more suggests medical attention may be required.
The ESS through Week 48 will be evaluated using the MMRM and estimates for the treatment 
effect at each study visit will be obtained using contrasts. Further, results of a categorical analysis 
of the ESS dichotomised at the clinically significant threshold of 10 will be reported. For this 
purpose, a repeated measures binary logistic regression model will be fitted using the generalised 
estimating equation approach. Descriptive statistics of both the original measurements as well 
as the dichotomised values will be reported by treatment group for each study visit.
7.5.2.7
Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire assessing sleep quality 
and disturbances over a preceding 1 month period (Buysse DJ et al., 1989). The questionnaire 
consists of 19 self-rated questions/items which are included in the scoring. These 19 items are 
combined to form seven component scores (subjective sleep quality, sleep latency, sleep 
duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, daytime 
dysfunction) each of which has a range of 0-3 points. In all components, a score of 0 indicates 
no difficulty, while a score of 3 indicates severe difficulty. The seven component scores are then 
added to yield one global score, with a range of 0-21 points, 0 indicating no difficulty and 21 
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indicating severe difficulties in all items. The derived variable will be the PSQI global score. A 
global score of 5 or more indicates poor sleep quality.
During the study, we have observed subjects systematically reporting bedtimes at implausible 
hours of the day. Specifically, it seems likely that a significant number of subjects have reported 
their bedtimes using a 12-hour clock rather than the expected 24-hour clock. To correct for this, 
we will use the following procedure: If the reported bedtime falls within 6 AM and 3 PM, and 
applying a correction of 12 hours would bring the calculated sleep duration within a 2-hour 
tolerance of the reported sleep duration, the corrected bedtime will be used instead of the 
originally reported one.
The PSQI will be analysed using the same methods described for the ESS in section 7.5.2.6 
above, with the modification of using the PSQI’s own clinically significant threshold of 5.
7.5.3
Additional variables
7.5.3.1
Health care and home care resource use
The subjects will be given a home diary for recording their use of health and home care 
resources. The diary will be filled in on a weekly basis. Any hospital inpatient days, other 
institutional care, any additional hospital emergency unit visits, days in other institutional care, 
and any outpatient visits to physicians or other relevant service providers will be recorded. In 
addition, all non-medical assistive devices that the subjects have in use at baseline are recorded,
and thereafter all new devices that they start using due to ALS will be recorded in the diary each 
week. Regarding home care, the diary will contain information of the number of formal 
(paid/public services) and informal (unpaid e.g. by spouse, other family members, friends or 
other volunteers) home care hours received. Additionally, information will be collected about 
the number of times such home care has been received during the nighttime. Details of the home 
diary will be described in a separate document.
Health and home care resource use data will be aggregated over the course of the study for each 
subject, and summarised using descriptive statistics. Any further analysis for potential 
pharmacoeconomic purposes will be reported separately.
Time to any assistive device and any respiratory assistive device will be analysed as additional 
endpoints. They are analysed following the strategy outlined for other time-to-event endpoints 
in section 7.5.2.3.
7.5.4
Sensitivity analyses
All sensitivity analyses are performed based on the ITT population, unless otherwise specified.
7.5.4.1
Full analysis set
Method:

Use the FAS population (see 6.1).
Analyses that will be adjusted:
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
Primary analysis SVC MMRM

CAFS through 48 weeks

Time to respiratory event

CGI through 48 weeks

Supine Borg CR 10 scale at 12 weeks

Slope of change in the ALSFRS-R respiratory domain through 48 weeks
7.5.4.2
Per-protocol population
Method:

Use the appropriate PP population (see 6.1).
Analyses that will be adjusted:

With PP up to week 12 (PP1):
o
Primary analysis SVC MMRM
o
Supine Borg CR 10 scale at 12 weeks

With PP up to week 48 (PP2):
o
CAFS through 48 weeks
o
Time to respiratory event
o
CGI through 48 weeks
o
Slope of change in the ALSFRS-R respiratory domain through 48 weeks
7.5.4.3
Use randomisation strata from CRF data
Method:

Adjust for STRATAV instead of STRATAR in models. This corrects for randomisations 
stratified based on incorrect information about stratification factors.
Analyses that will be adjusted:

Primary analysis SVC MMRM

Slope of change in the ALSFRS-R respiratory domain through 48 weeks
7.5.4.4
Analyses without missing data imputation
Method:

Do not use missing data imputation; drop observations that list an imputation method.
Analyses that will be adjusted:

All efficacy analyses performed with missing data imputation. See 6.2.5.
7.5.4.5
Include unacceptable quality SVC measurements
Method:

Do not treat SVC measurements with unacceptable quality as missing.
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Analyses that will be adjusted:

Primary analysis SVC MMRM.

All analyses of time-to-event endpoints with SVC components.
7.5.4.6
Exclude subjects that changed SVC supine angle during the study
Method:

Use a new analysis population consisting only of subjects who had the same SVC supine 
measurement angle throughout their study visits.
Analyses that will be adjusted:

Primary analysis SVC MMRM.

All analyses of time-to-event endpoints with SVC components.
7.5.4.7
Exclude SVC supine measurements performed with > 15 degree angle
Method:

Treat SVC data performed with > 15 degree angle as missing.

Follow primary analysis methods otherwise: i.e. impute if applicable.
Analyses that will be adjusted:

Primary analysis SVC MMRM.

All analyses of time-to-event endpoints with SVC components.
7.5.4.8
Combined impact of position and angle on SVC supine results
Method:

Use a new analysis population consisting only of subjects who had the same SVC supine 
measurement angle throughout their study visits.

Treat SVC data performed with > 15 degree angle as missing.

Follow primary analysis methods otherwise: i.e. impute if applicable.
Analyses that will be adjusted:

Primary analysis SVC MMRM.

All analyses of time-to-event endpoints with SVC components.
7.5.4.9
Adjust for riluzole use at baseline
Method:

Inlcude a term in the model for riluzole use at baseline.

Assume no interaction effects.
Analyses that will be adjusted:
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
Primary analysis SVC MMRM.

Slope of change in the ALSFRS-R respiratory domain through 48 weeks
7.5.4.10 Adjust for effect of paper questionnaire collection
Method:

Include term in model for whether data point was collected electronically or on paper.
Analyses that will be adjusted:

MMRM analyses of: ALSFRS-R, CGI, Borg CR10, ESS, PSQI.

Cox models of time-to-event endpoints with ALSFRS-R components.
7.5.4.11 Exclude efficacy data after initiation of NIV
Method:

Treat data points collected on or after the date of NIV initiation as missing.

Follow primary analysis methods otherwise: i.e. impute if applicable.
Analyses that will be adjusted:

Primary analysis SVC MMRM

CAFS through 48 weeks

Time to respiratory event

CGI through 48 weeks

Supine Borg CR 10 scale at 12 weeks

Slope of change in the ALSFRS-R respiratory domain through 48 weeks
7.6
Pharmacokinetics and pharmacodynamics
Concentration levels of levosimendan, OR-1855, OR-1896 and riluzole will be reported using 
descriptive statistics. Concentrations of levosimendan and its metabolites will also be reported 
by acetylation status.
Concentration-effect plots will be shown with respect to supine SVC and QTcF/QTcB.
Concentrations of levosimendan and its metabolites will be summarised with descriptive 
statistics at each visit by acetylation status (2 levels, with a third pooled group) and previous 
antibiotic use status. Previous antibiotic use will be categorised as ever-use, and additionally as 
0, 1, 2, or 3+ uses. Antibiotic use status will be updated at each visit. Antibiotics will be identified 
among concomitant medications with the 2nd level ATC codes J01, J02, J04 and J05.
A more detailed population-level analysis of pharmacokinetics/pharmacodynamics will be 
planned and reported separately.
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7.7
Pharmacogenomics
Acetylation status will be determined by bioanalytics, and categorized into four and two levels
for reporting. Descriptive statistics for both will be reported by treatment group.
The two-level categorization of acetylation status will be used to stratify the reporting of 
concentration levels of levosimendan and its metabolites, dose changes, and safety. It will also 
be used to determine subgroups for the statistical analysis some efficacy endpoints (see 6.2.14).
7.8
Exploratory biomarkers
Analysis of exploratory biomarkers will be planned and reported separately.
The analysis is currently planned to at least describe correlations between change from baseline
in ALSFRS-R and supine SVC, and change from baseline in creatinine, creatine kinase, troponin 
T, LDH, albumin, ALP, bilirubin, GGT, and glucose.
7.9
Safety
The analyses presented in this section will be reported for the Safety population, including all 
subjects having received any study treatment.
7.9.1
Deaths
The number of deaths will be reported with descriptive statistics by treatment group and relation 
to study treatment: before, during or after stopping. The number of deaths occurring after the 
end of official follow-up will be reported separately.
Kaplan-Meier curves will be used to describe survival in each treatment group up to:
1. Completion of the End of Study visit, or 25 days after last study treatment.
2. Completion of the Week 48 visit, or study discontinuation.
7.9.2
Adverse events
Adverse events (AEs) will be classified by system organ classes (SOC) and preferred terms
(PTs) using the MedDRA dictionary version 23.0.
A treatment-emergent AE (TEAE) is defined as any event arising or worsening after the start of 
study drug administration until 25 days after the last study medication intake.
A summary of TEAEs and non-TEAEs will be presented, showing total numbers of events and 
subjects having events:
1. Fatal outcome
2. SAE status
3. Other significant AEs
4. AESI status
5. Causality
6. Severity
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7. Actions taken
The number of TEAEs, and number and proportion (%) of subjects having TEAEs by SOC and 
PT will be given by treatment group. The number of events will also be broken down by:
1. Severity (mild, moderate, severe)
2. Causality (related, not related)
3. Timing with respect to starting treatment (disjoint union of: ≤ 2 weeks, ≤ 4 weeks, ≤ 8 
weeks, ≤ 12 weeks, ≤ 24 weeks, ≤ 48 weeks)
4. Tertiles of OR-1896 concentration at the Week 4 visit (total of 4 groups: None, and others 
classified into Low, Medium, and High according to observed tertiles)
5. Dose change groups (see 7.4)
Incidence rates for first events adjusted for exposure time will also be reported. They are 
calculated by dividing the number of subjects ever experiencing the event while on treatment by 
the number of days subjects were exposed to the study treatment.
All serious adverse events (SAEs) and other significant AEs will be evaluated case by case.
Narrative descriptions will be included in the study report for all AEs leading to death, other 
SAEs, AEs leading to study treatment withdrawal, and certain other significant AEs (OSAEs).
Groups of treatment emergent AEs of special interest (AESIs) are defined by Standardized 
MedDRA Queries (SMQs) where noted, and by in-house search categories (IHSCs) defined as 
lists of preferred terms, otherwise. Statistics for the following AESIs will be reported:
1. Decrease in red cell parameters
2. Drug related hepatic disorders - comprehensive search (SMQ)
3. Haemorrhages (SMQ)
4. Headache
5. Hypokalaemia (SMQ)
6. Hypotension
7. Increased heart rate
8. Ischaemic heart disease (SMQ)
9. Neurocognitive disorder
10. Palpitations
11. Suicide/self-injury (SMQ)
12. Supraventricular tachyarrhythmias (SMQ)
13. Ventricular tachyarrhythmias (SMQ)
See Appendix 10.2 for the queries used to create the groups. If an SMQ has both a broad and a 
narrow definition, the narrow search will be used.
In addition to standard AE reporting, detailed characteristics will be reported for AESIs:
1. SAE status
2. Need for concomitant medications
3. Severity
4. Changes in dosage
5. Outcome
6. Timing with respect to starting treatment
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7. Duration of event
8. Safety subgroups (listed in 6.2.14)
Further, for AESIs, 95% confidence intervals (CIs) will be reported for incidence proportions 
and incidence rates, and risk ratios and incidence rate ratios (with 95% CIs) between the 
treatment groups will be estimated.
7.9.3
Laboratory values
Protocol-specified laboratory safety variables will be evaluated using descriptive statistics, line 
plots, and shift plots, showing the baseline value and post baseline values up to the end of 
treatment. Frequencies of normal and abnormal (low and high) laboratory findings will be 
summarised based on reference ranges provided for each analyte, and clinical significance of the 
findings will be evaluated.
Results from additional laboratory variables that were not specified in the protocol will not be 
summarised, but will appear in patient data listings.
A listing of patients fulfilling Hy’s law criteria will be provided. That is, patients meeting all of 
the following criteria at a given visit:
1. Aspartate or alanine transaminase (AST, ALT) ≥ 3x the upper limit of normal (ULN)
2. Serum alkaline phosphatase < 2x ULN
3. Bilirubin ≥ 2x ULN
Ratios of AST and ALT to ULN will be plotted against ratios of bilirubin to ULN for all subject-
visits. Comparisons of both AST and ALT to the thresholds of > 2, 3, 5, and 10 times their 
respective ULN will be summarised.
Renal impairment status will be determined from creatinine clearance (eGFR) (NICE) (Unwin 
et. al, 2011):

Normal: ≥ 90 mL/min

Mild reduction: 60 to  89 mL/min

Mild to moderate reduction: 45  to 59 mL/min

Moderate to severe reduction: 30  to 44 mL/min

Severe reduction: 15  to 29 mL/min

Kidney failure / End stage renal disease: < 15 mL/min
Hepatic impairment status will be determined as:

Normal: Total bilirubin and AST ≤ ULN

Mild hepatic impairment: Total bilirubin > ULN to 1.5 x ULN or (Total bilirubin ≤ ULN 
and AST > ULN)

Moderate impairment: Total bilirubin > 1.5 to 3 x ULN, any AST

Severe impairment: Total bilirubin > 3 x ULN, any AST
Additionally, descriptive statistics of the following categorised analytes will be reported:
Renal impairment thresholds based on creatinine levels in the blood (CTCAE v5.0):
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
Grade 1: > ULN–1.5 x ULN

Grade 2: > 1.5–3.0 x baseline or > 1.5–3.0 x ULN

Grade 3: > 3.0 x baseline or > 3.0–6.0 xULN

Grade 4: > 6.0 x ULN
Low potassium levels (hypokalemia) in blood (Unwin et al, 2011; Castro, 2019):  

Mild: 3 to 3.4 mmol/L

Moderate: 2.5 to < 3 mmol/L

Severe: < 2.5 mmol/L
Haemoglobin levels in bood (WHO, 2011 ):

Non-pregnant women: 
o
Mild: 110–119 g/L
o
Moderate: 80–109 g/L
o
Severe: < 80 g/L

Pregnant women:
o
Mild: 100–109 g/L
o
Moderate: 70–99 g/L
o
Severe: < 70 g/L

Men:
o
Mild: 110–129 g/L
o
Moderate: 80–109 g/L
o
Severe: < 80 g/L
Haematocrit levels in blood (Cohen et al, 2017 ): 

Women:
o
Low: < 37%
o
High: > 47%
o
Normal: 37% to 47%

Men:
o
Low: < 42%
o
High: > 52%
o
Normal: 42% to 52%
Erythrocytes count in blood (Dean, 2005 ): 

Women:
o
Low: < 3.5 x 1012/L
o
High: > 5.5 x 1012/L
o
Normal: 3.5–5.5 x 1012/L

Men:
o
Low: < 4.3 x 1012/L
o
High: > 5.9 x 1012/L
o
Normal: 4.3–5.9 x 1012/L
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7.9.4
12-lead ECG
Descriptive statistics of standard 12-lead ECG variables and abnormal ECG findings will be 
tabulated by treatment group for each study visit.
QT values will be corrected (QTc) according to Bazett’s (QTcB) and Fridericia’s (QTcF) 
formulae. Disjoint comparisons of QTc values to the following thresholds will be summarised:
1. Absolute values > 450 ms, > 480 ms, and > 500 ms.
2. Changes from baseline > 30 ms, and > 60 ms.
Cardiac safety will be assessed by modelling the dose-response of post-dose OR-1896 
concentration vs. ΔΔQTcF at each visit with PK samples. ΔΔQTcF is defined as the difference 
between change from baseline between placebo and treatment, where the placebo effect is 
estimated for each visit with an ANOVA model.
Disjoint comparisons of Masterscope heart rate (EGHRMS) changes from baseline to the 
protocol-defined thresholds of > 20 bpm and > 30 bpm will be summarised by treatment group, 
visit, and dose level at the visit.
For subjects whose dose-level is increased at Week 2, changes in Masterscope heart rate between 
the measurements taken before dosing at the Week 2 and Week 4 visits will be described.
For subjects whose dose-level is reduced, changes in Mastercope heart rate between the last 
measurement on the higher dose and the following measurement on the lower dose will be 
described.
The correlation between OR-1896 concentration and post-dose Overread heart rate (EGHROR) 
will be described with semi-log scatterplots at each study visit.
Drug-drug interactions with medications known to affect QT interval (see 7.10.1) will be 
evaluated for QT, QTcF and QTcB with descriptive statistics.
7.9.5
Vitals signs
Descriptive statistics of subject weight, BMI, vital signs (i.e. pulse rate and both systolic and 
diastolic blood pressure in supine and sitting positions, as well as their orthostatic change) will 
be tabulated by treatment group for each study visit.
Additionally, pulse rate and blood pressure will be described by medication groups of interest at 
baseline. See Appendix 10.3 for definitions of the medication groups.
Descriptive statistics will also be reported for the following categorised measurements:

systolic blood pressure:
o
< 90 mmHg and a decrease of ≥ 20 mmHg
o
> 140–160 mmHg and an increase of ≥ 20 mmHg
o
> 160 mmHg and an increase of ≥ 20 mmHg

high orthostatic change in systolic blood pressure: ≥ 20 mmHg decrease

diastolic blood pressure:
o
< 60 mmHg and a decrease of ≥ 20 mmHg
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o
> 90–100 mmHg and an increase of ≥ 20 mmHg
o
> 100 mmHg and an increase of ≥ 20 mmHg

high orthostatic change in diastolic blood pressure: ≥ 10 mmHg decrease

pulse rate:
o
< 60 bpm and a decrease of ≥ 15 bpm
o
> 100 bpm and an increase of ≥ 15 bpm

change from baseline body weight:
o
a decrease of:

> 7–10%

> 10–20%

> 20%
o
an increase of:

> 7–10%

> 10–20%

> 20%
Drug-drug interactions will be evaluated with descriptive statistics:

for systolic and diastolic blood pressure, with medications associated with BP changes

for pulse rate, with medications associated with pulse rate changes 
See 7.10.1 for definitions of the medication groups.
7.9.6
Physical findings and other observations
Special situations and physical examination findings will be summarised by treatment group
using descriptive statistics.
7.10 Additional analyses
7.10.1 Prior and concomitant treatments
Prior and concomitant treatments will be coded using the anatomical therapeutic chemical 
(ATC) classification system, WhoDrug version V201909. The number and percentage of 
subjects using concomitant treatments at baseline will be summarised by pharmacological 
subgroup and chemical substance. 
The following categories define groups of interest used in safety subgroup analyses:
1. Medications associated with hypotension / decrease in BP
2. Medications associated with hypertension / increase in BP
3. Medications associated with tachycardia / increased heart rate
4. Medications associated with bradycardia / decreased heart rate
5. Medications known to affect QT interval
The medication groups have been derived from validated databases: SIDER 4.1, 2015 
(http://sideeffects.embl.de/) for medications affecting BP and HR; and CredibleMeds for 
medications affecting QT (https://www.crediblemeds.org/). Only medications with a reported 
frequency > 0% (in  SIDER) or those in a “known risk” category (in CredibleMeds) were 
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included in the lists. Finally, riluzole and edaravone were not be included in any of these groups; 
they are covered as separate groups of their own. See Appendix 10.3 for full lists of product 
names used to define the categories.
7.10.2 Suicidality
Suicidality will be summarised at each visit by treatment group using descriptive statistics.
Additionally, suicidality at any point over the course of the study will be described, and tested 
for a difference between the treatment groups with Fisher’s exact test.
7.10.3 COVID-19
The number of subjects affected with any changes to study visit procedures, the number of 
protocol deviations, and study visits performed as a telephone contact rather than a protocol-
specified on-site visit due to COVID-19 will be summarized by treatment group with descriptive 
statistics.
Both confirmed and suspected infections of COVID-19 will be reported as adverse events. The 
number of affected subjects will then be found as part of regular AE reporting (see 7.9.2).
In addition to appearing in standard reporting, protocol deviations and AEs related to COVID-
19 will also be summarised in a dedicated section. 
We expect precautionary measures to result in an increase of missing data for the remainder of 
the study. This will primarily affect Week 48 visits, and particularly measurements that cannot 
be performed over the phone, such as the SVC. Missing data due to COVID-19 will be treated 
the same as other missing data, following the procedures specified in in 6.2.5.
Efficacy measurements that were collected after the World Health Organization declared the 
COVID-19 outbreak a pandemic on March 11, 2020 will be flagged in the data. The potential 
impact of the pandemic on the treatment effect will be evaluated by including a term for whether 
the measurement was taken before or after the pandemic declaration in the MMRM for SVC and 
for ALSFRS-R. These analyses will be performed without any missing data imputation. 
Descriptive statistics for SVC and ALSFRS-R will be reported by visit, treatment group, and 
timing with respect to the pandemic declaration.
7.11 Changes from the clinical study protocol
Specification of the statistical model used in the primary efficacy analysis has been clarified.
All references to “treatment arm” have been changed to “treatment group” instead, to be 
consistent with the terminology used in the study’s title.
Statistical hypotheses have been reworded to match model parameters. The core of the content 
remains unchanged.
Changed wording in the “data sets to be analysed” section to refer to “important protocol 
deviations” rather than “relevant major protocol deviations” when talking about the per-protocol 
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population. This change was made to be consistent with terminology across study 
communication. The core meaning remains unchanged.
Per-protocol analyses will be conducted in two separate PP populations, depending on the 
endpoint: PP up to week 12, and PP up to week 48. As key endpoints are assessed at different 
time points during the study, this provides better control for excluding subjects with deviations 
that could have affected the efficacy analyses.
Expanded interim analysis section to cover recommendation process in more detail.
Unacceptable quality SVC measurements will be excluded from the primary analysis.
Additional endpoints:
1. Time to any assistive device
2. Time to any respiratory assistive device
3. Time to continuous use of NIV during the night
4. Time to continuous use of NIV during the day and night
5. Time to tracheostomy, continuous ventilator dependence, or death
Additional analyses:
1. King’s clinical stage will be estimated from the ALSFRS-R.
2. Restricted mean survival time will be described for time-to-event endpoints.
3. Dose change profiles will be described.
4. Correlations for biomarkers will be described, in a separate report.
5. Concentration-effect plots will be shown for SVC and QTc vs. OR-1896.
6. Adverse events will be reported by timing with respect to starting treatment, OR-1896 
concentration at the Week 4 visit, and dose change profile.
7. Incidence rates will be reported for AEs.
8. Groups of TEAEs of special interest will be reported.
9. Confidence intervals for incidence proportions, incidence rates, risk ratios and incidence 
rate ratios will be reported for AESIs.
10. Narrative descriptions will be written for deaths, TESAEs and other significant TEAEs.
11. AEs will be reported in safety subgroups.
12. Many new categorical analyses for laboratory results will be included.
13. Cardiac safety will be assessed by modelling OR-1896 dose-response with ΔΔQTcF.
14. Groups of concomitant medications of interest will be reported.
15. Medical history groups of interest will be reported.
16. Difference in suicidality between the treatment groups will be tested.
17. Effects of COVID-19 will be summarised.
ANOVAs will not be used to evaluate the effect of acetylation status on metabolites or HR.
MMRMs will not be used to examine treatment effects on vital signs or 12-lead ECG parameters
or laboratory results.
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7.12 Execution of statistical analyses
Statistical analyses will be performed by or under the supervision of Global Data Science and 
Analytics at Orion Pharma.
7.13 Software
Statistical analyses, tables and subject data listings will be performed with SAS® for Windows 
version 9.4 (SAS Institute Inc., Cary, NC, USA).
Sample size calculations were performed with nQuery version 8 (Statistical Solutions Ltd, Cork, 
T12 NX7D, Ireland).
8.
REFERENCES
Berry JD et al. (2013) The Combined Assessment of Function and Survival (CAFS): a new 
endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 14 
(3): 162-8.
Borg GA (1982) Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 14 (5): 377-
81.
Buysse DJ et al. (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric 
practice and research. Psychiatry Res. 28 (2): 193-213.
Cedarbaum JM et al. (1999) The ALSFRS-R: a revised ALS functional rating scale that 
incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J 
Neurol Sci. 169 (1-2): 13-21.
Cudkowicz ME et al. (2013) Dexpramipexole versus placebo for patients with amyotrophic 
lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 
12 (11): 1059-67.
Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep. 14 (6): 540-5.
Lan GKK et al. (1983) Discrete sequential boundaries for clinical trials. Biometrika. 70 (3): 659-
63.
O'Brien PC et al. (1979) A multiple testing procedure for clinical trials. Biometrics. 35 (3): 549-
56.
Quanjer PH et al. (2012) Multi-ethnic reference values for spirometry for the 3-95-yr age range: 
the global lung function 2012 equations. Eur Respir J. 40 (6): 1324-43.
Shefner JM et al. (2016) A randomized, placebo-controlled, double-blind phase IIb trial 
evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral 
sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 17 (5-6): 426-35.
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9.
REVISION HISTORY
Version
Date
Summary
1.0
2020-06-18
Sent for internal approval.
0.121
2020-06-17
Added descriptive statistics for time to discontinuing study 
and treatment. Added missing citations.
0.118
2020-06-17
Moved appendices to separate files, with links added.
0.117
2020-06-17
Specified pre-dose timepoint for HR comparisons between 
Weeks 2 and 4. Clarified criteria for AE narratives. 
Clarified process of deriving CM groups of interest. Added 
PK by antibiotic use descriptive statistics.
0.112
2020-06-12
Limited scope of post-NIV exclusion sensitivity analysis.
Dropped duplicated endpoint for ALSFRS-R item 12 ≤ 1.
Clarified ambiguous category thresholds in lab values.
Specified that labs outside those specified in the protocol 
won’t be summarised. Specified source for HR in ECG 
analyses.
0.107
2020-06-03
Corrected incorrect upper bound for severe haemoglobin 
levels for males from 70 to 80 g/L.
0.102
2020-05-14
Clarified missing data procedures for time-to-event and 
CAFS endpoints. Based CAFS inference on the Hodges-
Lehmann estimator confidence interval, to better support 
pooling multiple imputation analysis results. Changed
terminology to refer to “treatment group” rather than 
“treatment arm”. Added details about randomisation 
specifics. Listed general topics used for evaluating PP 
eligibility.
0.96
2020-05-07
Added second PP population, resulting in PP up to week 12 
and PP up to week 48 populations. Fleshed out the concept 
of intercurrent events. Restructured the seconday endpoints 
section to describe analyses closer to the definitions of 
endpoints. Described missing data methods in greatly 
improved detail.
0.85
2020-04-08
Added PSQI bedtime correction algorithm. Updated 
MedDRA and WhoDrug dictionary versions. Defined renal 
impairment. Added further lab threshold analyses. Defined
MH subgroups. Defined CM subgroups. Added section for 
intercurrent events. Added section for COVID-19. Added 
more detail to sensitivity analysis definitions. Added further 
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descriptions of deaths in the safety section. Added a 
comprehensive list of changes from the study protocol.
Updated appendices. Use mean and most severe as repeated 
measurement summary statistic for 12-lead ECG.
0.69
2020-03-17
Use ITT as primary population.
0.68
2020-02-26
Added suicidality SMQ, refined vital signs thresholds, 
specified OR-1896 concentrations over levosimendan, and 
removed “delayed diagnosis” term.
0.66
2019-12-02
Added revision history.
0.64
2019-11-27
Sent to FDA for review.
10. APPENDICES
10.1 Medical history groups of interest
https://pallas.orion.fi/webtop/urn.htm?id=090017ff8243e30b&version=0.1
10.2 Adverse events of special interest
https://pallas.orion.fi/webtop/urn.htm?id=090017ff8243e35a&version=0.1
10.3 Concomitant treatment groups of interest
https://pallas.orion.fi/webtop/urn.htm?id=090017ff8243e35b&version=0.1
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Signature page 
eSigned 
 
 
 
 
 
Written by: 
 
Date dd.mm.yyyy (UTC) 
Justification 
Electronically signed by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18.06.2020 07:28:07
18.06.2020 08:35:09
18.06.2020 08:39:21
Approved
Approved
Approved
3119002 REFALS Statistical analysis plan
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