Clinical trial NCT03948178
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Orion Corporation, Orion Pharma
Start date: 2019-06-26; Completion date: 2020-11-18
Enrollment: 227 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study provides an opportunity for subjects in the REFALS (3119002; NCT03505021) study to continue treatment with oral levosimendan. The study will also provide more information about long-term safety and effectiveness of oral levosimendan in patients with ALS.

This is an open-label study, so that all eligible subjects that complete the double-blind REFALS study (48-weeks of treatment) will have the opportunity to receive oral levosimendan treatment. The primary objective, in addition to continuing treatment for subjects enrolled in the REFALS study, is to evaluate long-term safety of oral levosimendan in ALS patients. Another important objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS.

This study is open only to patients taking part in the REFALS study.

Detailed description:

Arms: arm 1: Oral Levosimendan; Levosimendan 1mg capsules for oral administration, once to twice a day, continued as long as clinically beneficial. The total study duration is up to 3 years.
Interventions: intervention 1: Levosimendan
Intervention descriptions: intervention 1: Levosimendan 1 mg capsule for oral administration

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Document type: 
Clinical study protocol 
Title: 
Effects of oral levosimendan (ODM-109) on respiratory function in 
patients with ALS: open-label extension for patients completing study 
3119002 
NCT Number: 
NCT03948178 
Document Date: 
26 March 2020 
 


ODM-109
Clinical study protocol 3119003 – Amendment 1
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CLINICAL STUDY PROTOCOL – AMENDMENT 1
EFFECTS OF ORAL LEVOSIMENDAN (ODM-109) ON RESPIRATORY FUNCTION IN 
PATIENTS WITH ALS: OPEN-LABEL EXTENSION FOR PATIENTS COMPLETING 
STUDY 3119002
Study code:
3119003
Study design:
Open, non-randomised, uncontrolled multicentre study
Short study title:
REFALS-ES
Phase:
III
Standard:
GCP
EudraCT number: 
2018-004180-31
IND number:
134169
Study Coordinating Investigator:
Merit Cudkowicz, MD
Sponsor:
Orion Corporation Orion Pharma
Orionintie 1, FI-02200 Espoo, Finland
Date:
26 March 2020
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Sponsor approvals:
Development Leader:
Clinical Study Director: 
Study Statistician:
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................... 3
SYNOPSIS .................................................................................................................................... 7
ABBREVIATIONS AND DEFINITION OF TERMS............................................................................... 9
1.
INTRODUCTION ................................................................................................................ 11
1.1
Background................................................................................................................ 11
1.2
Rationale of the study ................................................................................................ 12
1.2.1
Rationale of the study design ................................................................................ 12
1.2.2
Rationale for selected doses.................................................................................. 12
1.3
Benefit-risk assessment.............................................................................................. 13
1.3.1
Potential benefits associated with levosimendan .................................................. 13
1.3.2
Potential risks associated with levosimendan ....................................................... 13
1.3.3
Potential risks associated with the study assessments........................................... 13
2.
STUDY OBJECTIVES.......................................................................................................... 14
2.1
Primary objective....................................................................................................... 14
2.2
Secondary objective................................................................................................... 14
3.
OVERALL STUDY DESIGN AND PLAN................................................................................. 14
4.
SELECTION OF STUDY POPULATION.................................................................................. 15
4.1
Number of subjects .................................................................................................... 15
4.2
Inclusion criteria ........................................................................................................ 15
4.3
Exclusion criteria ....................................................................................................... 15
4.4
Information collected on screening failures............................................................... 16
4.5
Removal of subjects from treatment or assessment................................................... 16
5.
STUDY TREATMENTS........................................................................................................ 17
5.1
Investigational medicinal product.............................................................................. 17
5.1.1
Test product........................................................................................................... 17
5.1.2
Control product ..................................................................................................... 17
5.2
Dosing........................................................................................................................ 17
5.2.1
Selection and timing of doses................................................................................ 17
5.2.2
Dose adjustment .................................................................................................... 17
5.3
Method of assigning study subjects to treatment groups........................................... 18
5.4
Blinding...................................................................................................................... 18
5.5
Emergency procedures............................................................................................... 18
5.5.1
Treatment of emergencies..................................................................................... 18
5.6
Prior and concomitant treatments .............................................................................. 18
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5.6.1
Prohibited treatments during the study.................................................................. 18
5.6.2
Permitted treatments during the study................................................................... 18
5.7
Treatment compliance and exposure ......................................................................... 19
5.8
Availability of investigational medicinal product after termination of study............ 19
6.
STUDY PROCEDURES AND ASSESSMENTS.......................................................................... 19
6.1
Study procedures........................................................................................................ 19
6.1.1
Procedures during the baseline visit...................................................................... 21
6.1.2
Procedures during the treatment period ................................................................ 21
6.1.3
Additional visits .................................................................................................... 22
6.1.4
Procedures during the post-treatment period ........................................................ 23
6.2
Efficacy assessments.................................................................................................. 23
6.2.1
Slow Vital Capacity .............................................................................................. 23
6.2.2
Revised ALS Functional Rating Scale.................................................................. 23
6.2.3
Need for respiratory support ................................................................................. 23
6.2.4
Borg Category Ratio 10 Scale............................................................................... 24
6.2.5
Health care and home care resource use ............................................................... 24
6.2.6
Other assessments ................................................................................................. 24
6.3
Pharmacokinetic assessments .................................................................................... 24
6.4
Safety assessments..................................................................................................... 24
6.4.1
Adverse events ...................................................................................................... 24
6.4.1.1
Definitions ........................................................................................................ 24
6.4.1.2
Assessment of adverse events .......................................................................... 25
6.4.1.3
Reporting of serious adverse events by the investigator .................................. 26
6.4.1.4
Reporting of serious adverse events to competent authorities and ethics 
committees........................................................................................................ 27
6.4.2
Special situations................................................................................................... 27
6.4.3
Pregnancy during the study................................................................................... 27
6.4.4
Clinical safety assessments ................................................................................... 28
6.4.5
Laboratory safety assessments .............................................................................. 28
6.4.6
Assessment of suicidality...................................................................................... 28
6.5
Changes implemented due to COVID-19 pandemic ................................................. 29
7.
DATA COLLECTION AND MANAGEMENT........................................................................... 31
8.
STATISTICAL METHODS.................................................................................................... 31
8.1
Statistical hypotheses................................................................................................. 31
8.2
Estimation of sample size .......................................................................................... 32
8.3
Analysis populations.................................................................................................. 32
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8.4
Statistical analyses ..................................................................................................... 32
8.4.1
Demographic and other baseline characteristics ................................................... 32
8.4.2
Treatment compliance and extent of exposure...................................................... 32
8.4.3
Analysis of efficacy............................................................................................... 32
8.4.4
Pharmacokinetic analysis ...................................................................................... 33
8.4.5
Safety analysis....................................................................................................... 33
8.4.5.1
Analysis of adverse events ............................................................................... 33
8.4.5.2
Clinical safety analysis..................................................................................... 33
8.4.5.3
Laboratory safety analysis................................................................................ 33
8.4.5.4
Analysis of prior and concomitant treatments.................................................. 33
8.4.5.5
Analysis of Suicidality ..................................................................................... 33
8.5
Interim analyses ......................................................................................................... 33
9.
DATA QUALITY ASSURANCE............................................................................................. 34
9.1
Training...................................................................................................................... 34
9.2
Case report forms....................................................................................................... 34
9.3
Monitoring, audits and inspections............................................................................ 34
9.4
Laboratories and other vendors.................................................................................. 35
10.
FURTHER REQUIREMENTS AND GENERAL INFORMATION.................................................. 35
10.1
Investigators and study administrative structure........................................................ 35
10.1.1
Investigators .......................................................................................................... 35
10.1.2
Data and safety monitoring board ......................................................................... 35
10.2
Amendments to study protocol .................................................................................. 35
10.3
Insurance.................................................................................................................... 36
10.4
Financial disclosure ................................................................................................... 36
10.5
Retention of records................................................................................................... 36
10.6
Completion of the study............................................................................................. 36
10.7
Reports, publications and communication of results................................................. 37
11.
ETHICS............................................................................................................................. 37
11.1
Ethics committee........................................................................................................ 37
11.2
Ethical conduct of the study....................................................................................... 37
11.3
Subject information and informed consent................................................................ 38
11.4
Subject data protection............................................................................................... 38
12.
REFERENCE LIST .............................................................................................................. 38
13.
SUMMARY OF CHANGES TO AMENDMENT 1...................................................................... 40
13.1
Revision history ......................................................................................................... 40
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13.2
Summary of changes.................................................................................................. 40
14.
APPENDICES..................................................................................................................... 41
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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: open-label 
extension for patients completing study 3119002
Study code: 3119003
Investigator: The study coordinating investigator is Merit Cudkowicz, MD
Study centres: This will be a multinational study in approximately 100 centres.
Development phase: III
Objectives: 
Primary: The primary objective, in addition to continuing treatment for subjects in REFALS study, is to evaluate 
long-term safety of oral levosimendan in amyotrophic lateral sclerosis (ALS) patients.
Secondary: The secondary objective is to explore long-term effectiveness of oral levosimendan in the treatment of 
patients with ALS, by continuing to observe rate of disease progression during the treatment.
Methodology: Open, non-randomised, uncontrolled multicentre extension to study 3119002. Open-label 
levosimendan treatment will normally be started at the end-of-study visit for study 3119002. Subjects will attend the 
study centre at least every 3 months during the levosimendan treatment and will be reassessed (by telephone or 
centre visit) 2 weeks after each dose change.
Number of subjects: All subjects completing 48-weeks treatment period in the REFALS study may be eligible for 
this extension study. The maximum number of subjects is therefore 450.
Diagnosis and main criteria for inclusion: Subjects must meet all of the following criteria to be included into the 
study:
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, a witness may sign the consent form to indicate that the 
subject has given verbal consent.
2.
Subjects who completed 48 weeks of treatment according to the REFALS study protocol.
3.
Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study. 
Subjects will not be included into this study if they meet any of the following criteria:
1.
Development (or significant worsening from baseline of the REFALS study) of serious cardiovascular disease 
(e.g. myocardial infarction, heart failure, arrhythmia, stroke, or second or third degree atrioventricular (AV) 
block).
2.
Pulse/heart rate repeatedly > 100 bpm after 5-minute rest at baseline. If the pulse/heart rate is > 100 bpm in the 
first recording, then a second recording must be done after another 5 min rest to confirm pulse/heart rate > 100 
bpm. 
3.
Systolic blood pressure (SBP) < 90 mmHg.
4.
Severe renal impairment (creatinine clearance < 30 ml/min or creatinine > 170 µmol/l at 48 week visit of the 
REFALS study, or on dialysis.
5.
Severe hepatic impairment at the discretion of the investigator.
6.
Women of reproductive age without a negative pregnancy test and without a commitment to using a highly 
effective method of contraception (e.g. oral hormonal 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.
7.
Subject judged to be actively suicidal by the investigator.
8.
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.
Investigational product, dose and mode of administration: Test product will be Levosimendan 1 mg capsules 
administered orally. The target maintenance dose of oral levosimendan will be 2 mg/day taken as 1 mg b.i.d. 
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Levosimendan treatment will be started at 1 mg/day, with increase to 2 mg/day after 2 weeks treatment if well 
tolerated.
Frequency/duration of treatment: The subject may continue the treatment as long as clinically indicated or until 
the study ends.
Variables and methods of assessments:
Efficacy assessments:
Slow vital capacity (SVC): SVC will be assessed in the sitting and supine position once at each centre visit during 
the study including the baseline, i.e. in the morning before the study treatment administration.
Revised ALS Functional Rating Scale (ALSFRS-R): ALSFRS-R will be assessed at each centre visit and telephone 
contact. 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. 
Need for respiratory support: The use of any respiratory support, including Bilevel Positive Airway Pressure 
(BiPAP) and invasive mechanical ventilation, will be recorded. The time to starting or changing the degree of 
respiratory support will be calculated.
Borg Category Ratio 10 Scale (CR 10): Borg CR 10 scale will be used in the assessment of dyspnoea. 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 position (immediately before the SVC measurements). Orthostatic changes between sitting and 
supine positions will be calculated.
Health care and home care resource use: Health care and home care resource use will be recorded for possible later 
use in pharmacoeconomic analysis.
Other assessments: Subject’s status for tracheostomy and survival will be recorded at all visits.
Safety assessments
Safety will be assessed by adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG) and by assessment of 
suicidality.
Statistical methods:
Analysis of efficacy:
All subjects who have received at least 1 dose of study treatment will be included into the analyses. Full analysis set 
will also include assessments from the REFALS study from participating subjects. Analyses will be performed with 
and without data from the REFALS study, depending on the analysis type. When appropriate, between-subject 
comparisons will be performed using the randomised treatment arm in the REFALS study.
Slope of decline in sitting and supine SVC and ALSFRS-R will be estimated using a random slope model. Median 
time to non-invasive mask ventilation (NIV) or death and to decline (by at least 1 point) in the ALSFRS-R respiratory 
domain will be evaluated using Kaplan-Meier estimates. 
Borg CR10 (sitting, supine and orthostatic changes) will be evaluated using mixed model for repeated measures. 
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.
Analysis of safety:
The AEs will be displayed as event counts and subject counts in a frequency table. The number and proportion (%) 
of subjects having each AE as well as the AE severity (mild, moderate, severe) and causality (related, not related) 
to the study treatment will be given. SAEs and other significant AEs will be evaluated case-by-case.
The actual values and changes from baseline in pulse/heart rate and blood pressure will be summarised using 
descriptive statistics. Any abnormal 12-lead ECG findings, special situations and suicidality data will be summarised 
using descriptive statistics.
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ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event 
ALS
Amyotrophic lateral sclerosis
ALSFRS-R
Revised ALS Functional Rating Scale
b.i.d.
Twice a day
BiPAP
Bilevel Positive Airway Pressure
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
CNS
Central nervous system
CR10
Category Ratio 10
CRA
Clinical research associate
CRO
Contract research organisation
CRF
Case report form
DSMB
Data and safety monitoring board
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
GCP
Good clinical practice
GMP
Good manufacturing practice 
HF
Heart failure
IC
Informed consent
IRB
Institutional review board
i.v.
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
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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)
SAE
Serious adverse event
SBP
Systolic blood pressure
SMA
Site management associate
SUSAR
Suspected unexpected serious adverse reactions
SVC
Slow vital capacity
Note on usage of terms:
Orion Corporation Orion Pharma is hereafter in this document called “Orion”.
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). No cure currently exists for ALS, the mainstay of treatment is 
symptom management and palliative care. The first drug product approved to treat ALS was
riluzole, which has modest effect (approx. 3 months) on survival (Bensimon G et al., 1994) and 
no symptomatic effects. Another approved drug, 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 and is available in only few countries. In addition,
dextromethorphan/quinidine is available on some markets and 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).
Levosimendan is a calcium sensitising drug that improves force generation in both cardiac and 
skeletal muscle through binding to troponin C, without increasing oxygen consumption. 
Levosimendan does not cross the blood brain barrier or cause central nervous system (CNS) 
adverse effects. Intravenous (i.v.) levosimendan (Simdax®) is approved for treatment of acutely 
decompensated heart failure in approximately 60 countries. Levosimendan improved diaphragm 
neuromechanical efficiency in healthy volunteers (Doorduin J et al., 2012) and had positive 
effects on supine slow vital capacity (SVC) in patients with ALS.
In the LEVALS phase II study (3119001), including 66 patients with ALS (sitting SVC ranging 
from 60 to 90% of predicted) oral levosimendan 1 or 2 mg improved supine (but not sitting) 
SVC after 14 days of treatment compared to placebo. Vital capacity in the supine rather than 
sitting position better reflects the loss of diaphragm function in ALS patients that commonly 
manifests in problematic orthopnoea and sleep disruption (Lechtzin N et al., 2002). Supine SVC 
may thus also be a better measure of diaphragm function than SVC in the sitting position. Oral 
levosimendan was well tolerated, the most frequent treatment-related adverse effects being 
headache and tachycardia, related to its known effects as an inodilator. A 6-month extension 
study did not identify additional safety issues.
The currently ongoing REFALS phase III study (3119002; NCT03505021; EudraCT 2017-
002754-36) will evaluate whether changes in supine SVC are translated to clinical benefit for 
patients with ALS. A total of 450 adult patients, from Europe, Australia and North America, 
with definite, probable or laboratory supported probable ALS and some degree of respiratory 
dysfunction (sitting SVC ranging from 60 to 90%) will be treated with oral levosimendan (target 
2 mg daily) or placebo for 48 weeks in a double-blind, parallel-group design. The primary 
endpoint will be supine SVC with important secondary endpoints including ALSFRS-R adjusted 
for patient survival (combined assessment of function and survival [CAFS]), the occurrence of 
respiratory events, clinical global impression, Borg Category Ratio 10 (CR10) scale for 
dyspnoea and scales assessing sleep. Safety will be assessed using standard measures including 
adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG) and laboratory safety tests 
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at regular intervals throughout the 48-week treatment period. The subjects will record use of 
healthcare resources in a diary.
The REFALS-ES study (3119003) is an open-label extension for subjects who complete the 
double-blind REFALS study (3119002) and who wish to continue treatment with oral 
levosimendan.
1.2
Rationale of the study
1.2.1
Rationale of the study design
This study provides an opportunity for subjects in the REFALS study to continue treatment with 
oral levosimendan. The study will also provide more information about long-term safety and 
effectiveness of oral levosimendan in patients with ALS, to supplement data from the double-
blind REFALS study.
This is an open-label study, so that all eligible subjects that complete the double-blind REFALS 
study will have the opportunity to receive oral levosimendan treatment. Apart from completing 
the REFALS study, eligibility criteria for REFALS-ES study are restricted to safety criteria that 
may have changed since the start of the REFALS study. The subjects will be able to participate 
in the study and receive levosimendan for as long as it is considered clinically beneficial. In 
addition, as a long term extension, the objective is to limit disruption to usual patient care and 
to reduce subject inconvenience and study commitments. Thus safety and efficacy measures and 
study restrictions are reduced to more closely reflect typical patient care than in the double-blind 
study. On completing 48 weeks double-blind treatment in the REFALS study, all subjects will 
stop blinded treatment, with the REFALS end-of-study visit 14-25 days later serving as the 
baseline visit for REFALS-ES study and re-initiation of the treatment. Since the half-life of the 
most important active metabolite of levosimendan, OR-1896, exceeds 60 hours, the actual drug-
free period will be somewhat shorter than this. This off-treatment period allows evaluation of 
reversal of ongoing AEs as well as observation of the effects of withdrawal of prolonged 
levosimendan treatment. It also reduces any risk of unblinding occurring as a result of an abrupt 
change in the treatment for subjects receiving placebo in REFALS study. As levosimendan is 
intended for treatment of respiratory symptoms rather than preventing or delaying disease 
progression, the break in treatment is not expected to result in a significant risk to subject well-
being.
The study will continue at least until the time of marketing approval of oral levosimendan, 
cessation of development of oral levosimendan for ALS, or 3 years, whichever occurs first in 
each participating country. Continuation after this time will be at the discretion of the sponsor. 
On termination of the study, an appropriate method of continued treatment supply will be sought 
for any subjects still requiring treatment with oral levosimendan.
1.2.2
Rationale for selected doses
The target maintenance dose of levosimendan in this study will be the same as in the REFALS
study, i.e. 2 mg per day administered as 1 mg b.i.d. The subjects in the placebo-arm in the 
REFALS study will receive levosimendan for the first time in the REFALS-ES study. For 
subjects in the levosimendan-arm in the REFALS study there will be 14-25 days drug-free post-
treatment period before entering the REFALS-ES study. In order to reduce the risk for headache 
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and marked increase in heart rate, the subjects will start the treatment at 1 mg/day, and if 
tolerated and considered appropriate, the treatment dose should be increased to 1 mg b.i.d. after 
two weeks of treatment. After that, changes to the daily dose of the study treatment are allowed
at any time. It will also be possible, given the slow elimination of metabolites of levosimendan,
to administer levosimendan less frequently than 1 mg daily in the event that dose is not 
adequately tolerated. All dose changes are re-assessed approximately 2 weeks after the change.
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 2 weeks treatment with
levosimendan significantly improved respiratory function in ALS patients, presumably by 
enhancing the skeletal muscle function of the diaphragm. It is anticipated that such an effect may 
be larger during longer treatment and in turn improve patients’ well-being and functional ability.
Levosimendan is not expected to significantly affect underlying disease progression.
1.3.2
Potential risks associated with levosimendan
Safety data with oral levosimendan are primarily based on treatment of patients with heart failure 
and extensive experience with the i.v. preparation, although 66 patients with ALS received 
levosimendan in the LEVALS study. Available data indicate that levosimendan or its active 
metabolites do not typically cause clinically significant direct CNS effects. Headache (due to 
vasodilatation), increased heart rate and palpitations have been the most commonly reported 
adverse drug reactions in healthy subjects and/or ALS patients treated with levosimendan.
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 studies with oral 
levosimendan in chronic heart failure (CHF) (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, in the LEVALS, phase IIa study conducted in 
ALS patients, no differences in supraventricular or ventricular tachyarrhythmias were seen 
between placebo and levosimendan treatments. There were no differences either in the numbers
of severe AEs or serious adverse events (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. 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 may be collected for safety laboratory and levosimendan concentration analyses
can be conducted, if clinically indicated. The risks of blood sampling include fainting and pain, 
bruising, swelling or rarely infection of the injection site. Respiratory assessments may be 
burdensome for patients with ALS.
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2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective, in addition to continuing treatment for subjects in REFALS study, is to 
evaluate long-term safety of oral levosimendan in ALS patients.
2.2
Secondary objective
The secondary objective is to explore long-term effectiveness of oral levosimendan in the 
treatment of patients with ALS, by continuing to observe rate of disease progression during the 
treatment.
3.
OVERALL STUDY DESIGN AND PLAN
This is an open, non-randomised, uncontrolled, multicentre phase III extension study to the
REFALS study.
The subjects will give informed consent (IC) to continue in this open-label extension study at
the 48-week or end-of-study visit of the REFALS (or between these visits). The REFALS end-
of-study visit will double as the REFALS-ES baseline visit. Visits to the study centre are flexible 
but occur at least every 3 months. Subject assessments will be conducted 2 weeks after starting 
the study treatment and after each change in the dose: such visits may be at study centre or 
conducted remotely where feasible (see section 6.1.3). A telephone contact will be performed 
for all subjects 6 weeks after starting the treatment.
The subject may continue the treatment as long as clinically indicated (see withdrawal criteria 
in section 4.5) or until the study ends.
An end-of-study visit will take place 14-25 days after the last study treatment administration for 
each subject. 
The study design is presented in Figure 1.
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Figure 1.
Study design
4.
SELECTION OF STUDY POPULATION
4.1
Number of subjects
All subjects completing 48-weeks treatment period in the REFALS study may be eligible for
this extension study. The maximum number of subjects is therefore 450.
4.2
Inclusion criteria
Subjects must meet all of the following criteria to be included into the study:
1. Written or verbal IC for participation in the study will be obtained from the subject. In case 
that the study subject him/herself cannot sign the IC, a witness may sign the consent form to 
indicate that the subject has given verbal consent.
2. Subjects who completed 48 weeks of treatment according to the REFALS study protocol.
3. Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the 
REFALS study. 
4.3
Exclusion criteria
Subjects will not be included into this study if they meet any of the following criteria:
1.
Development (or significant worsening from baseline of the REFALS study) of serious 
cardiovascular disease (e.g. myocardial infarction, heart failure, arrhythmia, stroke, or 
second or third degree atrioventricular [AV] block).
2.
Pulse/heart rate repeatedly > 100 bpm after 5-minute rest at baseline. If the pulse/heart rate
is > 100 bpm in the first recording, then a second recording must be done after another 5 min 
rest to confirm pulse/heart rate > 100 bpm.
TC = telephone contact, EOS = end-of-study
1 Dose increased to 1 mg b.i.d. if the 1 mg/day dosing was well tolerated
2 Additional visit approx. 2 weeks after any dose change at visit 2
2 wks 
± 3 d
14-25 days
Visit 1
Baseline
Visit 21
Visit 32
Visit 4
EOS visit
Visits at least every 3 
months, additional visit 
approx. 2 weeks after any 
dose change 
4 wks
± 3 d
TC
6 wks
± 3 d
Visit n
1 mg/day
EOS visit for 
REFALS study
                Treatment period
Post-treatment 
period
Maximum 2 mg/day
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3.
Systolic blood pressure (SBP) < 90 mmHg.
4.
Severe renal impairment (creatinine clearance < 30 ml/min or creatinine > 170 µmol/l at 
48 week visit of the REFALS study, or on dialysis.
5.
Severe hepatic impairment at the discretion of the investigator.
6.
Women of reproductive age without a negative pregnancy test and without a commitment 
to using a highly effective method of contraception (e.g. oral hormonal 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.
7.
Subject judged to be actively suicidal by the investigator.
8.
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, 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.
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 for the following reasons: 

The subject starts another study with investigational medicinal product.

Uncontrolled pulse/heart rate increase from baseline (visit 1) despite maximal dose 
reduction (see section 5.2.2).

Life-threatening supraventricular or ventricular arrhythmia.

Pregnancy.

The investigator judges that it is in the best interest of the subject to stop the study 
treatment due to any other abnormality compromising subject safety. However, the 
investigator should consult the medical monitor whenever possible in these instances.
Irrespective of the reason for discontinuation, the subject should be invited to complete the end-
of-study assessments. As long as the subject consents, all relevant assessments, at least those of 
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safety, should be performed, preferably according to the schedule for the end-of-study 
assessments.
The study monitor must be notified about premature discontinuations by email/phone/fax within 
24 hours in the event of discontinuation due to an SAE (see section 6.4.1.3) or within 7 days in 
the event of discontinuation due to another reason.
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 medicinal product
5.1.1
Test product
Test product will be Levosimendan 1 mg capsules administered orally.
5.1.2
Control product
No control product will be used.
5.2
Dosing
5.2.1
Selection and timing of doses
All subjects will receive levosimendan in this study. The target maintenance dose of oral 
levosimendan will be 2 mg/day (see section 5.2.2) taken as 1 mg b.i.d. Levosimendan treatment 
will be started at 1 mg/day. The subject should be reviewed 2 weeks after initiation of 
levosimendan at which time the dose should be increased to 2 mg/day, if considered appropriate 
and the 1 mg/day dose was well tolerated. Since OR-1896 has a very long elimination half-life, 
it is permitted to use also less frequent dosing than 1 mg once daily (e.g. 1 mg on alternate days) 
if levosimendan 1 mg/day is not well tolerated. The subject should be re-assessed 2 weeks after 
each dose change. 
Single daily doses should be taken in the morning. 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.
5.2.2
Dose adjustment
The levosimendan dose will be adjusted according to tolerability, including pulse/heart rate. It 
is recommended to reduce the daily dose of the study treatment (or discontinue the treatment if 
no further dose reduction is possible) if resting pulse/heart rate is repeatedly > 30 bpm more than 
the pre-treatment value or the subject has marked symptoms related to tachycardia (see section 
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6.4.4). It is further advised not to increase the dose at week 2 visit or any later time point if the 
resting pulse/heart rate change is close to this recommended limit.
After the initial two weeks of treatment with levosimendan 1 mg/day, changes in dose can take 
place at any time but it should be remembered that the full effect of a dose change may take 2 
weeks to develop, at which point the subject should be reassessed before making any further 
dosing decision.
5.3
Method of assigning study subjects to treatment groups
No randomisation will be applied in this study. The subjects will receive their subject numbers 
in the REFALS study and the same subject numbers will be used in this study.
5.4
Blinding
This is an open-label study.
5.5
Emergency procedures
5.5.1
Treatment of emergencies
Emergencies will be treated according to the decision of the physician in charge or the 
investigator, when available.
5.6
Prior and concomitant treatments
All relevant concomitant treatments during the study (including all medical treatments for ALS), 
including the post-treatment period, must be recorded. Subjects may not take part in another 
clinical study while participating in this extension study.
5.6.1
Prohibited treatments during the study
Other medications are not restricted, except as part of another clinical study.
5.6.2
Permitted treatments during the study
Supplements and other treatments for ALS are not prohibited during this study, although 
possibility of drug interactions should always be considered. Botulinum toxin is not excluded if 
considered clinically required. Treatment with riluzole and edaravone can be started, 
discontinued or adjusted as indicated.
Any other treatments, except as part of another clinical study, 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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5.7
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.
5.8
Availability of investigational medicinal product after termination of 
study
On termination of the study, an appropriate method to continue treatment will be sought for any 
subjects still requiring treatment with oral levosimendan.
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
Baseline
Treatment period
Post-treatment period
REFALS 
End-of-study visit
Visit 1
Baseline D1
Telephone contact
Study centre visit
End-of-study visit 
14-25 d after last study 
treatment administration
IC
x1
Weight
x
x
x
Height and BMI
x
Physical examination
x
Heart rate and BP
x
Pulse/heart rate and BP
x
x (only pulse/heart rate)
x
x
12-lead ECG
x
x
x
Pregnancy test for females of childbearing potential
x
x
x
Laboratory safety assessments
Haematology
x
Chemistry
x
Urinalysis
x
SVC sitting
x2,3
x4
x3
SVC supine
x2
x3
x4
x3
Eligibility criteria and decision of entry
x
Study treatment
x
ALSFRS-R
x
x
x
x
Borg CR10 scale
x
x
x
Use of health care and home care resources and non-
medical assistive devices
x
x
x
Assessment of suicidality
x
x
x
Status for NIV support, invasive mechanical 
ventilation by intubation or tracheostomy and 
survival
x
x
x
x
AEs and SAEs
x
Concomitant treatments
x
1 If not given earlier
2 Using MasterScope
3 Local equipment
4 MasterScope will be used for all study centre visits up to 3 months, all subsequent visits use local equipment
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6.1.1
Procedures during the baseline visit
A prospective subject will receive both written and verbal information about the study at the 48-
week or end-of-study visit for the REFALS study (or between these visits) and will have an 
opportunity to ask questions and sufficient time to decide whether or not to participate in the 
extension 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) before any study specific procedures 
will be performed.
End-of-study visit assessments for the REFALS study will be used as baseline for this study. 
The following procedures for the REFALS study will be carried forward to this extension study:

Weight will be recorded.

SVC supine will be assessed using the MasterScope.

The Borg CR10 scale to assess the intensity of dyspnoea will be completed at rest in 
sitting and supine positions (immediately before SVC measurement).

Blood pressure (supine) will be recorded.

A pregnancy test will be performed for females of childbearing potential.

Suicidality will be assessed.

AEs, SAEs and concomitant treatments will be recorded.
In addition the following procedures will be performed before starting the study treatment in the 
REFALS-ES:

Inclusion and exclusion criteria for this extension study will be assessed.

SVC sitting and supine (local equipment) will be assessed. Baseline SVC sitting will also 
be performed with the MasterScope.

ALSFRS-R will be assessed.

Pulse/heart rate will be recorded.

Use of health care and home care resources and non-medical assistive devices will be 
recorded.
If the subject is eligible, the study treatment will be dispensed. The first dose of the study 
treatment will be administered at the study centre, and blood pressure (supine) and pulse/heart 
rate will be recorded approximately 1 hour after the administration. It is recommended that 
subjects remain at the study centre for at least 2 hours after the first dose of levosimendan.
6.1.2
Procedures during the treatment period
Visits will be performed either by telephone or attendance at the study centre. For simplicity, all 
visits of the same type involve the same procedures.
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Any planned follow-up may take place at the study centre and may occur at any time, but should 
not be less frequent than every 3 months. The only fixed follow-up points are dose assessment
at 2 weeks and telephone contact 6 weeks after start of the study treatment. 
Any visit may be performed by telephone provided:

A reliable measure of resting pulse/heart rate can be obtained and documented.

The minimum 3-monthly study centre visit schedule is maintained.
In case a subject is no longer able to travel to the study centre, but levosimendan is considered
to still be of clinical value, wholly remote monitoring by telephone contacts may be acceptable. 
This must be agreed in advance by the sponsor and the medical monitor, and an acceptable 
method of dispensing study treatment must be established. 
Procedures during visits are presented in Table 2. The morning dose of study treatment will be 
administered at the study centre during the study centre visit days. In addition, additional visits 
or contacts approximately 2 weeks after dose change can occur at any time (see section 6.1.3).
Table 2.
Procedures during the treatment period
Time
Study centre visit1
Telephone contact
Weight
x
Pulse/heart rate and BP 
x
Pulse/heart rate only
12-lead ECG
x
Pregnancy test for females of childbearing potential
x
SVC supine and sitting
x2
Study treatment
x
ALSFRS-R
x
x
Borg CR10 scale
x
Use of health care and home care resources use and non-
medical assistive devices
x
x
Assessment of suicidality
x
x
Status for NIV support, invasive mechanical ventilation by 
intubation or tracheostomy and survival
x
x
AEs and SAEs
x
x
Medical history and current medical conditions
x
x
Concomitant treatments
x
x
1 All procedures will be performed pre-dose
2 MasterScope used up to 3 months 
During the telephone contact a caregiver can take the telephone contact on behalf of the subject 
in case the subject is unable to communicate verbally due to disease progression.
6.1.3
Additional visits
Additional centre visits or telephone contacts will be performed after changing the dose of the 
study treatment (see section 5.2.2), approximately 2 weeks after the dose change. Procedures at 
these visits/contacts will be the same as described in Table 2.
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6.1.4
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:

Pulse/heart rate and BP will be recorded.

SVC supine and sitting will be assessed.

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.
In case it is not possible for the subjects to travel to the study centre, the end-of-study visit may 
be performed by telephone (except pregnancy test, BP and SVC).
6.2
Efficacy assessments
6.2.1
Slow Vital Capacity
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. 
SVC will be assessed in the sitting and supine position once at each centre visit during the study 
including the baseline (visit 1), i.e. in the morning before the study treatment administration.
The MasterScope (used in the REFALS study) will be used in all study centre visits during the 
first 3 months (so that all subjects have at least 1 post-baseline assessment with the device), after 
which each centre will use its own standard pulmonary function test equipment. At baseline 
(visit 1), the SVC will be assessed by using both MasterScope and the local equipment. 
6.2.2
Revised ALS Functional Rating Scale
ALSFRS-R (Cedarbaum JM et al., 1999) will be assessed at each centre visit and telephone 
contact. 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. 
6.2.3
Need for respiratory support
The use of any respiratory support, including Bilevel Positive Airway Pressure (BiPAP) and 
invasive mechanical ventilation, will be recorded. The time to starting or changing the degree of 
respiratory support will be calculated.
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6.2.4
Borg Category Ratio 10 Scale
Borg Category Ratio 10 (CR 10) 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 position (immediately before the 
SVC measurements). Orthostatic changes between sitting and supine positions will be 
calculated.
6.2.5
Health care and home care resource use
For possible later use in pharmacoeconomic analysis, any hospital inpatient days, other 
institutional care, any additional hospital emergency unit visits, days in other institutional care, 
and the amount of formal and informal home care received, 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.
6.2.6
Other assessments
Subject’s status for tracheostomy and survival will be recorded at all visits.
6.3
Pharmacokinetic assessments
No formal PK assessments samples will be taken. Levosimendan concentration sample may be 
taken for later analysis if clinically indicated e.g. in assessment of an AE.
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study.
6.4
Safety assessments
6.4.1
Adverse events
6.4.1.1
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, symptoms that the investigator considers to be due to expected progression of ALS 
are not considered as an AE, except for disease progression leading to death during the study.
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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 
6.4.1.3 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 
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 marked haematological and other laboratory abnormalities (other 
than those meeting the definition of serious) and any events that lead to an intervention,
including

withdrawal of the investigational product

reduction of its dose

significant additional concomitant therapy
6.4.1.2
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.
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.
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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.
6.4.1.3
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.
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.

symptoms that the investigator considers to be due to expected progression of ALS, 
except for disease progression leading to death during the study
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, the 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 report it 
electronically or to fill in the SAE form within 24 hours, the person receiving the report will 
forward the information to Orion Drug Safety. 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).
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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. 
6.4.1.4
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 ECs and 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 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.
6.4.2
Special situations
The 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.
6.4.3
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 
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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.
6.4.4
Clinical safety assessments
Pulse/heart rate, and systolic and diastolic blood pressure will be measured in a supine position
after at least 5 minutes at rest before morning dose of study treatment at all study centre visits.
For telephone contacts a pulse/heart rate assessment measured in a supine position after at least 
5 minutes at rest before morning dose up to 3 days prior to the contact will be accepted.
Pulse rate will normally be assessed by manual palpation over at least 30 seconds by a qualified 
healthcare professional. Alternatively, mean heart rate as measured by the 12-lead ECG or a 
continuous ECG monitor may be used, however heart rate values measured by an automated 
sphygmomanometer are not accepted. Where possible, abnormal values should be re-checked 
(ensuring the subject is at rest) before making a decision concerning the levosimendan dose.
A standard 12-lead ECG will be recorded in a supine position after at least 5 minutes at rest at 
each centre visit during the treatment period, before the morning dose of the study treatment.
6.4.5
Laboratory safety assessments
A pregnancy test for female subjects of childbearing potential will be performed at baseline and 
at each study centre visit during the treatment period and at the end-of-study visit.
Local safety laboratory tests may be performed if clinically indicated (for example in assessment 
of an AE). 
Instructions for the collection, handling, storage and transportation of samples will be provided
before the start of the study.
6.4.6
Assessment of suicidality
Suicidality will be assessed by asking the following standard questions at each visit:
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’.
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6.5
Changes implemented due to COVID-19 pandemic
The following arrangements should be applied in the event that the subjects are not able to attend 
the study centre, either for baseline or treatment period visits, as a direct result of the COVID-
19 pandemic. 
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. SVC and weight will not be assessed while these arrangements apply.
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.
Baseline visit
It will be possible for subjects to enter the study provided all eligibility criteria can be verified. 
In case baseline procedures described in Table 1 and in section 6.1.1 cannot be performed at the 
study centre due to restrictions related to COVID-19, a telephone visit (could also be a home 
visit or video call) should be arranged (see table below). 12-lead ECG, laboratory safety 
assessments, pregnancy test and vital signs are essential for the evaluation of eligibility and must 
be obtained locally if they cannot be performed at the study centre. 
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All the eligibility criteria should be reviewed and discussed with the subject. In case all data 
needed to evaluate eligibility are not available, entry of the subject may be delayed until the tests 
can be performed. 
Procedures at remote visits
Time
REFALS 
End-of-study 
visit
Visit 1
Baseline
Telephone visit
to replace 3-
monthly centre 
visit
IC (in case not collected at the study centre prior to the baseline 
visit)
x1
Pulse/heart rate and BP (supine)
x2
x2
x8
12-lead ECG
x3
x3,7
x3
Laboratory safety assessments4
Haematology
x
x7
Chemistry
x
x7
Urinalysis
x
x7
Pregnancy test for females of childbearing potential
x5
x7
x5
Eligibility criteria and decision of entry
x
Study treatment
x6
x6
ALSFRS-R
x
x
Borg CR10 scale
x
x7
x
Use of health care and home care resources and non-medical 
assistive devices
x
x
Assessment of suicidality
x
x7
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
Concomitant treatments
x
x
x
1 If IC is taken over the phone, it should be documented and confirmed by normal consent procedures as soon as 
possible.
2 Performed in supine position after at least 5 min rest before the morning dose of the study treatment. The 
assessment should normally be done by a health care professional. The use of alternative methods, including home 
devices are subject to sponsor approval.
3 The measurement should be taken using the local ECG device after at least 5 min rest. A copy of the trace (paper 
or electronic) will be provided.
4 Standard biochemical, electrolyte and haematological test panels of the local laboratory will be accepted (at least 
Creatinine needed, exclusion criterion 4). A copy of the laboratory report with local reference range should be 
provided.
5 Test kits for urine pregnancy test should be provided to the subject for testing at home (unless taken in a local 
laboratory).
6 Study treatment shipped to subject’s home.
7 Performed only in case not performed at REFALS end-of-study or study entry is delayed.
8 Performed locally.
Visits during the treatment period 
During the treatment period any visit may be performed by telephone (see section 6.1.2). In case 
the first dose of study treatment is taken at the subject’s home instead of the study centre, 
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arrangements should be made for the pulse rate to be measured before and 1 h after the first 
study treatment administration.
If the subjects are unable to attend the study centre at least once every 3 months, a specific 
telephone assessment as described in the table above should be performed. A 12-lead ECG 
recording should be performed along with blood pressure and heart rate measurement. A 
pregnancy test should also be obtained where applicable. In case these assessments cannot be 
obtained at the specified time, the benefit:risk ratio for the subject to continue in the study should 
be reassessed. 
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 and laboratory results, if applicable. 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. All data on the eCRFs must be verifiable in the source data or patient records 
unless eCRF data are declared as source data.
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. 
An authorised person will code medical history, current medical condition and AEs using 
standard coding dictionaries. Prior and concomitant treatments will be coded.
Further details regarding data collection and management are presented in the data management 
plan.
Statistical analyses, tables and subject data listings will be performed with SAS® for Windows 
(SAS Institute Inc., Cary, NC, USA).
8.
STATISTICAL METHODS
8.1
Statistical hypotheses
No formal hypothesis will be made
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8.2
Estimation of sample size
No formal sample size calculation will be performed.
8.3
Analysis populations
All subjects who have received at least 1 dose of study treatment will be included into the 
analyses. Full analysis set will also include assessments from the REFALS study from 
participating subjects. Analyses will be performed with and without data from the REFALS 
study, depending on the analysis type.
8.4
Statistical analyses
Statistical analyses are described in more detail in the statistical analysis plan.
8.4.1
Demographic and other baseline characteristics
All relevant demographic and baseline characteristics will be summarised using descriptive 
statistics. The summary will be based on data collected at initiation of study 3119002 and 
covering all relevant changes prior to initiation of this study. The number and reasons for 
discontinuations will be listed and tabulated by treatment groups.
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
Slope of decline in sitting and supine SVC and ALSFRS-R will be estimated using a random 
slope model. Estimation will be performed with and without the data collected in the REFALS 
study. When appropriate, between-subject comparisons will be performed using the randomised 
treatment arm in the REFALS study including a treatment-by-study interaction term. 
Median time to NIV or death and to decline (by at least 1 point) in the ALSFRS-R respiratory 
domain will be evaluated using Kaplan-Meier estimates. Estimation will be performed with and 
without the data collected in the REFALS study. When appropriate, between-subject
comparisons will be performed using the randomised treatment arm in the REFALS study, and 
Cox’ proportional hazard regression model including treatment by study interaction term. 
Borg CR10 (sitting, supine and orthostatic changes) will be evaluated using mixed model for 
repeated measures (MMRM) with and without the data collected in the REFALS study. When 
appropriate, between-subject comparisons will be performed using the randomised treatment 
arm in the REFALS study and appropriate MMRM including treatment by study interaction 
term. 
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.
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To avoid selection bias in estimations, sensitivity analyses including all the subjects enrolled in
the REFALS study will be considered. No imputation for missing data is planned. All efficacy 
data will be listed and summarised over time using appropriate descriptive statistics.
8.4.4
Pharmacokinetic analysis
In case PK samples are taken, levosimendan, OR-1855 and OR-1896 concentrations will be
summarised using descriptive statistics. Metabolites OR-1855 and OR-1896 will be further 
summarised by subject acetylation status collected in the main study.
8.4.5
Safety analysis
8.4.5.1
Analysis of adverse events
AEs reported during the study will be classified by system organ class and preferred terms using 
the Medical Dictionary for Regulatory Activities (MedDRA) coding system. The AEs will be 
displayed as event counts and subject counts in a frequency table. The number and proportion 
(%) of subjects having each AE as well as the AE severity (mild, moderate, severe) and causality 
(related, not related) to the study treatment will be given. SAEs and other significant AEs will 
be evaluated case-by-case.
When appropriate, between-subject comparisons will be performed using the randomised 
treatment arm in the REFALS study. AEs reported as part of the REFALS study may be used to 
complement the safety profile.
8.4.5.2
Clinical safety analysis
The actual values and changes from baseline in pulse/heart rate and blood pressure will be
summarised using descriptive statistics. Any abnormal 12-lead ECG findings and special 
situations will be summarised.
8.4.5.3
Laboratory safety analysis
In case recorded, laboratory values and changes from baseline will be summarised using 
descriptive statistics. 
8.4.5.4
Analysis of prior and concomitant treatments
The number and percentage of subjects using concomitant treatments will be summarised by 
pharmacological subgroup and chemical substance. The summary of prior medications will be 
based on data collected at initiation of the REFALS study and covering all relevant changes prior 
to initiation of this study.
8.4.5.5
Analysis of Suicidality
Suicidality will be summarised using descriptive statistics.
8.5
Interim analyses
No interim analysis is planned for this study.
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9.
DATA QUALITY ASSURANCE
9.1
Training
An initiation 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.
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 CRO will implement a risk based monitoring strategy which will combine a centralised 
monitoring team of site management associates (SMAs) supported by a clinical research 
associate (CRA) who will perform on site visits.
In this innovative real world research model, the site relationship is streamlined from onsite and 
in-house CRAs to centralised (regional) SMAs. The SMAs use state-of-the-art analytical tools 
to combine site management, data review, query processing, and central monitoring into a single 
role, which reduces resource allocation and site burden. During the last interim monitoring visit 
for pivotal phase activities, PRA will conduct a hand-off call (Site Initiation for OLE) for each 
site, which would include site staff and the CRA and SMA assigned to the site.
The CRA will perform on site visits if needed in line with the risk management assessment plan 
and to perform close out activities at the end of the study.
The SMA/CRA will ensure that the study complies with good clinical practice (GCP) and 
applicable regulatory requirements and that the protocol is followed in all aspects, accurate 
recording of results, reporting of AEs, drug accountability and record keeping. 
The study may be audited by independent representative(s) of the sponsor or inspected by the 
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.
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9.4
Laboratories and other vendors
A local laboratory will be used for possible laboratory safety measurements and ECG analyses.
Details regarding spirometry and possible laboratory safety measurements and ECG analyses 
are presented in the separate instructions. Quality certificates are required from all safety 
laboratories.
In case levosimendan concentration samples are taken, 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 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
No formal data and safety monitoring board (DSMB) reviews specifically for this study are 
planned. The DSMB of the REFALS study will review the data from this extension study until 
completion of the REFALS study. The DSMB may also decide to conduct further meetings to 
review safety data from this extension study, if clinically indicated. 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.
Further details regarding the composition and responsibility of the REFALS study DSMB are 
presented in the DSMB charter.
10.2 Amendments to 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 or CA. Only in the event of a 
need to eliminate an immediate hazard(s) to study subjects, the investigator may implement 
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.
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Any changes to the study protocol are subject to prior discussion with, and approval by, the 
sponsor and the principal 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 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 or 
CA need not to be notified and in-house approval (including approval by the principal
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 Retention of records
The investigator agrees to keep the following documentation in the investigator’s study file: 
study subject records, 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.
10.6 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.
10.7 Reports, publications and communication of results
Statistical analysis will be performed by or under the supervision of the sponsor according to the 
statistical analysis plan.
The study report will be prepared by or under the supervision of the sponsor. The final report 
will be approved by the appropriate representatives of the sponsor and the investigators. 
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.
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.
The study shall not be initiated before favourable opinion from the EC and approval from the 
CA has been obtained for the study.
The study will be conducted in compliance with the protocol, GCP (ICH E6[R2]) and applicable 
regulatory requirements. A substantial amendment shall not be implemented until the protocol 
amendment has received a favourable opinion from the EC and approval from the CA. Only in 
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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 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. After this, the subject 
will be given sufficient time to make a decision regarding participation in 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
United States 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.
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.
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.
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Borg GA (1982) Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 14 (5): 377-
81.
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.
Doorduin J et al. (2012) The calcium sensitizer levosimendan improves human diaphragm 
function. Am J Respir Crit Care Med. 185 (1): 90-5.
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. February 2016. 
https://www.nice.org.uk/guidance/NG42
Turner MR et al. (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet 
Neurol. 12 (3): 310-22.
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13. SUMMARY OF CHANGES TO AMENDMENT 1
13.1 Revision history
Protocol and amendments
Date
Applies to
Clinical study protocol
07 January 2019
Global
Amendment 1
26 March 2020
Global
Country specific amendments
Date
Applies to
Amendment 1
30 April 2019
Sweden
13.2 Summary of changes
The changes incorporated in this amended protocol from the original protocol dated 07 Jan 2019 are described in the following. The
modifications of the text are indicated by strikethrough (for deletions) and underline (for additions).
The following changes were made due to COVID-19 pandemic:
Section
Previous text
New text
Rationale for the change
6.5 Changes 
implemented due to 
COVID-19 
pandemic
-
Whole text is new, see the section 6.5.
New sections 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, header and footer sections were updated to reflect the version details of the current document
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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: open-label extension for patients completing study 
3119002 
NCT Number: 
NCT03948178 
Document Date: 
16 December 2020 
 


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STATISTICAL ANALYSIS PLAN
EFFECTS OF ORAL LEVOSIMENDAN (ODM-109) ON RESPIRATORY FUNCTION IN 
PATIENTS WITH ALS: OPEN-LABEL EXTENSION FOR PATIENTS COMPLETING 
STUDY 3119002
3119003
REFALS-ES
Phase III study
Standard: GCP
Sponsor: ORION PHARMA
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................... 2
ABBREVIATIONS.......................................................................................................................... 4
1.
GENERAL REMARKS........................................................................................................... 6
2.
OVERALL STUDY DESIGN AND PLAN................................................................................... 6
3.
STUDY OBJECTIVES............................................................................................................ 7
3.1
Primary objective......................................................................................................... 7
3.2
Secondary objectives ................................................................................................... 7
4.
STATISTICAL HYPOTHESES................................................................................................. 7
5.
DETERMINATION OF SAMPLE SIZE...................................................................................... 7
6.
GENERAL STATISTICAL CONSIDERATIONS.......................................................................... 7
6.1
Data sets to be analysed ............................................................................................... 7
6.2
Statistical issues ........................................................................................................... 7
6.2.1
Randomization ........................................................................................................ 7
6.2.2
Significance level and confidence intervals............................................................ 7
6.2.3
Multiplicity.............................................................................................................. 8
6.2.4
Intercurrent events................................................................................................... 8
6.2.5
Dropouts and missing data...................................................................................... 8
6.2.6
Outliers.................................................................................................................... 8
6.2.7
Baseline values........................................................................................................ 8
6.2.8
Multiple measurements ........................................................................................... 8
6.2.9
Multiple timepoints ................................................................................................. 8
6.2.10
Checking model assumptions.................................................................................. 8
6.2.11
Transformations ...................................................................................................... 8
6.2.12
Multicentre studies.................................................................................................. 8
6.2.13
Interim analyses and data monitoring ..................................................................... 9
6.2.14
Subgroups................................................................................................................ 9
6.2.15
Descriptive statistics................................................................................................ 9
7.
STATISTICAL ANALYSES..................................................................................................... 9
7.1
Disposition of subjects................................................................................................. 9
7.2
Demographic and other baseline characteristics........................................................ 10
7.3
Medical history .......................................................................................................... 11
7.4
Extent of exposure and treatment compliance........................................................... 11
7.5
Efficacy...................................................................................................................... 11
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7.5.1
Primary efficacy variable(s).................................................................................. 11
7.5.1.1
Slow Vital Capacity.......................................................................................... 11
7.5.2
Secondary efficacy variables................................................................................. 12
7.5.2.1
Revised ALS Functional Rating Scale ............................................................. 12
7.5.2.2
Time-to-event endpoints................................................................................... 13
7.5.2.3
Borg Category Ratio 10 Scale .......................................................................... 13
7.5.3
Additional variables .............................................................................................. 14
7.5.3.1
Health care and home care resource use........................................................... 14
7.5.4
Sensitivity analyses ............................................................................................... 14
7.6
Pharmacokinetics and pharmacodynamics ................................................................ 14
7.7
Pharmacogenomics .................................................................................................... 15
7.8
Exploratory biomarkers ............................................................................................. 15
7.9
Safety ......................................................................................................................... 15
7.9.1
Deaths.................................................................................................................... 15
7.9.2
Adverse events ...................................................................................................... 15
7.9.3
Laboratory values.................................................................................................. 17
7.9.4
12-lead ECG.......................................................................................................... 17
7.9.5
Vitals signs ............................................................................................................ 17
7.9.6
Physical findings and other observations.............................................................. 17
7.10
Additional analyses.................................................................................................... 18
7.10.1
Prior and concomitant treatments.......................................................................... 18
7.10.2
Suicidality.............................................................................................................. 18
7.10.3
COVID-19............................................................................................................. 18
7.10.4
Combined analyses with the main study............................................................... 18
7.11
Changes from the clinical study protocol .................................................................. 19
7.12
Execution of statistical analyses ................................................................................ 19
7.13
Software ..................................................................................................................... 19
8.
REFERENCES.................................................................................................................... 19
9.
REVISION HISTORY........................................................................................................... 20
10.
APPENDICES..................................................................................................................... 20
10.1
Medical history groups of interest ............................................................................. 20
10.2
Adverse events of special interest.............................................................................. 20
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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
FAS
Full analysis set
HR
Heart rate
IHSC
In-house search category
ITT
Intent-to-treat
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
NIV
Non-invasive mask ventilation
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PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per-protocol
PR
Pulse rate
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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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 an open, non-randomised, uncontrolled, multicentre phase III extension study to the 
REFALS study.
The subjects will give informed consent (IC) to continue in this open-label extension study at 
the 48-week or end-of-study visit of the REFALS (or between these visits). The REFALS end-
of-study visit will double as the REFALS-ES baseline visit. Visits to the study centre are 
flexible but occur at least every 3 months. Subject assessments will be conducted 2 weeks after 
starting the study treatment and after each change in the dose: such visits may be at study 
centre or conducted remotely where feasible (see section 6.1.3 in the protocol). A telephone 
contact will be performed for all subjects 6 weeks after starting the treatment.
The subject may continue the treatment as long as clinically indicated (see withdrawal criteria 
in section 4.5 in the protocol) or until the study ends.
An end-of-study visit will take place 14-25 days after the last study treatment administration 
for each subject. 
The study design is presented in Figure 1.
Figure 1. Study design
TC = telephone contact, EOS = end-of-study
1 Dose increased to 1 mg b.i.d. if the 1 mg/day dosing was well tolerated
2 Additional visit approx. 2 weeks after any dose change at visit 2
2 wks 
± 3 d
14-25 days
Visit 1
Baseline
Visit 21
Visit 32
Visit 4
EOS visit
Visits at least every 3 
months, additional visit 
approx. 2 weeks after any 
dose change 
4 wks
± 3 d
TC
6 wks
± 3 d
Visit n
1 mg/day
EOS visit for 
REFALS study
                Treatment period
Post-treatment 
period
Maximum 2 mg/day
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3.
STUDY OBJECTIVES
3.1
Primary objective
The primary objective, in addition to continuing treatment for subjects in REFALS study, is to 
evaluate long-term safety of oral levosimendan in ALS patients.
3.2
Secondary objectives
The secondary objective is to explore long-term effectiveness of oral levosimendan in the 
treatment of patients with ALS, by continuing to observe rate of disease progression during the 
treatment.
4.
STATISTICAL HYPOTHESES
No formal statistical hypotheses are specified.
5.
DETERMINATION OF SAMPLE SIZE
No sample size estimation is done. The maximum number of participants is bounded by the 
number of subjects completing REFALS.
6.
GENERAL STATISTICAL CONSIDERATIONS
6.1
Data sets to be analysed
All analyses will be performed in the safety population, including subjects who receive at least 
1 dose of study treatment. No other analysis populations are planned.
6.2
Statistical issues
6.2.1
Randomization
No randomization is done in the extension study. Subjects were randomized to either 
levosimendan or placebo in a 2:1 ratio for the main study. That randomization will be used for 
reporting this study, dividing subjects into arms having received prior levosimendan or 
placebo.
6.2.2
Significance level and confidence intervals
Not applicable. There are no formal hypothesis tests.
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6.2.3
Multiplicity
No adjustment for multiplicity is planned.
6.2.4
Intercurrent events
Not applicable.
6.2.5
Dropouts and missing data
Analyses are performed without missing data handling, in a complete-case manner.
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.
6.2.7
Baseline values
Planned pre-dose values from the baseline visit (which can be either the REFALS end-of-study 
visit or a separate baseline visit specifically for this study) are used as baseline values.
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.
If there are multiple measurements for a given parameter-visit-timepoint combination, values 
from the measurement that was performed last will be used.
6.2.9
Multiple timepoints
Visits following the Week 2 (and possible Week 4) site visit(s) and the Week 6 TC will be 
binned based on time elapsed since the baseline visit; visits falling into the same interval of 
time will be given the same label for reporting. The binning will be done on a monthly level, 
with visit days rounded to the nearest full month, using a conversion factor of 1 month = 
30.4375 days.
6.2.10 Checking model assumptions
Not applicable.
6.2.11 Transformations
No data transformations are planned.
6.2.12 Multicentre studies
Subject disposition will be tabulated by centre. No additional reporting by centre will be done.
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6.2.13 Interim analyses and data monitoring
None planned.
6.2.14 Subgroups
Summary of AEs and AESIs will be presented in the subgroups of: age; sex; race; BMI; 
acetylation status; and baseline medical history groups of interest (see 7.3).
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.
7.
STATISTICAL ANALYSES
The subject’s assigned arm from REFALS will be used when reporting by treatment group.
7.1
Disposition of subjects
329 subjects completed the REFALS study. Of those, 28 were ineligible to continue to the 
extension study, and 54 otherwise eligible subjects did not wish to continue. Of the remaining 
247 subjects who wished to continue, 20 were delayed due to COVID-19 related restrictions, 
and did not start the study before the recruitment was closed. In total, 227 subjects were 
screened and started the extension.
The number of subjects will be tabulated by treatment group for the following populations:
-
Screened population
-
Safety population
-
Discontinued 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 and study 
discontinuations, will be listed and tabulated by treatment group. 
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7.2
Demographic and other baseline characteristics
Descriptive statistics (see 6.2.15) of demographic and other baseline characteristics will be 
tabulated for the safety population, 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. El Escorial criteria for ALS diagnosis
14. Disease duration (time from symptom onset to baseline)
15. Below median disease duration (time from symptom onset to baseline)
16. Time from symptom onset to baseline (observed tertiles)
17. Time from symptom onset to baseline (observed quartiles)
18. Acetylation status (slow, rapid; see 7.7)
19. Acetylation status (4 groups; see 7.7)
20. Cardiac or vascular abnormality (see 7.3)
21. Ischaemic heart disease (see 7.3)
22. Cardiac arrhythmias (see 7.3)
23. Cardiac failure (see 7.3)
24. SVC (sitting) at baseline
25. Below median SVC (sitting) at baseline
26. SVC (supine) at baseline
27. Below median SVC (supine) at baseline
28. King’s clinical stage at baseline (see 7.5.2.1)
29. ALSFRS-R at baseline
30. Below median ALSFRS-R at baseline
31. ALSFRS-R bulbar subdomain at baseline
32. ALSFRS-R fine motor subdomain at baseline
33. ALSFRS-R gross motor subdomain at baseline
34. ALSFRS-R respiratory subdomain at baseline
35. ALS progression rate at baseline
36. ALS progression rate at baseline (< 1 point/month, ≥1 point/month)
37. ALS progression rate at baseline (observed tertiles)
Values for the above variables will be summarized also at REFALS baseline as part of the 
additional combined reporting described in 7.10.4.
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7.3
Medical history
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.1. Descriptive statistics will be provided by body system organ class 
(SOC), and preferred term (PT), 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:
1. Cardiac or vascular abnormality
2. Ischaemic heart disease (SMQ)
3. Cardiac arrhythmias (SMQ)
4. Cardiac failure (SMQ)
Both past and present findings at 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”)
4) downtitrated to 0.5 mg directly (“decreased directly”).
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
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 
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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 the sitting and supine position once at each centre visit during the 
study including the baseline (visit 1), i.e. in the morning before the study treatment 
administration. The MasterScope (used in the REFALS study) with centralised reading will be 
used in all study centre visits during the first 3 months (so that all subjects have at least 1 post-
baseline assessment with the device), after which each centre will either use its own standard 
pulmonary function test equipment or continue using the MasterScope without centralised 
reading. At baseline (visit 1), the SVC will be assessed by using both MasterScope and the 
local equipment.
Descriptive statistics will be reported by treatment group for SVC in both supine and sitting 
positions (including original values, and change from baseline) at each study visit. For supine 
SVC, descriptive statistics will also be further broken down by angle of measurement.
Slope of decline will be estimated for both treatment groups, using a random slope model for 
change from baseline. To facilitate comparison with the main study, the model will be adjusted 
for REFALS randomization strata, and include the baseline measurement as a covariate.
Measurements made with local devices (or MasterScope without centralised reading) and 
MasterScope devices with centralised reading will be reported separately, along with a third 
combined measurement which includes measurements from either type of device, preferring 
the MasterScope measurement with centralised reading if both are present on a given visit.
Measurements of unacceptable quality (BTRGRCD = “U”) will be excluded from reporting.
7.5.2
Secondary efficacy variables
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.
Descriptive statistics will be reported by treatment group for all items in the scale, as well as 
each subdomain and the total scale at each study visit (original values, and change from 
baseline).
Slope of decline will be estimated for both treatment groups, using a random slope model for 
change from baseline. To facilitate comparison with the main study, the model will be adjusted 
for REFALS randomization strata, and include the baseline measurement as a covariate.
Further, time to decline from baseline in an ALSFRS-R respiratory domain score (items 10–
12) will be described (see 7.5.2.2).
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To describe the study population, 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 status at baseline.
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
Time-to-event endpoints
The following time-to-event secondary efficacy variables will be evaluated:
1. Time to NIV or death (NIVDEATH)
2. Time to decline from baseline in any ALSFRS-R respiratory domain score (FRSBR1D)
The data for the time-to-event variables will be stored in the ADTTE dataset with parameter 
names corresponding to those in parentheses above.
Premature discontinuations will be treated as right-censored in the analyses. Censoring rules 
for different scenarios are described in Table 1. For the purpose 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 descriptive purposes, Kaplan-Meier survival curves will be plotted.
7.5.2.3
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.
Descriptive statistics for all Borg CR10 variables (original values, and change from baseline) 
will be reported by treatment group for each study visit.
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Table 1. Censoring rules for time-to-event analyses.
Scenario
Censored
End date
Event criteria fulfilled
No
Date of endpoint assessment
Event criteria fulfilled at baseline
Yes
Date of baseline visit
Event criteria never assessed
Yes
Date of baseline visit
Discontinued study
Yes
Date of last endpoint assessment
Discontinued study treatment (1 day 
after*)
Yes
Date of last endpoint assessment
Died, when death not part of event criteria
Yes
Date of last endpoint assessment
Died, when death is part of event criteria
No
Date of death
*) to account for potential events following immediately after the study treatment 
discontinuation.
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.
7.5.4
Sensitivity analyses
None planned.
7.6
Pharmacokinetics and pharmacodynamics
None planned. Blood samples were not collected.
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7.7
Pharmacogenomics
Acetylation status was determined by bioanalytics in the main study, 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 
safety.
7.8
Exploratory biomarkers
None pre-planned for the clinical study report.
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 treatment or within 25 days of stopping, or later.
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 23.1.
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
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. Dose change groups (see 7.4)
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Incidence rates for subjects’ 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. Asthenia or fatigue
2. Decrease in red cell parameters
3. Drug related hepatic disorders - comprehensive search (SMQ)
4. Haemorrhages (SMQ)
5. Headache
6. Hypokalaemia (SMQ)
7. Hypotension
8. Increased heart rate
9. Ischaemic heart disease (SMQ)
10. Neurocognitive disorder
11. Palpitations
12. Suicide/self-injury (SMQ)
13. Supraventricular tachyarrhythmias (SMQ)
14. 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
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.
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7.9.3
Laboratory values
Laboratory variables are not collected as part of the regular study visits. However, baseline 
values from the REFALS end-of-study visit will be summarised with descriptive statistics. See 
REFALS SAP for further definitions.
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.
Disjoint comparisons of heart rate changes from baseline to the thresholds of > 20 bpm and > 
30 bpm will be summarised by treatment group at each study visit.
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 position) will be tabulated by treatment group for each study 
visit.
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

diastolic blood pressure:
o
< 60 mmHg and a decrease of ≥ 20 mmHg
o
> 90–100 mmHg and an increase of ≥ 20 mmHg
o
> 100 mmHg and an increase of ≥ 20 mmHg

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%
7.9.6
Physical findings and other observations
Special situations and physical examination findings will be summarised by treatment group
using descriptive statistics.
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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 prior (started before baseline) and concomitant (ongoing at end of follow-up, or 
stopped after baseline) treatments will be summarised by pharmacological subgroup and 
chemical substance.
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.
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. 
7.10.4 Combined analyses with the main study
Additional analyses combining the data collected in REFALS with the data collected in 
REFALS-ES will be performed outside the scope of the clinical study report. This section 
outlines the currently planned analyses.
The primary population used for combined reporting will be the REFALS safety population. 
REFALS study baseline characteristics will be reported for the REFALS-ES safety population.
Descriptive statistics for change from REFALS baseline will be reported for supine SVC, 
ALFSFR-R and Borg endpoints, as well as vital signs (pulse rate, systolic and diastolic blood 
pressure).
Descriptive statistics for supine SVC and ALSFRS-R endpoints over the course of both studies 
will be reported in relevant efficacy subgroups identified in the REFALS study.
Random slope models will be fitted using data from both studies to estimate the rate of decline 
in supine SVC and ALSFSR-R endpoints over an extended follow-up period. A time-by-study-
by-arm interaction will be investigated to potentially identify a change in slopes for the 
placebo arm transitioning over to active treatment for REFALS-ES.
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Kaplan-Meier curves will be estimated for the time-to-event endpoints described in 7.5.2.2, 
and additionally time to invasive ventilation (tracheostomy or intubation) or death, and time to 
death. Estimation will start from the REFALS baseline and continue until the end of the 
extension study.
Adverse events and the number of deaths over the course of both studies will be summarised.
7.11 Changes from the clinical study protocol
Due to the results of the main study, and the consequent early termination of this extension 
study, the scope of reporting has been narrowed.
Most statistical analyses have been removed; instead, we report only descriptive statistics.
The analysis population is referred to as “safety population” rather than “full analysis set” for 
clarity, as the definition completely aligns with the safety population concept.
Protocol-defined reporting of REFALS baseline characteristics has been moved to additional 
analyses. Baseline characteristic reporting now reflects status at REFALS-ES baseline. 
7.12 Execution of statistical analyses
Statistical analyses will be performed by or under the supervision of Data Science 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).
8.
REFERENCES
Borg GA (1982) Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 14 (5): 
377-81.
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.
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.
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Statistical analysis plan 3119003
20 (20)
9.
REVISION HISTORY
Version
Date
Summary
0.19
2020-12-16
Cleaned up version for approval. No content changes.
0.18
2020-12-16
Revised based on comments reviewers. Primary change 
was to add additional combined analyses separately.
0.1
2020-12-04
Initial draft based on REFALS SAP.
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=0.2
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