Clinical trial NCT03541603
Conditions: Hypertension Pulmonary Secondary Heart Failure, Right Sided Heart Failure With Normal Ejection Fraction
Keywords: PH-HFpEF
Sponsor: Tenax Therapeutics, Inc.
Start date: 2018-11-14; Completion date: 2020-04-07
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2 study to evaluate the efficacy and safety of intermittent levosimendan compared with placebo in hemodynamic improvement with exercise in PH-HFpEF subjects

Detailed description:
Levosimendan and its prolonged active metabolite, OR-1896, have been shown to have favorable hemodynamic effects in subjects with pulmonary hypertension and right heart failure. Clinical studies that have been conducted in subjects with right heart failure and pulmonary hypertension suggest levosimendan may be an effective therapy in treatment of subjects with PH-HFpEF. This study will provide demonstration of levosimendan/OR-1896's effectiveness in critical measures of hemodynamic response in weekly administration of levosimendan and the concomitant response as measured by exercise capacity, subject quality of life, and changes in functional capacity. These data will support and guide the Phase 3 development of levosimendan in PH-HFpEF subjects.

Arms: arm 1: 0.075 - 0.1µg/kg/min for 24 hrs (weekly) arm 2: 0.075 - 0.1µg/kg/min for 24 hrs (weekly)
Interventions: intervention 1: Levosimendan intervention 2: Matching Placebo
Intervention descriptions: intervention 1: A sterile 2.5 mg/mL concentrate solution that is diluted in 5% Dextrose or 0.9 Normal Saline to achieve a 50 microgram/min solution for infusion intervention 2: A sterile 2.5mg/mL concentrate solution that is diluted in 5% Dextrose or 0.9 Normal Saline to achieve a 50 microgram/min solution for infusion

Protocol documents:
Prot_000.pdf: 
TNX-LVO-04; Version 4.0   15 May 2019 
PROTOCOL:  TNX-LVO-04 
TITLE: 
A Double-Blind, Randomized, Placebo-Controlled Study of 
Levosimendan in Pulmonary Hypertension Patients with Heart 
Failure and Preserved Left Ventricular Ejection Fraction (PH-
HFpEF) 
DRUG: 
Levosimendan (Simdax) Injection  
IND NUMBER: 
NCT NUMBER: 
IND 47,025 
NCT03541603 
SPONSOR*: 
Tenax Therapeutics, Inc. 
One Copley Parkway 
Morrisville, NC 27560 
info@tenaxthera.com 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
Stuart Rich, MD 
Professor of Medicine, Northwestern U. Feinberg School of Medicine; 
Director, Pulmonary Vascular Disease Program 
PROTOCOL 
VERSION AND 
DATE: 
Version 4.0, 15 May 2019 
*Tenax Therapeutics, Inc. (Tenax): The term “Sponsor” is used throughout the protocol to represent this legal
entity.
This study will be conducted under Food & Drug Administration IND regulations (21 CFR Part 312). 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 


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PROTOCOL SIGNATURE PAGE 
Sponsor’s Approval   
Signature: 
Date: 
May 15, 2019 
Kevin Crawford, MS 
Associate Director, Clinical Operations 
Tenax Therapeutics, Inc 
Signature: 
Douglas Hay. PhD 
EVP, Regulatory Affairs 
Tenax Therapeutics, Inc 
Principal Investigator’s Approval   
Signature: 
Date:
May 15, 2019 
Stuart Rich, MD 
Professor of Medicine, Northwestern U. Feinberg School of 
Medicine; Director, Pulmonary Vascular Disease Program 
Date: 
May 15, 2019 


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15 May 2019  
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TNX-LVO-04; Version 4.0   15 May 2019  
Investigator’s Acknowledgement 
I have read this protocol no. TNX-LVO-04 
Title:  A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in 
Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular 
Ejection Fraction (PH-HFpEF) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the Sponsor.  It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an Investigator for this study to be terminated. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from the study I will communicate my intention immediately in 
writing to the Sponsor. 
 
 
 
 
 
Name of Principal Investigator 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 


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LIST OF STUDY CONTACTS 
Study Sponsor: 
Tenax Therapeutics, Inc. 
One Copley Parkway 
Morrisville, NC 27560 
Kevin M. Crawford, MS, CCRA 
Associate Director of Clinical Operations 
Telephone: (919) 855-2145 
Fax: (919) 855-2133 
k.crawford@tenaxthera.com 
 
Medical Monitor: 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
 
Medpace, Inc. 
Telephone: (513) 579-9911 
Fax: (513) 579-0444 
E-mail:medpace-
safetynotification@medpace.com 
 
SAE Reporting: 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
 
Medpace SAE hotline 
Telephone: (800) 730-5779, dial “3” or 
(513) 579-9911, dial “3” 
Fax: (866) 336-5320 or (513) 570-5196 
E-mail: medpace-
safetynotification@medpace.com 
 
  


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................. 2 
LIST OF STUDY CONTACTS ....................................................................................... 4 
ABBREVIATIONS ........................................................................................................ 10 
STUDY SYNOPSIS ....................................................................................................... 11 
TIME AND EVENTS SCHEDULE ............................................................................... 16 
1. 
BACKGROUND INFORMATION ................................................................... 18 
1.1 
Condition Background and Current Treatment .................................................. 18 
1.2 
Product Background ........................................................................................... 18 
1.2.1 
Preclinical Information ................................................................................ 19 
1.2.2 
Clinical Pharmacology ................................................................................. 19 
1.2.3 
Chronic Intermittent Studies of IV Levosimendan in Heart Failure and 
Pulmonary Hypertension Patients ................................................................ 20 
1.2.4 
Levosimendan Clinical Safety ..................................................................... 21 
1.2.5 
Rationale for Chronic Intermittent (weekly) Levosimendan for PH-HFpEF 
Patients ......................................................................................................... 22 
1.2.6 
Target Plasma Concentrations of OR-1896 in intermittent treatment of PH-
HFpEF Patients ............................................................................................ 23 
2. 
STUDY OBJECTIVES AND PURPOSE .......................................................... 24 
2.1 
Rationale for the Study ....................................................................................... 24 
2.2 
Study Objectives ................................................................................................. 24 
2.2.1 
Primary Objectives ...................................................................................... 24 
2.2.2 
Secondary Objectives .................................................................................. 24 
2.2.3 
Exploratory Objectives ................................................................................ 25 
3. 
STUDY DESIGN ............................................................................................... 25 
3.1 
Study Design ...................................................................................................... 25 
3.2 
Number and Type of Subjects ............................................................................ 26 
3.3 
Investigational Product ....................................................................................... 26 


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3.4 
Sites and Regions ............................................................................................... 27 
4. 
STUDY POPULATION ..................................................................................... 27 
4.1 
Inclusion Criteria ................................................................................................ 27 
4.2 
Exclusion Criteria ............................................................................................... 28 
4.3 
Restrictions ......................................................................................................... 30 
4.4 
Withdrawal of Subjects ...................................................................................... 30 
4.4.1 
Reasons for Discontinuation ........................................................................ 30 
4.4.2 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ........................ 31 
5. 
PRIOR AND CONCOMITANT TREATMENT ............................................... 31 
5.1 
Prior Treatment ................................................................................................... 31 
5.2 
Concomitant Treatment ...................................................................................... 31 
6. 
RANDOMIZATION .......................................................................................... 32 
6.1 
Allocation of Subjects to Treatment ................................................................... 32 
7. 
INVESTIGATIONAL PRODUCT .................................................................... 33 
7.1 
Levosimendan..................................................................................................... 33 
7.2 
Matching Placebo ............................................................................................... 33 
7.3 
Packaging ........................................................................................................... 33 
7.4 
Labeling .............................................................................................................. 33 
7.5 
Preparation and Handling ................................................................................... 34 
7.5.1 
Lead-in and Double-blind ............................................................................ 35 
7.5.2 
Dosage and Administration ......................................................................... 35 
7.5.3 
Dose Adjustment .......................................................................................... 36 
7.5.4 
Dose-limiting Events ................................................................................... 36 
7.5.5 
Blinding the Treatment Assignment ............................................................ 36 
7.5.6 
Unblinding the Treatment Assignment ........................................................ 37 
7.6 
Packaging, Storage, and Handling...................................................................... 37 
7.6.1 
Preparation and Handling ............................................................................ 37 
7.6.2 
Storage ......................................................................................................... 38 
7.7 
Investigational Product Quality Complaints ...................................................... 38 
7.8 
Drug Accountability ........................................................................................... 38 


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7.9 
Subject Compliance ............................................................................................ 39 
8. 
STUDY PROCEDURES .................................................................................... 39 
8.1 
Screening Visit (< 28 Days prior to Day 0) ........................................................ 40 
8.2 
Day 0 (Lead-in Infusion, Visit 1) ....................................................................... 41 
8.3 
Day 0 (Double-blind Randomization, Visit 1) ................................................... 42 
8.4 
Weeks 2-5 (Weekly Infusion Visits 2, 3, 4, and 5) ............................................ 43 
8.5 
Interim Office Visit (Between Weeks 3 and 4) .................................................. 43 
8.6 
Week 6 (Visit 6) ................................................................................................. 44 
8.7 
Early Termination ............................................................................................... 45 
8.8 
Open Label Extension ........................................................................................ 45 
8.9 
Study Evaluations and Procedures ..................................................................... 45 
8.9.1 
Demographic and Other Baseline Characteristics ....................................... 45 
8.9.2 
Efficacy Measures ........................................................................................ 45 
8.9.2.1 
Right Heart Catheterization ............................................................... 45 
8.9.2.2 
6-Minute Walk Test (6MWT) ........................................................... 46 
8.9.2.3 
Echocardiogram Complete with Contrast ......................................... 46 
8.9.3 
Safety, Pharmacokinetic, and Pharmacogenomic Assessments .................. 46 
8.9.3.1 
Medical and Medication History ....................................................... 47 
8.9.3.2 
Physical Examination (Including Height and Weight) ...................... 47 
8.9.3.3 
Adverse Event Collection .................................................................. 47 
8.9.3.4 
Vital Signs ......................................................................................... 47 
8.9.3.5 
Clinical Laboratory Evaluations ........................................................ 47 
8.9.3.6 
Pregnancy Test .................................................................................. 48 
8.9.3.7 
Electrocardiogram ............................................................................. 48 
8.9.3.8 
Clinical Pharmacology Assessments ................................................. 48 
8.9.3.9 
Pharmacogenomic Assessments ........................................................ 49 
8.9.3.10 Quality of Life Assessments .............................................................. 49 
8.10 
Retention of Testing Samples ............................................................................. 49 
9. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ................ 50 
9.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ................................................................................................................. 50 
9.1.1 
Severity Categorization ................................................................................ 50 
9.1.2 
Relationship Categorization ......................................................................... 51 
9.1.3 
Outcome Categorization .............................................................................. 51 


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9.1.4 
Symptoms of the Disease Under Study ....................................................... 51 
9.1.5 
Study-specific Events of Interest ................................................................. 52 
9.1.6 
Clinical Laboratory Evaluations .................................................................. 53 
9.1.7 
Pregnancy ..................................................................................................... 53 
9.1.8 
Abuse, Misuse, Overdose, and Medication Error ........................................ 54 
9.2 
Serious Adverse Event Procedures ..................................................................... 55 
9.2.1 
Reference Safety Information ...................................................................... 55 
9.2.2 
Reporting Procedures ................................................................................... 55 
9.2.3 
Serious Adverse Event Definition ............................................................... 56 
9.2.4 
Serious Adverse Event Onset and Resolution Dates ................................... 56 
9.2.5 
Fatal Outcome .............................................................................................. 57 
9.2.6 
Regulatory Agency, Institutional Review Board, and Site Reporting ......... 57 
9.2.7 
Serious Adverse Event Collection Timeframe ............................................ 57 
10. 
DATA MANAGEMENT AND STATISTICAL METHODS ........................... 57 
10.1 
Data Collection ................................................................................................... 57 
10.2 
Clinical Data Management ................................................................................. 58 
10.3 
Statistical Analysis Process ................................................................................ 58 
10.4 
Selection of Subjects to be Included in the Analyses ......................................... 58 
10.5 
Subject Disposition ............................................................................................. 59 
10.6 
Demographic and Baseline Characteristics ........................................................ 59 
10.7 
Investigational Product Exposure ....................................................................... 59 
10.8 
Prior and Concomitant Medication .................................................................... 59 
10.9 
Efficacy Analyses ............................................................................................... 60 
10.9.1 Primary Efficacy Variable ........................................................................... 60 
10.9.2 Secondary Efficacy Variables ...................................................................... 60 
10.9.3 Exploratory Efficacy Variables ................................................................... 61 
10.10 Safety Analyses .................................................................................................. 61 
10.11 Pharmacokinetic Collection and Analyses ......................................................... 61 
10.12 Sample Size Calculation and Power Considerations .......................................... 61 
11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ....................... 61 
11.1 
Sponsor’s Responsibilities.................................................................................. 62 


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11.1.1 Good Clinical Practice Compliance ............................................................. 62 
11.1.2 Public Posting of Study Information ........................................................... 62 
11.1.3 Study Suspension, Termination, and Completion ....................................... 62 
11.2 
Investigator’s Responsibilities............................................................................ 62 
11.2.1 Good Clinical Practice Compliance ............................................................. 62 
11.2.2 Protocol Adherence and Investigator Agreement ........................................ 63 
11.2.3 Documentation and Retention of Records ................................................... 63 
11.2.3.1 Case Report Forms ............................................................................ 63 
11.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents ......................................................................................... 64 
11.2.3.3 Audit/Inspection ................................................................................ 64 
11.2.3.4 Financial Disclosure .......................................................................... 64 
11.3 
Ethical Considerations ........................................................................................ 65 
11.3.1 Informed Consent ........................................................................................ 65 
11.3.2 Institutional Review Board .......................................................................... 65 
11.4 
Privacy and Confidentiality ................................................................................ 66 
11.5 
Publication Policy ............................................................................................... 66 
12. 
REFERENCES ................................................................................................... 67 
13. 
APPENDICES .................................................................................................... 71 
13.1 
APPENDIX 1: Summary of Changes to Previous Protocol Amendments......... 71 
14. 
ATTACHMENTS .............................................................................................. 82 
14.1 
ATTACHMENT 1: Study Drug Dose and Dosing Table .................................. 83 
14.2 
ATTACHMENT 2: Diagnosis of Pulmonary Hypertension .............................. 85 
14.3 
ATTACHMENT 3: Child-Pugh Classification .................................................. 86 
14.4 
ATTACHMENT 4: Likert Scale ........................................................................ 87 
14.5 
ATTACHMENT 5: Cardiac Event Recommendations and Management ......... 88 
14.6 
ATTACHMENT 6: Procedure for Right Heart Catheterization at Rest and With 
Exercise .............................................................................................................. 89 
  


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ABBREVIATIONS 
6MWT 
AE 
6-minute walk test 
adverse event 
 
ICH 
International Conference 
on Harmonization 
ANCOVA 
analysis of covariance 
 
IND 
Investigational New Drug 
BMI 
body mass index 
 
IRB 
Institutional Review Board 
BUN 
blood urea nitrogen 
 
ITT 
intention-to-treat 
CABG 
coronary artery bypass graft 
 
IWRS 
Interactive Web Response 
System 
CADD 
Continuous ambulatory 
delivery device 
 
IV 
intravenous 
CDER 
Center for Drug Evaluation 
and Research 
 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
CFR 
Code of Federal Regulations 
 
PCI 
Percutaneous coronary 
intervention 
CK 
Creatine kinase 
 
NDA 
New Drug Application 
Cmax 
maximum plasma 
concentration 
 
PD 
Pharmacodynamic 
Cmin 
minimum plasma 
concentration 
 
PH 
Pulmonary hypertension 
CRA 
Clinical Research Associate 
 
PK 
pharmacokinetic 
eCRF 
electronic Case Report Form 
 
PP 
per-protocol 
CRO 
Contract Research 
Organization 
 
QoL 
quality of life 
ECG 
electrocardiogram 
 
RBC 
red blood cell 
EMA 
European Medicines Agency 
 
SAE 
serious adverse event 
FDA 
Food and Drug 
Administration 
 
SAP 
Statistical Analysis Plan 
eGFR 
estimated glomerular 
filtration rate 
 
SBP 
systolic blood pressure 
GCP 
Good Clinical Practice 
 
SmPC 
Summary of Product 
Characteristics 
HCG 
human chorionic 
gonadotropin 
 
TAPSE 
Tricuspid annular plane 
systolic excursion 
HFpEF 
heart failure with preserved 
ejection fraction 
 
tmax 
time to maximum plasma 
concentration 
HIPAA 
Health Insurance Portability 
and Accountability Act 
 
TMF 
Trial Master File 
IB 
Investigator’s Brochure 
 
 
 
 
 
WBC 
white blood cell 


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STUDY SYNOPSIS 
Sponsor/Company 
Tenax Therapeutics, Inc. 
 
 
Finished product: 
Simdax (levosimendan) 
injection 
Active ingredient:  
(-)-(R)-[[4-(1,4,5,6-tetrahydro-
4-methyl-6-oxo-3-
pyridazinyl)phenyl]hydrazono] 
propanedinitrile 
Study code: TNX-LVO-04 
Date: 15 May 2019; Version 4.0 
Study title:  A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Patients 
with Pulmonary Hypertension with Heart Failure and Preserved Ejection Fraction (PH-HFpEF) 
Investigators and study centers: Multicenter study (target 20-25 sites in the United States) 
Development phase: 2 
Objectives: To evaluate the efficacy and safety of intermittent levosimendan compared with 
placebo in hemodynamic improvement with exercise in PH-HFpEF subjects. 
Methodology: Enrolled PH-HFpEF subjects will receive a lead-in 24-hour levosimendan infusion 
to determine their hemodynamic response and eligibility for the double-blind phase of the study. A 
total of 36 “responders” will be randomized in the double-blind, placebo-controlled phase. 
“Responders” will be identified as those subjects with a ≥4mmHg reduction in PCWP during 
bicycle exercise (25 watts) and no more than a 10% decrease in cardiac index between the baseline 
measurements and repeated measurements following the initial infusion.  Study drug will be 
administered via i.v. infusion over 24 hours weekly through Week 5 via a PICC line. Infusions 
(Week 2-5) will be done in the subject’s home by a study nurse. Patients will return to the study site 
for a visit between the Week 3 Week 4 infusions for assessment of subject safety/response and need 
for dose adjustment. Each subject will return on Week 6 for assessment of efficacy and safety on 
study drug.  A right heart catheter will be inserted to obtain hemodynamic measurements at rest and 
exercise at baseline, the following day after the lead-in 24-hour infusion, and during Week 6.    
All subjects randomized will have the opportunity to participate in an Open-label protocol 
extension. 
Sample size: During the Lead-in phase of the study, a sufficient number of subjects will be enrolled 
and receive levosimendan to identify a total of 36 ‘responders’.  The levosimendan ‘responders’ 
will be randomized 1:1, levosimendan or placebo, for the double-blind phase of the study.  
 
 


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Diagnosis and main criteria for inclusion and exclusion:  
Patients must meet the following criteria to be enrolled in the study: 
Inclusion Criteria: 
       Enrollment Criteria: 
1. Men or women, 18 years of age 
2. Confirmed diagnosis of WHO Group 2 Pulmonary Hypertension (PH) with heart failure 
and preserved ejection fraction (HFpEF). 
3. WHO Group 2 Pulmonary Hypertension subjects with heart failure and preserved ejection 
fraction as defined by: 
a. 
Mean pulmonary arterial pressure (mPAP) >35 mmHg at rest or with legs up (at 
baseline right heart catheter/Lead-In) 
b. Pulmonary capillary wedge pressure (PCWP) ≥20 mmHg at rest or with legs up 
(at baseline right heart catheter/Lead-In) 
c. 
NYHA Class II or III  
d. LVEF ≥40% by echocardiogram within three months of enrollment with no 
change in clinical status suggesting the potential for deterioration in systolic 
function 
4. Signed (by the subjects or their legally acceptable representatives) informed consent 
document indicating that they understand the purpose of and procedures required for the 
study and are willing to participate in the study. 
5. Ability to walk at least 50 meters, but not more than 550 meters in a six-minute walk test. 
6. Long term oxygen treatment (if applicable) must be stable for 30 days prior to enrollment. 
7. Subjects on a chronic medication or therapy for any underlying cardiac condition must be 
on a stable dose for ≥30 days prior to randomization, with the exception of diuretics and 
antihypertensive medication for blood pressure control which may be discontinued if 
deemed appropriate. 
8. Subjects on chronic medications for any underlying respiratory condition must be on a 
stable dose for ≥30 days prior to randomization 
 
Note:  With regard to Inclusion Criteria 6-8, “stable” refers to changes in oxygenation therapy 
or medications no greater than a 100% increase or a 50% decrease, as needed to optimize the 
patient. 
 
 


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       Randomization Criterion:  
9. Response to Lead-in Levosimendan:  Patients who demonstrate a ≥4mmHg reduction in 
PCWP from baseline measured during bicycle exercise (25 watts) with no more than a 
10% decrease from baseline in cardiac index following the 24-hr infusion of 
levosimendan.                           
 
Exclusion Criteria: 
1. Previous PCI or cardiac surgery (CABG) unless documented to have a negative stress test 
within the last 12 months. 
2. Clinically symptomatic mitral or aortic valvular heart disease. 
3. Cardiac index greater than 4.0 L/min/m2 
4. In the opinion of the Principal Investigator, the subject has a primary diagnosis of PH other 
than WHO Group 2 PH-HFpEF 
5. Congenital heart disease other than surgically corrected pre and post tricuspid shunts for at 
least 5 years  
6. Symptomatic coronary artery disease based on a positive stress test. 
7. Patients planning lung or heart transplant; or cardiac surgery in the next 4 months 
8. Patients diagnosed with pulmonary hypertension associated with clinically significant lung 
disease at the time of initial diagnosis, or patients with a congenital defect of the lung. 
a. 
Clinically significant obstructive lung disease is defined as FEV1/FVC <60% of 
predicted, unless a high resolution chest CT scan shows no more than mild areas 
of emphysematous changes. 
b. Clinically significant restrictive lung disease is defined as a FVC of <60% of 
predicted, unless a high resolution chest CT scan shows no more than mild areas 
of interstitial lung disease or pulmonary fibrosis. 
9. Dialysis at randomization (either hemodialysis, peritoneal dialysis, continuous venovenous 
hemofiltration, or ultrafiltration) 
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
11. Liver dysfunction with Child Pugh Class B or C (see Attachment 3) 
12. Evidence of systemic bacterial, systemic fungal, or viral infection in last 2 weeks 
13. Weight >150 kg 
14. Symptomatic low systolic blood pressure (SBP) that cannot be managed to ensure 
SBP > 100 mmHg at initiation of study drug  


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15. Heart rate  100 bpm with study drug, symptomatic and persistent for at least 10 minutes 
at Lead-in. 
16. Hemoglobin < 80 g/L 
17. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline 
18. Pregnant, suspected to be pregnant, or breast-feeding 
19. Known allergic reaction or sensitivity to levosimendan or excipients. 
20. A history of Torsades de Pointes 
21. Received levosimendan within 30 days before the planned start of study drug 
22. Received an experimental drug or used an experimental medical device within 30 days 
before the planned start of study drug 
23. Concomitant administration of pulmonary vasodilator therapy, or taken within 14 days of 
randomization 
24. Employees of the investigator or study center, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study center, as well as 
family members of the employees or the investigator 
25. Inability to comply with planned study procedures 
Investigational product, dose and mode of administration:  
Lead-in Phase 
Levosimendan, supplied as a concentrated solution (2.5 mg/mL), will be mixed with diluent and 
administered intravenously at 0.10 µg/kg/min for 24 hours ±30 min.     
Double-blind Phase 
Study drug concentrated solution (2.5 mg/mL), levosimendan or placebo, will be mixed with 
diluent and administered via a PICC line as weekly infusions at 0.075 µg/kg/min for 24 hrs.  
Patients will have a dose escalation between Weeks 4 and 5 (0.10 µg/kg/min for 24 hrs) unless 
there has been a meaningful change in blood pressure or heart rate (Attachment 5). Infusion rates 
may be reduced to 0.05 µg/kg/min if the higher dose is not well-tolerated at any time during the 
initial 5 weeks.   
Concomitant Therapy:   All subjects must be optimally managed on diuretics and oxygen therapy 
as indicated by standard of care. Concomitant administration of pulmonary vasodilators is NOT 
permitted. Patients must not have taken any pulmonary vasodilators within 30 days of enrolment. 
Duration of treatment: The first 36 subjects responding to the open-label lead-in 24-hour 0.10 
µg/kg/min levosimendan infusion, in the absence of significant hypotension or tachycardia, will be 
randomized to levosimendan or placebo (1:1). A PICC line will be placed prior to randomization.   
Randomized subjects will receive weekly home infusions of study drug on Week 2 and 3 at 0.075 
µg/kg/min for 24 hours. Patients will have a dose escalation between Weeks 4 and 5 (0.10 
µg/kg/min for 24 hrs) unless there has been a meaningful change in blood pressure or heart rate. 


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Reference product, dose and mode of administration: Matching placebo. 
Criteria for Evaluation:  
Primary Endpoint:     
• 
Change from baseline PCWP during bicycle exercise (25 watts) at Week 6 
Secondary Endpoints: 
• 
Change in Cardiac Index at rest and with exercise at Week 6 
• 
Change in PVR effect at rest and with exercise at Week 6 
• 
Change in PCWP when supine and legs elevated at Week 6 
• 
Patient global assessment (based on a six-point Likert scale) at Week 6  
• 
Exercise duration 6-min walk test at Week 6 
• 
Physician’s Assessment of Functional Class 
• 
Clinical Events:  Death and hospitalizations  
Exploratory Endpoint: 
• 
Change in echo measurements of RV size and TAPSE 
Evaluation and statistical methods:  
A total of 36 randomized subjects (at 1:1 levosimendan vs. placebo) will provide >80% power to 
detect the difference at two-sided 0.05 level, assuming a SD=5mmHg in PCWP and a treatment 
difference of ≥4.81 mmHg.  
The primary analysis will be on the Full Analysis Set, defined as those subjects that received study 
drug and completed their Week 6 office visit.  Hemodynamic responses during the initial lead-in 
infusion will be summarized using descriptive statistics for all subjects receiving levosimendan and 
in PH-HFpEF subgroups. 
The hemodynamic variables will be analyzed using ANCOVA with effects for treatment and 
investigative site.   A sensitivity analysis will include an adjustment for baseline.   An additional 
analysis will be performed on the per protocol set that completed the study without major protocol 
deviations.    
All secondary analyses will be performed in the Full Analysis Set and PP Analysis Set.   Exercise 
tolerance differences will be tested using an ANOVA with effects for treatment and investigative site.  
Treatment differences in the Patients response identified by Likert Scale will be analyzed by a Mann–
Whitney–Wilcoxon test.   


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TIME AND EVENTS SCHEDULE 
 
Study Phase/ 
Event 
 
Screening 
Lead-In 
Infusion 
Weeks 2-5 
(+ 48 hrs.) 
 
Interim Office 
Visit 
 
Week 6 
(3-6 days following 
completion of the  
Week 5 infusion.) 
 
< 28 Days 
Prior to Day 0 
Day 0 
(Visit 1)15 
Weekly Infusion 
(Visit 2, 3, 4, 5)11, 15  
Between Week 3 
and Week 412 
Office Visit 
(Visit 6)11  
Informed Consent 
X 
 
 
 
 
Inclusion / Exclusion 
X 
 
 
 
 
History of Qualifying Hemodynamics  
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Examination 
X 
 
 
 
 
Body Weight 
X 
X 
 
X 
 
Urine Pregnancy Test1 
X 
 
 
 
 
Serum Chemistry & Hematology –  
Local Lab 
X 
 
 
 
X 
Child Pugh Class 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
Electrocardiogram (EKG) 
X 
 
 
 
X 
Echocardiography2  
X 
 
 
 
X 
Lead-in Dose3 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Study Drug Administration4 
 
 
X 
 
 
Right Heart Cath and Hemodynamics5 
 
X 
 
 
X 
PICC line insertion6 
 
X 
 
 
 
Dose Escalation 
 
 
X13 
 
 
Quality of Life (Likert)7 
 
 
 
X 
X 
NYHA Functional Class  
X 
 
 
X 
X 
6 - Minute Walk Test8 
X 
 
 
X 
X 
Adverse Events/SAEs 
X 
X 
X 
X 
X 
Concomitant Procedures 
 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
PK Sample9 
 
X 
 
 
X 
Genotyping Sample10 
 
X 
 
 
 
Arrhythmia Monitoring 
X14 
 
X14 
 
 
 


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Footnotes for Time and Events Schedule 
 
1. Pregnancy tests for women of childbearing potential only. Additional serum or urine pregnancy testing 
may be performed as required by local regulations (if performed, pregnancy tests must be negative for 
subjects to continue in the study). Pregnancy test results must be available before study drug 
administration. 
2. Echocardiography or measurement of ventricles.  
3. Lead-in dose may be performed on same day as Screening Visit procedures. 
4. Week 2, 3, 4, and 5. Confirm that the subject’s diuretic dose has remained consistent in the last week. 
5. Invasive hemodynamics will be assessed via a right heart catheter.  A Swan-Ganz catheter will be 
inserted via the internal jugular (right or left) or subclavian vein (right or left).  Hemodynamic 
measurements and determinations include: cardiac index (CI), cardiac output (CO), mean pulmonary 
artery pressure (mPAP), and pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP, 
pulmonary vascular resistance (PVR), stroke volume index (SVI), stroke volume (SV). Measurements 
will be taken initially when the subject is supine, legs elevated and at supine bicycle exercise (25 watts).  
A levosimendan-treated subject will be identified as a responder if there is a 4mmHg reduction in 
PCWP (with the cardiac index the same or increased) at the end of the 24-hr acute infusion. (see 
Attachment 6) 
6. PICC line insertion will occur only for those patients randomized to the double-blind portion of the 
study 
7. Likert Scale should be completed at Interim Office Visit and at Week 6 
8. 6-min walk test will be conducted according to ATS Statement: Guidelines for the Six-Minute Walk 
Test 
9. Blood samples will be taken at the end of study drug infusion (24 ± 2 hours).  An additional sample for 
pharmacokinetic analysis will be collected at Week 6 or upon termination from the study, whichever 
comes first.  PK samples will be sent to a central laboratory. A separate blood sample will be collected 
for acetylation status genotyping at the end of study drug infusion. 
10. Blood sample will be collected for analysis of acetylation status. No further testing on these samples 
will be conducted 
11. Visits at Weeks 2, 3, 4, 5, and 6 should occur within +48 hours of the scheduled visit (section 8.4).  
12. This office should occur within 48 hours prior to the Week 4 infusion for assessment of performance 
and safety (see section 8.5). 
13. Subjects will have a dose escalation between Weeks 4 and 5 (0.10 µg/kg/min for 24 hrs.) unless there 
has been a meaningful change in blood pressure or heart rate (Attachment 5). The home health care 
nurse will be notified by the site to confirm up-titration or any dose adjustments.  
14. Arrhythmia monitoring will be performed at Screening and Week 5. An electronic monitoring device 
will be applied for approximately 72 hours prior to the Lead-In dose. At Week 5, the device is to be 
applied prior to (< 1 hour) the 24-hour infusion and will collect data over the following 72 hours 
(approximately). 
15. Subjects who receive levosimendan during the Lead-In dose but are not randomized into the trial, will 
be followed for safety for 2 weeks post end of 24-hour infusion. A phone contact will be made to the 
subject at 24 hours, 7 days, and 14 days post infusion by investigational site personnel to assess adverse 
events. Please see section 8.7 for further details regarding subjects who terminate the study early. 
 
 


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1. 
BACKGROUND INFORMATION 
1.1 
Condition Background and Current Treatment  
Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart 
failure, representing about 50% of all heart failure cases and increasing out of proportion to the 
incidence of heart failure characterized by reduced left ventricular ejection fraction. (1)  
Sustained elevations in left atrial pressure cause pulmonary venous congestion which often 
leads to elevation of pulmonary pressures leading to severe right ventricular failure with a low 
cardiac output, edema, hypoxemia, and severely limited exercise capacity. (2)  Pulmonary 
hypertension (PH) in subjects with heart failure and preserved ejection fraction (PH-HFpEF) is 
a common form of pulmonary hypertension and has an estimated US prevalence exceeding 1.5 
million. (3) 
 PH-HFpEF has been classified within Group II of the WHO clinical classification of PH, 
characterized by PH arising from left heart disease. (4,5,6).  Regardless of the basis of left heart 
disease, PH initially develops from a passive backward transmission of filling pressures, mainly 
driven by left ventricular (LV) diastolic function, resulting in a chronic increase in left atrial 
pressure and a loss of left atrial compliance. These mechanical components of pulmonary 
venous congestion may trigger pulmonary vasoconstriction, decreased nitric oxide (NO) 
availability, increased endothelin expression, desensitization to natriuretic peptide-induced 
vasodilation, and vascular remodeling.   Finally, these changes often lead to advanced 
pulmonary vascular disease, increased right ventricle (RV) afterload, and RV failure.  PH-
HFpEF is defined hemodynamically by a pulmonary artery pressure (mPAP) ≥25 mmHg, a 
pulmonary capillary wedge pressure (PCWP) >15 mmHg, and a diastolic pressure gradient 
[diastolic PAP – PCWP] >7mmHg. (7) 
In clinical trials of HFpEF, pharmacologic treatment has been largely neutral; only exercise 
training and weight loss appear to improve exercise intolerance and quality of life. (8) ESC 
guidelines in the treatment of PH-HFpEF subjects acknowledge that the accepted treatment 
target is a reduction of pulmonary wedge pressures using diuretics for congestion. However, 
clinical studies have demonstrated neutral results with identified concerns that PH-targeted 
therapies could have detrimental effects due to rapid increases in LV filling pressures, resulting 
in acute pulmonary edema.  Thus, the ESC guidelines specify that there are currently no 
established strategies to treat pulmonary vascular disease (PVD) and right ventricular disease 
(RVD) in HFpEF, with a recommendation (class III) not to use approved PAH treatments in 
PH-HFpEF subjects. (4,9).  With no demonstrated effective therapy, these subjects have a poor 
outcome (5 yr. survival <50%, frequent hospitalizations). (10)   
1.2 
Product Background 
Levosimendan is a calcium sensitizer and potassium channel activator drug approved in over 
60 countries for intravenous use in hospitalized subjects with acutely decompensated heart 
failure (ADHF).  Approximately 1.5 million subjects have been treated with levosimendan 
worldwide by the end of December 2017.   


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A complete summary of the vast preclinical and clinical information in support of 
levosimendan’ s pharmacological effects, efficacy and safety is included in the Levosimendan 
(Simdax) Investigator’s Brochure (IB).  
1.2.1 
Preclinical Information 
Levosimendan’s activity is mediated through unique mechanisms of action, including:  
• Increased cardiac contractility by calcium sensitization of troponin C. (11-14) 
• Vasodilation through the opening of potassium channels. (15-18) 
• Cardioprotective effects via potassium channel opening in mitochondria. (19-22)     
 
Levosimendan has an active metabolite that extends its effects well beyond the infusion 
period.    Following intravenous or oral dosing, levosimendan is reduced by intestinal bacteria 
to form OR-1855 (limited activity) that is acetylated to form OR-1896, an active metabolite.  
While the parent half-life is approximately 1 hour and cleared a few hours after the end of 
intravenous infusion, OR-1896 has a prolonged half-life of 70-80 hours in heart failure 
subjects with roughly equal exposures of OR-1855 and OR-1896 maintained through 
deacetylation/ acetylation pathways.  The OR-1896 metabolite has been shown to retain 
similar hemodynamic and pharmacologic properties of levosimendan and maintain roughly 
equivalent effects to levosimendan in preclinical models.  This activity occurs despite 
considerably lower plasma concentrations relative to levosimendan, an apparent result of a 
large percentage of unbound OR-1896 in circulation. (22-27). Thus, in extended repeated 
dosing, levosimendan is essentially an active prodrug to an active metabolite moiety, OR-
1896. 
 
Levosimendan has been shown to be a potent and selective phosphodiesterase-3 (PDE3) 
inhibitor in vitro.   The drug is PDE3 selective with a PDE3/PDE4 inhibition ratio of 10,000. 
(15, 49). However, both isozymes must be inhibited in cardiomyocytes to exert an effect on 
the cAMP concentration and inotropic effects.  The classical PDE inhibitors (i.e., milrinone, 
enoximone, and amrinone) inhibit both PDE3 and PDE4 at therapeutic concentrations (e.g., 
milrinone selectivity for PDE3 vs. PDE4 is as low as 17-fold), which accounts fully for their 
inotropic effect.   
 
OR-1896 is equipotent to levosimendan in its inotropic effects in whole cardiomyocytes and 
isolated contractile apparatus preparations.  However, OR-1896 is profoundly less potent in 
the inhibition of both PDE3 and PDE4 isozymes.  This supports the hypothesis that the main 
component of the inotropic effect for both levosimendan and OR-1896 is a result of their 
binding to troponin C and not through PDE inhibition. (49) 
1.2.2 
Clinical Pharmacology 
Clinical observations demonstrate that short-term levosimendan administration is followed by 
long-term hemodynamic changes that parallel the levels of OR-1896. (28)  Thus, OR-1896 
greatly extends the parent levosimendan’s activity and provides the primary active moiety in 
subjects receiving intermittent intravenous levosimendan therapy.  
 


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Clinical studies have demonstrated therapeutic benefits to subjects with left ventricular 
dysfunction following acute doses and intermittent doses of levosimendan.  These include: 
1. Sustained therapeutic effects following a single 24-hr infusion of levosimendan in 
acute heart failure subjects: 
• Improved hemodynamics (29-31) without a significant increase in myocardial 
oxygen consumption. (32,33) 
• Reduced symptoms of acute heart failure. (29,30,34,35) 
• Beneficial effect on neurohormone levels. (34,35) 
• Sustained efficacy due to formation of an active metabolite (OR-1896). (36,37) 
• Additional benefit in subjects under beta-blockade. (29,38) 
 
2. Sustained therapeutic effects of repeated intermittent infusions of levosimendan in 
chronic advanced heart failure subjects: 
• Beneficial effect on neurohormonal levels (39) 
• Reduced hospitalizations (39) 
 
3. Demonstrated therapeutic effects of repeated 1-2mg daily oral doses of levosimendan 
in chronic advanced heart failure subjects including:  
• Beneficial effect on neurohormonal levels (40) 
• Improvement in QOL (40) 
• Successful weaning of continuous intravenous (IV) inotropes in inotrope 
dependent subjects. (41) 
 
Levosimendan improves endothelial function and enhances diastolic coronary flow by 
opening the adenosine triphosphate-sensitive potassium channels (42) and increasing nitric 
oxide production (43).  Levosimendan acts through direct binding to troponin-C at high 
systolic intracellular calcium concentration as well as detachment from it at low diastolic 
concentration are facilitated. Levosimendan displayed positive lusitropic effects relative to 
milrinone and nitroglycerin (44, 45).  The lusitropic effect of levosimendan is independent of 
the degree of the inotropic effect.   
1.2.3 
Chronic Intermittent Studies of IV Levosimendan in Heart Failure and 
Pulmonary Hypertension Patients 
The LEVO-REP, LION-HEART, and LAICA trials built on observations from earlier open-
label studies that suggested benefits from levosimendan in this intermittent use. (45-47) These 
studies in subjects with heart failure and left ventricular dysfunction (LVEF <35%) investigated 
the effects of intermittent levosimendan at 0.2 μg/kg/min was administered for 6 h at 2-week 
intervals over 6 weeks or for 24 h every 4 weeks (46-48) These studies demonstrated 
improvements in NT-proBNP levels, subject quality of life, along with favorable reductions in 
hospitalizations and death. 
Orion sponsored a placebo-controlled study of intermittent levosimendan in subjects with 
pulmonary hypertension (51).  Patients included those with PAH (Group 1, n=8), pulmonary 
venous hypertension from LV failure (Group 2, n=17), and chronic thromboembolic disease 


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(Group 4, n=3).    Levosimendan was administered 4 times at 2-week intervals as a continuous 
infusion of 0.2 μg/kg/min for 6 hours.  Levosimendan treatment was associated with significant 
reductions in pulmonary vascular resistance (PVR) at 24 hours; mean increase of 12% ±9%, 
levosimendan; 25%±11% placebo group (p=0.009)    The magnitude of the PVR response in 
levosimendan subjects was similar but not significant at eight weeks. Similar responses were 
observed in subject’s mean pulmonary artery pressure (mPAP).  Exercise capacity, pulmonary 
gas exchange, QOL, and days alive outside of the hospital were also improved on levosimendan 
but failed to reach significance.   Seven out of 13 PH subjects with WHO-FC IV improved by 
one class (p=0.008).  Borg dyspnoea scores, 6-MWD and NT-proBNP, improved significantly 
(p< 0.001).  Compared with baseline, the right atrial transverse dimension, end-systolic 
eccentricity index and tricuspid annular plane systolic excursion improved significantly (58.8 
± 13.1 mm vs. 53.7 ± 12.4 mm; 1.50 ± 0.27 vs. 1.38 ± 0.23; 15.0 (13.0, 16.0) mm vs. 15.8 (14.0, 
17.4) mm, p< 0.005, respectively). 
1.2.4 
Levosimendan Clinical Safety 
The primary safety events of interest in levosimendan administration are hypotension and 
tachycardia.  
In integrated safety data in heart failure subjects from placebo-controlled IV levosimendan 
studies, there are no differences in the frequencies of decreased BP in levosimendan treated 
subjects compared to placebo-treated subjects (23.1% vs. 23.1%). However, in the largest 
placebo-controlled trial with IV levosimendan (REVIVE II) a statistically significantly greater 
proportion of levosimendan-treated subjects experienced decrease in BP (52.6%) compared to 
the placebo group (37.9%), p < 0.001.   This study employed a high bolus dose, then titration 
after 1 hour to 0.2 μg/kg/min for 23 hours. 
In the integrated data of placebo-controlled IV levosimendan studies, atrial tachycardia and 
fibrillation are seen in 8.2% in the levosimendan group compared to 5.4% in the placebo group 
(p = 0.024). This difference was also seen in REVIVE II (9% vs. 2%, p < 0.001). In REVIVE 
II, a statistically significant difference in the incidences of ventricular tachycardia could also be 
seen (25% in the levosimendan group and 17% in the placebo group, p = 0.031). However, in 
the integrated data, the events in the grouping of ‘ventricular tachycardia and fibrillation’ are 
reported in 10.0% of the levosimendan treated subjects and in 11.3% of the placebo subjects (p 
= 0. 371).   
The incidences of worsening heart failure (15.6% vs. 28.4%, p < 0.001) and renal function 
disturbances (6.9% vs. 10.4%, p = 0.007) are significantly lower in the levosimendan group 
than in the placebo group. 
No statistically significant difference in cardiac ischemia (7.3% vs. 8.9%, p = 0.233), decreased 
hemoglobin (2.3% vs. 3.8%, p = 0.058), decreased potassium (4.9% vs. 7.0%, p = 0.059) or 
increased blood glucose (1.6% vs. 2.6%, p = 0.117) are seen between levosimendan and placebo 
groups. It is noteworthy that although no statistically significant differences in the frequency of 
decreased hemoglobin and decreased potassium are seen, the numerical differences favor 


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levosimendan. This contrasts with the laboratory safety variable analyses; in IV studies 
decreases in hemoglobin and serum potassium have been consistently reported (29, 47). 
In pulmonary hypertension subjects eleven (61%) of levosimendan-treated subjects 
experienced at least one AE compared with 8 (80%) of placebo-treated subjects (51).  The 
majority were mild to moderate; no statistically significant differences were observed in any 
AE.  The most commonly observed AEs in PH subjects were hypotension and headache, 
paralleling the most common AEs observed in HF subjects.  Four levosimendan subjects 
experienced eight hypotensive events.  Two of the hypotensive events were symptomatic and 
experienced during the initial 24-hour infusion at 0.1 titrated to 0.2 µg/kg/min with a mean 
duration of 12 hours.  The other six asymptomatic hypotension events had a mean duration of 
3.2 hours.  Five dose-limiting hypotensive events occurred in three levosimendan subjects. 
 
One levosimendan subject discontinued the study prematurely because of prolonged 
hypotension, which started 20 minutes after completing the 24-hour infusion.  One subject 
experienced severe hypotension at the conclusion of their 24hr levosimendan dose. 
Greater increases in HR and decreases in blood pressure were observed in levosimendan-
treated subjects during the initial 24-hour infusion.  However, the HR and blood pressure 
responses during the subsequent 6-hour infusions were similar between groups. 
 
In marketed use, approximately 1.5 million subjects worldwide have been treated with 
Simdax® (levosimendan) injection. The most commonly reported adverse reactions in the 
adverse drug reaction reports received from healthcare professionals, consumers, regulatory 
authorities, clinical studies and observed in the worldwide literature are hypotension, 
ventricular tachycardia, cardiac failure and ventricular fibrillation. These events are included 
in the Simdax (levosimendan) EU Summary of Product Characteristics (SPC) (see 
Investigator’s Brochure for a copy of the SPC).  
1.2.5 
Rationale for Chronic Intermittent (weekly) Levosimendan for PH-HFpEF 
Patients 
The use of intravenous levosimendan in the treatment of PH-HFpEF subjects is based on the 
following. 
• Levosimendan uniquely enhances myocardial activity through a tripartite mechanism 
which involves acting as a calcium sensitizer in cardiomyocytes by increasing the 
sensitivity of troponin C fibers to ionic calcium and as a vasodilator and 
cytoprotective agent through the opening of adenosine triphosphate (ATP)-dependent 
potassium channels on vascular smooth muscle cells and in mitochondria. 
• Levosimendan enhances CO and systolic and diastolic function, promotes 
vasodilatation and peripheral perfusion, reduces pulmonary capillary wedge pressure 
(PCWP), alleviates symptoms of dyspnea and fatigue, and reduces levels of signifier 
neurohormones such as brain natriuretic peptide (BNP). 
• Preliminary clinical studies with levosimendan in subjects with right heart failure and 
pulmonary hypertension suggest the drug will lower pulmonary vascular resistance in 
PH-HFpEF subjects. 
• The data on the hemodynamic effects of levosimendan in the clinical studies of 
patients with LV failure consistently demonstrate that levosimendan will lower 


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PCWP, lower PA pressure, and increase cardiac output which is the desired effect of a 
treatment for PH-HFpEF. 
• Levosimendan clinical data in chronic intermittent dosing support a regimen of 
0.10µg/kg levosimendan for 24 hrs, followed by weekly levosimendan infusions of 
0.075µg/kg/min for 24 hrs (or 0.10µg/kg/min for 24 hrs in subjects that have not 
responded adequately to weekly therapy) should be safe and well-tolerated and 
maintain effective levels of the active metabolite OR-1896 in PH-HFpEF subjects.    
 
1.2.6 
Target Plasma Concentrations of OR-1896 in intermittent treatment of PH-
HFpEF Patients 
Levosimendan represents an active prodrug to the active metabolite OR-1896 with extended 
pharmacodynamic (PD) effects that parallel those of levosimendan. The elimination half-life 
of levosimendan itself is short (approximately 1 hour), whereas that of the metabolite OR-
1896 is long (70-80 hours in heart failure subjects). During a long-term oral dosing of 
levosimendan with constant daily dose, the OR-1896 plasma levels achieve a steady-state 
with minimal daily variation.  
 
The PERSIST Study of daily oral levosimendan doses of 1 and 2 mg for 180 days or more 
demonstrated substantial reductions in NT-proBNP and dose-related improvement in the 
Minnesota Living with Heart Failure quality of life score (MLHFQOL).  Thus, the observed 
levosimendan low dose with steady state OR-1896 concentrations of ~2.5ng/mL was 
associated with robust efficacy in HF subjects. 
 
Extended studies of IV levosimendan in HF subjects suggest a lower steady state 
concentration of OR-1896 may be efficacious.  The LEVO- REP and LION HEART studies 
of levosimendan in severe heart failure subjects (NYHA III/IV) were dosed at 0.2µg/kg/min 
infusions for 6 hrs. every two weeks for 6 weeks and 12 weeks, respectively.  Levosimendan-
treated subjects had reductions in NT-pro-BNP and increased exercise capacity with enhanced 
quality of life (QOL).  Steady state concentrations of OR-1896 were not determined in these 
studies of repetitive IV levosimendan. 
 
OR-1896 concentrations were modeled for the intravenous levosimendan dose regimen used 
in LEVO-REP and LION-HEART (0.2µg/kg/min for 6 hrs. every two weeks).  OR-1896 
concentrations displayed average Cmax and Cmin values of 1.5 ng/mL and 0.25 ng/mL, 
respectively, with a Cavg of approximately 1.0 ng/mL during each two-week dose interval.   
The effective target concentrations of OR-1896 are expected to be between 0.5 ng/mL and 2.5 
ng/mL in extended intermittent use.  
 
Full population PK simulations of OR-1896 plasma levels have been performed using 
available PK data of levosimendan, OR-1855, and OR-1896 from studies of IV and oral doses 
of levosimendan in heart failure subjects.  Simulations were based on central and peripheral 
compartment for levosimendan, central compartments for OR-1855 and OR-1896, and two 
transit compartments for levosimendan metabolizing to OR-1855. 
 
 


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Covariates included the following: 
• 
Acetylation status for metabolism from OR-1855 to OR-1896, and vice versa 
• 
Weight and sex on levosimendan central compartment volume of distribution 
• 
Age on levosimendan intercompartmental clearance 
 
These simulations supported an intravenous levosimendan initial dose of 0.10µg/kg/min for 
24 hours, followed by weekly doses of 0.075µg/kg/min for 24 hours through Week 3 and, 
0.10 µg/kg/min for 24 hours through Week 5.  This intravenous levosimendan regimen should 
provide effective OR-1896 concentrations between approximately 0.5 ng/mL and 2.5 ng/mL 
at half the rate of infusion used in LEVO-REP and LION-HEART, and the completed study 
in pulmonary hypertension subjects (Orion Study 3001064). 
 
2. 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
The study will evaluate the efficacy and safety of intermittent levosimendan compared with 
placebo in hemodynamic improvement with exercise in PH-HFpEF subjects.  This subject 
population represents a large and growing group with no established therapies to treat their 
pulmonary vascular disease (PVD) and right ventricular disease (RVD).  Levosimendan and its 
prolonged active metabolite, OR-1896, have been shown to have favorable hemodynamic 
effects in subjects with pulmonary hypertension and right heart failure. Clinical studies that 
have been conducted in subjects with right heart failure and pulmonary hypertension suggest 
levosimendan may be an effective therapy in treatment of subjects with PH-HFpEF. 
This study will provide demonstration of levosimendan/OR-1896’s effectiveness in critical 
measures of hemodynamic response in weekly administration of levosimendan and the 
concomitant response as measured by exercise capacity, subject quality of life, and changes in 
functional capacity. These data will support and guide the Phase 3 development of 
levosimendan in PH-HFpEF subjects. 
2.2 
Study Objectives 
2.2.1 
Primary Objectives 
This study will evaluate the efficacy and safety of intermittent (weekly) levosimendan infusions 
in hemodynamic improvement with exercise in PH-HFpEF subjects.   
2.2.2 
Secondary Objectives 
The study will evaluate the effectiveness of intermittent (weekly) levosimendan infusions in 
improving the following: 


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• Change in Cardiac Index at rest and with exercise at Week 6 
• Change in PVR effect at rest and with exercise at Week 6 
• Change in PCWP when supine and legs elevated at Week 6 
• Patient global assessment (based on a six-point Likert scale) at Week 6  
• Exercise duration 6-min walk test at Week 6  
• Physician’s Assessment of Functional Class 
• Clinical Events:  Death and hospitalizations 
o All cause hospitalizations 
o Hospitalizations attributed to any abnormality in cardiac and/or pulmonary 
status. 
2.2.3 
Exploratory Objectives 
Baseline echocardiographic measurements of RV and LV function to predict favorable response 
to levosimendan therapy. 
3. 
STUDY DESIGN 
3.1 
Study Design 
The Phase 2 study of levosimendan in PH-HFpEF subjects has been designed in two phases 
(Figure 1).  The lead-in phase will evaluate qualifying subject’s acute hemodynamic response 
to open-label levosimendan.  Patients that have clinically relevant responses to levosimendan 
will be randomized to levosimendan or placebo (1:1) and receive intermittent (weekly) study 
drug infusions (Week 2-5).  Patients who do not tolerate the initial levosimendan infusion due 
to excessive hypotension or tachycardia will be dropped from eligibility. Patients will be 
evaluated Week 6 to determine the efficacy and safety of levosimendan.   


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Figure 1: Study Design Flow Chart 
 
3.2 
Number and Type of Subjects 
The study will recruit male and female subjects meeting identified enrollment criteria for PH-
HFpEF into the lead-in open label phase to identify “responders” to levosimendan intravenous 
infusion of at 0.10 µg/kg/min for 24 hours ±30 min.  Subjects that have clinically relevant 
responses to levosimendan will be randomized to levosimendan or placebo (1:1) and receive 
intermittent (weekly) study drug infusions (Week 2-5).  The first 36 subjects who demonstrate 
a ≥4mmHg reduction in PCWP from baseline measured at bicycle exercise (25 watts) with no 
more than a 10% decrease from baseline in cardiac index will be classified as a “responder” to 
the lead-in levosimendan dose and be randomized to the double-blind phase of the study. 
Randomized subjects that have not received study drug weekly through Week 5 and returned 
for evaluation on Week 6 will be replaced to ensure 18 subjects have completed in each study 
group.  
3.3 
Investigational Product 
Levosimendan, or matching placebo supplied as a concentrated solution (2.5 mg/mL).  
Levosimendan will be administered in open-label lead-in dose intravenously at 0.10 µg/kg/min 
for 24 hours ±30 min. Patients responding to the lead-in levosimendan dose will be randomized 
to levosimendan or placebo and receive a weekly dose of study drug intravenously at 0.075 
µg/kg/min for 24 hours ±30 min and if tolerated titrated to 0.10 µg/kg/min for 24 hours ±30 
min at Week 4. 


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3.4 
Sites and Regions 
This study will be conducted at approximately 20-25 sites in the United States. 
4. 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Diagnosis and main criteria for inclusion and exclusion:  
Patients must meet the following criteria to be enrolled in the study: 
     Enrollment Criteria: 
1. Men or women, 18 years of age 
2. Diagnosis of WHO Group 2 Pulmonary Hypertension (PH) with heart 
failure and preserved ejection fraction (HFpEF) confirmed at the time of the 
diagnosis of pulmonary hypertension (see Attachment 2). 
3. Pulmonary Hypertension subjects with heart failure and preserved ejection 
fraction as defined by: 
a. Mean pulmonary arterial pressure (mPAP) > 35 mmHg at rest or 
with legs up (at baseline right heart catheter, Lead-In) 
b. Pulmonary capillary wedge pressure ≥20 mmHg at rest or with legs 
up (at baseline right heart catheter, Lead-In)  
c. NYHA Class II or III  
d. LVEF ≥40% by echocardiogram within three months of enrollment  
4. Signed (by the subjects or their legally acceptable representatives) informed 
consent document indicating that they understand the purpose of and 
procedures required for the study and are willing to participate in the study. 
5. Ability to walk at least 50 meters, but not more than 550 meters in a six-
minute walk test.  
6. Long term oxygen treatment (if applicable) must be stable for 30 days prior 
to enrollment. 


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7. Subjects on a chronic medication or therapy for any underlying cardiac 
condition must be on a stable dose for ≥30 days prior to randomization, 
with the exception of diuretics and antihypertensive medication for blood 
pressure control which may be discontinued if deemed appropriate. 
8. Subjects on chronic medications for any underlying respiratory condition 
must be on a stable dose for ≥30 days prior to randomization 
Note:  With regard to Inclusion Criteria 6-8, “stable” refers to changes in 
oxygenation therapy or medications no greater than a 100% increase or a 50% 
decrease, as needed to optimize the patient. 
       Randomization Criterion:  
9. Response to Open-Label Levosimendan:  Patients who demonstrate a 
≥4mmHg reduction in PCWP from baseline measured during bicycle 
exercise (25 watts) with no more than a 10% decrease from baseline in 
cardiac index with no clinically excessive hypotension or tachycardia (see 
Attachment 5).     
4.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met.  
1. Previous PCI or cardiac surgery (CABG) unless documented to have negative stress 
test within the last 12 months  
2. Clinically symptomatic mitral or aortic valvular heart disease. 
3. Cardiac index greater than 4.0 L/min/m2 
4. In the opinion of the Principal Investigator, the subject has a primary diagnosis of PH 
other than WHO Group 2 PH-HFpEF 
5. Congenital heart disease other than surgically corrected pre and post tricuspid shunts 
for at least 10 years  
6. Symptomatic coronary artery disease based on positive stress test   
7. Patients planning lung or heart transplant or cardiac surgery in the next 4 months 


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8. Patients diagnosed with pulmonary hypertension associated with clinically significant 
lung disease at the time of initial diagnosis, or patients with a congenital defect of the 
lung 
a. Clinically significant obstructive lung disease is defined as FEV1/FVC <60% 
of predicted, unless a high resolution chest CT scan shows no more than mild 
areas of emphysematous changes. 
b. Clinically significant restrictive lung disease is defined as disease a FVC of 
<60% of predicted, unless a high resolution chest CT scan shows no more than 
mild areas of interstitial lung disease or pulmonary fibrosis. 
9. Dialysis at randomization (either hemodialysis, peritoneal dialysis, continuous 
venovenous hemofiltration, or ultrafiltration) 
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
11. Liver dysfunction with Child Pugh Class B or C (see Attachment 3) 
12. Evidence of systemic bacterial, systemic fungal, or viral infection in last 2 weeks 
13. Weight >150 kg 
14. Symptomatic low systolic blood pressure (SBP) that cannot be managed to ensure 
SBP > 100 mmHg at initiation of study drug 
15. Heart rate  100 bpm with study drug, symptomatic and persistent for at least 10 
minutes at screening. 
16. Hemoglobin < 80 g/L 
17. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline 
18. Pregnant, suspected to be pregnant, or breast-feeding 
19. Known allergic reaction or sensitivity to levosimendan or excipients. 
20. A history of Torsades de Pointes 
21. Received levosimendan within 30 days before the planned start of study drug 
22. Received an experimental drug or used an experimental medical device within 30 days 
before the planned start of study drug 
23. Concomitant administration of pulmonary vasodilator therapy, or taken within 14 days 
of randomization 


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24. Employees of the investigator or study center, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study center, as well as 
family members of the employees or the investigator 
25. Inability to comply with planned study procedures 
4.3 
Restrictions 
Potential subjects must be willing to adhere to the following prohibitions and restrictions during 
the study to be eligible for participation.  
• Women of childbearing potential only must agree to remain on an effective method of 
birth control or remain abstinent throughout the study.  
• Medication or treatment for heart failure or respiratory disease must be maintained 
during the trial, unless contraindicated 
• All subjects must agree and comply with at-home infusions for the duration of the 
trial. 
4.4 
Withdrawal of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The Investigator or Sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The withdrawal of a 
subject from the investigational product by the Investigator should be discussed where possible 
with the Medical Monitor and/or Sponsor before the subject stops investigational product. 
If the investigational product is discontinued, regardless of the reason, the final evaluations are 
to be performed as completely as possible.  Whenever possible, all discontinued subjects should 
also undergo the protocol-specified Week 6 evaluations.  Comments (spontaneous or elicited) 
made by the subject must be recorded in the source documents.  The reason for termination, 
date of stopping investigational product, and the total amount of investigational product taken 
must be recorded on the electronic Case Report Form (eCRF) and source documents. 
4.4.1 
Reasons for Discontinuation 
The reason for withdrawal must be determined by the Investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than one reason, each 
reason should be documented in the source document and the most clinically relevant reason 
should be entered on the eCRF. 
If an adverse event (AE) is a reason for discontinuation, then “Adverse event” must be recorded 
as the reason for discontinuation on the eCRF. 


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Reasons for discontinuation include but are not limited to:  
• Adverse event  
• Protocol violation   
• Withdrawal by subject 
• Lost to follow-up 
• Lack of efficacy  
• Investigator decision  
4.4.2 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit 
At least three documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact).  One of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgment of receipt request) asking that they 
return any unused investigational product (if applicable) and return to the site for final safety 
evaluations. 
5. 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior Treatment 
Prior 
treatment 
includes 
all 
treatment 
(including 
herbal 
treatments, 
vitamins, 
nonpharmacological treatment such as psychotherapy as appropriate) received within 30 days 
(or the pharmacokinetic equivalent of 5 half-lives, whichever is longer) of and discontinued 
prior to the date of the first dose of investigational product.  Prior treatment information must 
be recorded on the appropriate eCRF page. 
5.2 
Concomitant Treatment  
All subjects must be optimally managed on diuretics and oxygen therapy as indicated by the 
standard of care. Diuretic dose may not be adjusted within 5 days of Levosimendan infusion.  
 
Concomitant administration of parenteral prostacyclin is not permitted.  
 
The long-term oxygen treatment (if applicable) must be stable for 30 days prior to enrollment, 
including delivery route and dose. 
 
Medication or treatment for heart failure or respiratory disease must be maintained during the 
trial, unless contraindicated.  


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6. 
RANDOMIZATION 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (e.g., demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during treatment, data collection and evaluation of clinical endpoints. 
Subjects will be randomly assigned to a treatment group using an interactive web response 
system (IWRS) after they have met all inclusion criteria and none of the exclusion criteria.  
If a potential subject is randomly assigned to treatment but is found to be ineligible before the 
study drug infusion is started, the investigator will not proceed with study drug administration. 
The potential subject will be considered randomized but not treated, and the sponsor must be 
notified. The investigator will document the reason that the potential subject is no longer a study 
candidate within the eCRF. 
Once a randomization number/unique identifier has been assigned, that number must not be 
used again if, for example, a subject is withdrawn from the study.  If a randomization 
number/unique identifier is allocated incorrectly the sponsor must be notified as soon as the 
error is discovered. 
6.1 
Allocation of Subjects to Treatment 
This is a double-blind, placebo/active-controlled study.  The actual treatment given to 
individual subjects is determined by the randomization schedule. 
Subject screening numbers are assigned to all subjects as they consent to take part in the study.  
Within each site (numbered uniquely within a protocol), this number is assigned to subjects 
according to the sequence of presentation for study participation.   
Upon randomization, subjects will be assigned to 1 of 2 treatment groups (levosimendan 0.075 
µg/kg/min for 24 hours (±30 min) or matching placebo) in a 1:1 ratio based on a computer-
generated randomization schedule.  
Lead-in Phase (Day 0) 
Levosimendan will be administered to all subjects meeting inclusion criteria into the study to 
assess clinically relevant response to levosimendan. The dose is 0.1 µg/kg/min for 24 hours 
(±30 min). 
Double-blind Phase (Weeks 2, 3, 4, 5, and 6) 
Study drug levosimendan or placebo (1:1 randomization), will be administered at study 
Weeks 2, 3, 4 and 5 via a CADD pump and initiated by the home healthcare nurse.   
During Weeks 2 and 3, patients will receive levosimendan or placebo at a rate of 0.075 
µg/kg/min for 24 hrs. 


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Patients will have a dose escalation at Weeks 4 and 5 at a rate of 0.10 µg/kg/min for 24 hrs 
unless there has been a meaningful change in blood pressure or heart rate (Attachment 5). 
After the completion of all Week 6 procedures, randomized subjects will be offered the option 
to enroll into an open-label study of levosimendan. Subjects will be required to sign a new 
informed consent form to enroll in this open-label trial. 
7. 
INVESTIGATIONAL PRODUCT 
7.1 
Levosimendan  
Levosimendan and matching placebo will be provided to investigators by the sponsor as a sterile 
clear, yellow to orange solution in clear glass vials. Each vial contains a 5 mL volume and is 
intended for a single use. Levosimendan is supplied at 2.5 mg/mL (12.5 mg/5 mL) and includes 
levosimendan, povidone, citric acid and ethanol.  Additional information is provided in the 
Simdax (levosimendan) injection Investigator’s Brochure and SmPC. 
Levosimendan and matching placebo are manufactured by the Orion Corporation, Espoo, 
Finland. 
7.2 
Matching Placebo 
Placebo is a sterile infusion solution that includes a coloring agent in order to achieve a similar 
color to levosimendan. The complete composition of placebo for levosimendan 2.5 mg/mL 
infusion concentrate includes riboflavin sodium phosphate, ethanol, and water for injection.  
7.3 
Packaging 
Levosimendan and placebo will be provided in sterile, single-use clear rubber-stoppered glass 
vials. Details on the packaging of study drug will be provided in the study manual.  
Initially, investigational sites will receive single vials of levosimendan to complete the Lead-In 
dose for approximately 6 patients. For subsequent dosing at Weeks 2 through 5, kits will be 
labeled (levosimendan and matching placebo) and will include 2 vials per kit to ensure 
sufficient supply is available for patients over 85kg in weight.  
7.4 
Labeling 
Study drug labels and cartons will contain information to meet the applicable regulatory 
requirements. 
Each vial will have appropriate directions for use and other information on each part. 


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Specialized drug accountability forms will be provided for tracking study drug administration. 
Information from the vial will be included on the subject’s drug accountability form to 
document drug reconstitution (vial usage). See the Pharmacy Manual for detailed instructions. 
7.5 
Preparation and Handling 
Study drug (levosimendan, placebo) will be prepared by study personnel blinded to the 
treatment group.  
Levosimendan 2.5 mg/mL (Simdax, Orion Corporation, Espoo, Finland) infusion concentrate 
is supplied in a volume of 5 mL (with a small overage) in clear rubber-stoppered glass vials. 
The composition of levosimendan 2.5 mg/mL infusion concentrates includes Levosimendan, 
povidone, citric acid, and ethanol.  
Study drug (levosimendan infusion concentrate, placebo concentrate) must be stored between 
2-8°C (35-46°F) in a temperature monitored refrigerator which can be locked and protected 
from light. 
The study drug should be prepared immediately prior to use. Dilution of the study drug should 
be performed as described below. 
One (or two) 5 mL vials of study drug (from one of the two subject pack boxes in a numbered 
package) are added to one 250 mL (or 500 mL) infusion bag of 5% Dextrose or 0.9 Normal 
Saline according to the subject’s body weight as follows.  
• For subjects < 85 kg by adding one (1) 5 mL vial of levosimendan/placebo 
infusion concentrate to one 250 mL infusion bag or bottle of 5% Dextrose or 0.9 
Normal Saline. 
• For subjects  85 kg by adding two (2) 5 mL vials of levosimendan/placebo 
infusion concentrate to one 500 mL infusion bag or bottle of 5% Dextrose or 0.9 
Normal Saline. 
The concentration of the study drug is approximately 50 µg/mL (12.5 mg/255 mL in a 250 mL 
bag; 25 mg/510 mL in a 500 mL bag). Immediately after dilution, the infusion bags are covered 
with IV/tubing sleeves to protect the infusion solution from light. Label information found on 
each vial is completed by the study nurse and then transferred to the infusion bag to confirm 
dilution. Empty vials must not be discarded but placed back in the box and stored for 
reconciliation. 
Since the stability of the diluted medication has been established for 30 hours only, the study 
drug infusion must not continue for more than 30 hours after the time of initial dilution. On 
completion of the 24-hour infusion period, all study medication bags (and contents) still covered 
by the amber sleeve should be destroyed appropriately and destruction will be documented. The 
colored plastic sleeves must not be removed or tampered with by the study center team 
members. 


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7.5.1 
Lead-in and Double-blind 
Lead-in Phase 
Levosimendan, supplied as a concentrated solution (2.5 mg/mL), will be mixed with diluent 
and administered intravenously at 0.10 µg/kg/min for 24 hours ±30 min. 
Double-blind Phase 
Study drug concentrated solution (2.5 mg/mL), levosimendan or placebo, will be mixed with 
diluent and administered via a PICC line as weekly infusions at 0.075 µg/kg/min for 24 hrs.   
Patients will have a dose escalation at Weeks 4 and 5 at a rate of 0.10 µg/kg/min for 24 hrs, 
unless there has been a meaningful change in blood pressure or heart rate (Attachment 5). 
Infusion rates may be reduced to 0.05 µg/kg/min if the higher dose is not well-tolerated at any 
time during the study (see Attachment 1).  
Infusions should typically occur as follows, unless there is the need for adjustment: 
Lead-In 
Infusion 
(in office) 
Week 2 
(Home) 
 
Week 3 
(Home) 
 
Week 4 
(Home) 
Week 5 
(Home) 
 
Week 6 
(in office) 
 
0.10 
µg/kg/min 
for 24 hrs 
0.075 
µg/kg/min 
for 24 hrs 
0.075 
µg/kg/min 
for 24 hrs 
0.10 
µg/kg/min 
for 24 hrs 
0.10 
µg/kg/min 
for 24 hrs 
Discontinuation or 
Enrollment into OL 
Prior to the Week 4 infusion, subjects will be assessed by the investigator per section 8.5.  
7.5.2 
Dosage and Administration 
Prior to initiating study drug infusion, subjects should be checked for (mean arterial pressure 
[MAP] < 60 mmHg, SBP < 100 mmHg).  Confirm the subject has not modified their diuretic 
dose in the last 5 days. 
During the Lead-In Phase, subjects will be administered a continuous intravenous (IV) infusion 
of a standard infusion dose of 0.10 µg/kg/min for 24 hours (±30 min); (levosimendan). No bolus 
of study drug will be administered.  
The infusion rate of study drug may be decreased, interrupted, or discontinued for safety 
reasons, according to the discretion of the investigator, as described in the following sections.  
To prevent possible medication errors or miscalculations, refer to Attachment 1 of this protocol 
before administration of study drug to calculate the appropriate infusion rate based on the 
subject’s preoperative body weight. 
See Section 7.5, Preparation and Handling for information on study drug preparation.  
The diluted infusion is administered intravenously by a peripheral or central route. No other 
treatments should be administered via the same line.  The concentration of the diluted infusion 


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is about 50 µg/mL in 5% Dextrose or 0.9% Normal Saline (12.5mg/255mL in a 250 mL bag; 
25mg/510mL, 2 vials in a 500 mL bag). 
The IV tubing should be primed to fill the volume to the IV entry site before starting the 
infusion.  
Patients will receive the infusion via a CADD pump. Patients will be allowed to resume their 
normal daily activity during the infusion but will not be allowed to engage in any activity that 
may subject the CADD pump to water exposure. 
7.5.3 
Dose Adjustment 
The infusion rate of study drug may be decreased or interrupted as clinically warranted if the 
subject has hypotension, tachycardia, or signs or symptoms consistent with hypovolemia (e.g., 
low SBP, decreasing urine output with rising blood urea nitrogen [BUN] and serum creatinine) 
Record the time of discontinuation or down titration. Patients should be monitored closely until 
clinically stable. See Attachment 1 for infusion rates and instructions on dose adjustments. 
Refer to the following subsections for additional guidance on events that require study drug 
discontinuation or dosage adjustment, permanent discontinuation, and re-initiating study drug 
in subjects in whom clinical stability has been restored. In the event of a dose interruption, the 
infusion should be extended the amount of time of the interruption, but no more than four hours.  
7.5.4 
Dose-limiting Events 
Dose limiting cardiac events and instructions are detailed in Attachment 5. In addition to these 
events, the dose may be adjusted at any time the physician judges that it is in the best interest 
of the patient to reduce the dose or discontinue the infusion.  
7.5.5 
Blinding the Treatment Assignment 
The blind is maintained by the use of matching placebo.   
Protective sheaths for the infusion line and bag will be used to protect the study drug from UV 
light and are required to be used at Lead-In and during the Week 2 through 5 infusion visits.  
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study (defined as Week 6) and the database is locked. Otherwise, the blind should be broken 
only if specific emergency treatment would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator must contact the sponsor or designee. Please consult the 
Pharmacy Manual for unblinding procedures should the sponsor or designee be unavailable. 
The sponsor must be informed as soon as possible. The date, time, and reason for the unblinding 
must be documented in the appropriate section of the eCRF and in the source document.   


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7.5.6 
Unblinding the Treatment Assignment 
Data that may potentially unblind the treatment assignment (e.g., investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process.  These data will be handled in such a way that, prior to unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available.  If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits.  
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject.  Prior to unblinding, and if the situation allows it, the investigator should first contact 
the Medpace Medical Monitor. 
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS, eCRF, and the 
source documents (as appropriate).  Upon breaking the blind, the subject is withdrawn from the 
study, but should be followed up for safety purposes.  Any code-breaks that occur must be 
reported to the Sponsor.  Instructions on breaking the blind for safety purposes are in the 
Pharmacy Manual.  
7.6 
Packaging, Storage, and Handling 
7.6.1 
Preparation and Handling 
Study drug (levosimendan, placebo) will be prepared by study personnel blinded to the 
treatment group.  
Levosimendan 2.5 mg/mL (Simdax, Orion Corporation, Espoo, Finland) infusion concentrate 
is supplied in a volume of 5 mL (with a small overage) in clear rubber-stoppered glass vials. 
The composition of levosimendan 2.5 mg/mL infusion concentrates includes: Levosimendan, 
povidone, citric acid and ethanol.  
The study drug should be prepared no more than 6 hours prior to the initiation of an infusion. 
Dilution of the study drug should be performed as described below. 
One (or two) 5 mL vials of study drug (from one of the two subject pack boxes in a numbered 
package) are added to one 250 mL (or 500 mL) infusion bag of 5% Dextrose or 0.9 Normal 
Saline according to the subject’s body weight as follows.  
• For subjects < 85 kg by adding one (1) 5 mL vial of levosimendan/placebo infusion 
concentrate to one 250 mL infusion bag or bottle of 5% Dextrose or 0.9 Normal Saline. 
• For subjects  85 kg by adding two (2) 5 mL vials of levosimendan/placebo infusion 
concentrate to one 500 mL infusion bag or bottle of 5% Dextrose or 0.9 Normal Saline. 


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The concentration of the study drug is approximately 50 µg/mL (12.5 mg/255 mL in a 250 mL 
bag; 25 mg/510 mL in a 500 mL bag). Immediately after dilution, the infusion bags are covered 
with IV/tubing sleeves to protect the infusion solution from light. The label found on each vial 
is completed by the study nurse and then label information transferred to the infusion bag to 
confirm dilution. Information from the label is transferred by the investigator (study nurse) on 
starting the infusion and included on the drug accountability documentation. The eCRF will be 
updated to confirm the study drug received by an individual subject. Empty vials must not be 
discarded but placed back in the box and stored for reconciliation. 
Since the stability of the diluted medication has been established for 30 hours only, the study 
drug infusion must not continue for more than 30 hours after the time of initial dilution. On 
completion of the 24-hour infusion period, all study medication bags (and contents) still covered 
by the amber sleeve should be destroyed appropriately, and destruction documented. The 
colored plastic sleeves must not be removed during infusion.  
7.6.2 
Storage 
Study drug (levosimendan infusion concentrate, placebo concentrate) must be stored between 
2-8°C (35-46°F) in a temperature monitored refrigerator which can be locked and protected 
from light. 
The Sponsor must be notified upon discovery of any excursion from the established range.  
Temperature excursions will require site investigation as to cause and remediation.  Tenax will 
determine the ultimate impact of excursions on the investigational product and will provide 
supporting documentation as necessary.  Under no circumstances should product be dispensed 
to subjects until the impact is determined and product is deemed appropriate for use. 
7.7 
Investigational Product Quality Complaints 
Investigators are required to report investigational product quality complaints to Tenax.  This 
includes any instances wherein the quality or performance of a Tenax product does not meet 
expectations (e.g., inadequate or faulty closure, product contamination, etc.). 
7.8 
Drug Accountability 
Investigators will be provided with sufficient amounts of levosimendan for the lead-in phase 
for the agreed number of subjects.  The Investigator or designee will acknowledge receipt of 
the investigational product documenting shipment content and condition.  The central depot for 
the home health services company will be provided with blinded drug supplies for doses at 
Weeks 2-5 and open-label levosimendan for the open-label extension.  Accurate records of all 
investigational product dispensed, used, returned, and/or destroyed must be maintained as 
detailed further in this section.  
The Investigator or his/her designee (as documented by the Investigator in the applicable study 
delegation of authority form) and home health care nurse will administer the investigational 


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product only to subjects included in this study following the procedures set out in the study 
protocol.  Each subject will be given only the investigational product carrying his/her treatment 
assignment.  All dispensing will be documented on the eCRFs and/or other investigational 
product record.  The Investigator and home health care nurse is responsible for assuring the 
retrieval of all study supplies from subjects during lead-in and double-blind phases of the study.  
During the open-label extension, the home health care nurse must request subjects to keep the 
empty investigational product packaging after use and return it to the site for drug accountability 
purposes.  
No investigational product stock or returned inventory from a Tenax sponsored study may be 
removed from a site where originally shipped without prior knowledge and consent by the 
Sponsor.  If such transfer is authorized, all applicable local, state, and national laws must be 
adhered to for the transfer. 
Tenax or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised. 
With the written agreement of Tenax, at the end of the study all unused stock, subject returned 
investigational product, and empty/used investigational product packaging may be destroyed at 
the site or a local facility.  In this case, destruction records identifying what was destroyed, 
when and how must be obtained with copies provided to Tenax.  Destruction of investigational 
products must be in accordance with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned.  All investigational products 
must be accounted for and all discrepancies investigated and documented to Tenax’ satisfaction.  
7.9 
Subject Compliance 
Study drug will be administered as an IV infusion by qualified staff (e.g., a qualified nurse, a 
member of the study staff, or an infusion specialist) and the details of each administration will 
be recorded in the eCRF (including start and stop date and times of the IV infusion). The 
investigator or designated study personnel will maintain a log of all study drug dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study. b 
8. 
STUDY PROCEDURES 
The Time and Events Schedule summarizes the frequency and timing of efficacy, safety, or 
other measurements.   
The study will be divided into a Screening phase, a Lead-In phase, and a Double-Blind 
treatment phase. Randomized and treated subjects will be followed for 6 weeks. At the end of 
6 weeks, subjects will have the opportunity to continue receiving open-label levosimendan as 
long as they meet the criteria listed in section 8.6.2. 


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The Screening, Lead-In, Interim Office (between Weeks 3 and 4) and Week 6 visits will occur 
at the investigator’s office. Infusions at Weeks 2, 3, 4 and 5 will occur at the subject’s home 
under the care of a home healthcare nurse. Subjects will be instructed to contact the investigator 
at any time during the 24 hour at home infusions to report adverse events, or at any time they 
would like to speak with the investigator regarding the study or to report adverse events during 
the entirety of the trial. During the at home care, any urgent issues related to the infusion or the 
infusion pump should be directed to the 24-hour Coram Pharmacy hotline. 
Visits during the Lead-In phase of the trial will require a subject to be hospitalized for the entire 
infusion period, which at a minimum will last 24 hours. Once the infusion is complete, 
hemodynamic measurements will be collected to ensure subject eligibility.  
Visits for Week 2 through Week 6 should be calculated based on the date of the Lead-in infusion 
(not the date of randomization). 
After confirmation of eligibility, patients will receive a blood pressure monitor for home use. 
Patients will be instructed to use the monitor if they notice any signs or symptoms of 
lightheadedness, dizziness, angina, or palpitations. The patients will also be instructed to 
contact the investigational site (24-hour medical hotline) to report any of these events or any 
adverse events. Patients should continue to use the monitor, as needed, post Lead-in infusion 
(Day 0) through the Week 6 visit. 
 
8.1 
Screening Visit (< 28 Days prior to Day 0) 
Before any study-related procedures are performed, the risks of the study will be explained to 
a potential subject, and the subject or his/her legal representative will be required to sign an 
informed consent form.  
In the Screening phase, which can occur over twenty-eight days, potential subjects will be 
screened to determine eligibility for participation in the study. Documentation of screening 
failure details should be recorded in the eCRF.  
At least 72 hours prior to the first infusion (Lead-In Visit), all patients will wear a small, 
lightweight cardiac monitoring sensor on their chest to measure heart rate and to detect any 
arrhythmias. This patch will remain on monitoring the patient for minimum of 72 hours prior 
to the Lead-In infusion. The patch is water resistant and can be worn in the shower by the 
patient. The patch will be removed prior to the first infusion of study drug.  
In addition to the above, the following procedures will be performed: 
 
• Obtain signed main study ICF (must be obtained prior to performance of any study-
specific tests or evaluations that are not considered standard of care). 
• Confirm inclusion/exclusion criteria  


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• History of qualifying hemodynamics  
• Conduct a medical history 
• Body weight 
• Record prior/concomitant medications including all prescription and non-prescription 
drugs, vitamins, and dietary or herbal supplements 
• Record demographic information 
• Perform complete physical examination, including height and body weight 
• Urine pregnancy test (women of child-bearing potential only)  
• Hematology and clinical chemistry blood samples  
• Measure vital signs: BP, PR, respiratory rate, temperature 
• Child-Pugh Class 
• NYHA Functional Class 
• Conduct 12-lead ECG 
• Echocardiogram (within 3 months of Day 0) 
o Must be repeated prior to Baseline 
• Perform 6MWT 
8.2 
Day 0 (Lead-in Infusion, Visit 1) 
This visit may be performed on the same day as the Screening Visit if all procedures have been 
completed.  
During the Lead-in Infusion (Day 0) the following procedures will be performed: 
 
• Measure vital signs: BP, PR, respiratory rate, temperature 
• Venous sheath placement for right heart catheterization. The sheath will remain 
following the baseline study, and the patient will be hospitalized where they will 


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receive the 24-hour levosimendan infusion (preferably through the venous sheath). 
The sheath will then be used for access for the right heart catheterization study 
following the 24-hour levosimendan infusion, and then removed (see Attachment 6). 
• Right heart catheterization measurements: baseline (prior to levosimendan infusion) 
and post 24-hour infusion 
o Establish qualifying baseline hemodynamics at rest and exercise 
o Establish qualifying response to levosimendan during exercise  
• Assess adverse events 
• Assess concomitant medications and/or procedures 
• Pharmacokinetic sampling (to be taken at the end of infusion: 24 + 2 hours) 
• Genotyping sample (to be taken at the end of insfusion: 24 + 2 hours) 
Subjects who do not respond to levosimendan based on hemodynamic measurements as defined 
in Section (7.5.3) will be withdrawn from screening. These subjects will be followed for safety, 
as outlined in section 8.7. 
If subject is deemed a screen failure, the pharmacokinetic and genotyping samples do not need 
to be collected. 
A PICC line will be placed in patients that meet eligibility criteria and who are randomized into 
the Double-Blind phase of the study. 
8.3 
Day 0 (Double-blind Randomization, Visit 1) 
Once eligibility is confirmed via hemodynamic measurements per section 8.9.2, post lead-in 
infusion, subjects will be randomized 1:1 to either receive levosimendan or placebo. This will 
occur at the same visit as the lead-in dose (Day 0). 
• Randomization via IWRS 
• PICC line placement (for randomized patients only) 
Follow-up in patients that are not randomized: Subjects that receive levosimendan during the 
Lead-In dose, but are not randomized into the trial, will followed for 2 weeks.  Phone contact 
will be made with the subject by the investigational staff at 24 hours (+24 hours), 7 days (+ 2 
days), and 14 days (+ 2 days) post Lead-In infusion.  


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8.4 
Weeks 2-5 (Weekly Infusion Visits 2, 3, 4, and 5) 
Visits at Weeks 2, 3, 4, and 5 should be performed within + 48 hours of the scheduled visit. 
Visits for Weeks 2-5 should be calculated based on the date of the Lead-in infusion. 
These visits will be performed at the subject’s home with the aid of the home health care nurse.  
The home health care nurse will remain with the patient for the first 2-3 hours of the infusion 
to ensure patient safety. The home health care nurse will visit the patient again at 24 hours to 
stop the infusion and assess the patient’s status. 
During visits where the home healthcare nurse is present, subjects may inform the nurse and/or 
investigator of any infusion related events or AEs. Questions regarding the infusion pump 
should be directed to the 24-hour Coram Pharmacy hotline.  
During this visit, the following procedures will be performed: 
 
• Record any changes in procedures, prescription and non-prescription drugs, vitamins, 
and dietary or herbal supplements 
• Measure vital signs prior to starting the infusion, after the first 2 hours (±30 min), and 
after 24 hours (±30 min). 
• Assess adverse events 
• Study drug administration 
At Week 5, all patients will be given a new cardiac monitoring sensor to wear on their chest to 
measure cardiac rhythm, as was done during Screening. This patch is to be applied prior to (< 
1 hour) the 24-hour infusion will remain monitoring the patient for minimum of 72 hours and 
returned to the investigational site at the Week 6 visit. 
8.5 
Interim Office Visit (Between Weeks 3 and 4) 
The Interim Office Visit should be performed 48 hours prior to the Week 4 Infusion visit. This 
visit will be performed at the investigator’s office. Infusions will not occur at the office during 
these visits. 
During this visit, the following procedures will be performed: 
 
• 6MWT 
• Quality of Life (QOL) assessment 


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• NYHA Functional Class determination 
• Body weight 
• Dispense cardiac monitoring patch 
• All procedures listed in section 8.4 (with exception of infusion) 
If no meaningful lowering of blood pressure is noted, or an increase in heart rate, the dose will 
be increased for all subjects to 0.10 µg/kg/min for 24 hrs. (see Attachment 5).  
The home health care nurse will be notified by the site of confirmation of up-titration or any 
dose adjustments. 
 
If for any reason the Interim Office Visit is not preformed, the dose level of levosimendan 
should remain at 0.075 µg/kg/min for 24 hrs.  
8.6 
Week 6 (Visit 6) 
Visits at Week 6 should be performed 3-6 days following completion of the Week 5 infusion. 
During this visit, the following procedures will be performed: 
 
• Record any changes in procedures, prescription and non-prescription drugs, vitamins, 
and dietary or herbal supplements 
 
• Measure vital signs: BP, PR, respiratory rate, temperature 
• Hematology and clinical chemistry blood samples  
• Conduct 12-lead ECG 
• Echocardiogram within +72 hours of the Week 6 visit 
• Right heart catheterization at rest and with exercise (section 8.9.2 and Attachment 6) 
• Quality of Life (QOL) assessment 
• Child-Pugh Class 
• NYHA Functional Class 
• Assess adverse events 
• Perform 6MWT 


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• Pharmacokinetic sampling (sample to be taken prior to enrollment in OL phase) 
8.7 
Early Termination 
If a subject terminates the study prematurely, procedures listed in the Week 6 visit should be 
performed as soon as possible. The RHC, echocardiogram, and 6MWT do not need to be 
performed for subjects who terminate the study early. 
Subjects will be followed for safety for 2 weeks after early termination. A phone contact will 
be made with the subject at 24 hours (+ 24 hours), 7 days (+ 2 days), and 14 days (+ 2 days) 
post infusion by investigational site personnel to assess any new or ongoing adverse events.  
If a subject discontinues greater than 24 hours after their prior infusion, the 24-hour phone 
contact does not need to be performed and the next phone contact beginning at 7 days should 
be completed.  
The vital status of all subjects will be collected at the end of the trial, regardless of reason for 
discontinuation.  
8.8 
Open Label Extension 
Randomized subjects will have the option to enter into an open-label study following the 
completion of all study procedures at Week 6. If a subject decides not to continue in the open 
label protocol after Week 6, safety follow up phone call procedures listed in section 8.7 should 
be followed. 
8.9 
Study Evaluations and Procedures 
Study procedures will occur according the Time and Events Schedule.  
8.9.1 
Demographic and Other Baseline Characteristics 
Demographics including date of birth, ethnicity and sex will be collected at the Screening visit.  
8.9.2 
Efficacy Measures 
8.9.2.1 Right Heart Catheterization 
Subjects will have hemodynamic measurements assessed at the Day 0 (pre and post infusion) 
and Week 6 visits. For inclusion into the study, a subject must have a mean pulmonary arterial 
pressure (mPAP) of > 35 mmHg and a pulmonary capillary wedge pressure (PCWP) of > 20 
mmHg.  


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Measurements will be recorded via RHC in the following sequence: as the subject is supine, 
legs elevated, and supine with bicycle exercise (25 watts).  See Attachment 6 for procedure. 
Subjects who qualify for the study will have a PICC line inserted for the Double-Blind phase 
of the study (i.e., prior to the Week 2 infusion).  
8.9.2.2 6-Minute Walk Test (6MWT) 
The 6MWT should be performed at approximately the same time of day at each study visit 
after the Baseline Visit and ideally, one of the first assessments to be performed. The ECHO 
and subject questionnaire should be performed after the 6MWT has been completed. Patients 
who discontinue study drug prior to Week 6 should continue to have all safety and efficacy 
assessments performed as scheduled through the Week 6 Visit, unless contraindicated. 
 
The 6MWT will be performed at the time points specified in the Time and Events Schedule 
using the methods described in the American Thoracic Society (ATS) Statement: Guidelines 
for the Six-Minute Walk Test (50).  Testing should be performed in a location where a rapid, 
appropriate response to an emergency is possible. The appropriate location of a crash cart 
should be determined by the physician supervising the facility. The test should be performed 
at approximately the same time of day when assessed and by the same evaluator whenever 
possible. 
8.9.2.3 Echocardiogram Complete with Contrast 
The 2-dimensional (2D) echocardiogram complete with contrast will be performed by trained 
personnel at the time points specified in the Time and Events Schedule. 
 
These assessments will be standard transthoracic 2D echocardiograms (with contrast to 
optimize accuracy and precision of intracardiac measurements). Details of specific 
measurements and plans for analysis will be included in the core lab analysis plan.  
 
These may include, but are not limited to: 
 
1. Left ventricular: systolic and diastolic function; size, mass, and geometry. 
2. Right ventricular size and function; pulmonary artery size. 
3. Left atrial dimensions, volumes, and pressures. 
4. Valvular (aortic, mitral, tricuspid and pulmonary) stenosis and regurgitation 
(severity). 
5. Pulmonary artery systolic pressure (PASP), Inferior vena cava (IVC) calibre 
8.9.3 
Safety, Pharmacokinetic, and Pharmacogenomic Assessments 
All safety evaluations will be performed at the time points listed in the Time and Events 
Schedule.  


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8.9.3.1 Medical and Medication History 
To be completed at the Screening Visit to ensure subjects meet the inclusion criteria for the 
study. Any clinically significant history should be noted in the eCRF.  
8.9.3.2 Physical Examination (Including Height and Weight) 
Abnormalities identified at the Screening Visit  will be documented in the subject’s source 
documents and on the medical history eCRF.  Changes after the Screening Visit will be captured 
as AEs on the AE eCRF page, as deemed by the Investigator. 
8.9.3.3 Adverse Event Collection 
Adverse events will be reported by the subject (or, when appropriate, by the subject’s physician, 
a caregiver, surrogate, or the subject’s legally acceptable representative) for the duration of the 
study.  Non-serious adverse events will be followed by the investigator from the signing of the 
Informed Consent until Week 6 or discontinuation of the study, whichever occurs first. Serious 
adverse events will be collected through Week 6. Specific details on adverse event reporting 
are provided in Section 9. 
8.9.3.4 Vital Signs 
Blood pressure should be determined by cuff (using the same method, the same arm, and in the 
same position throughout the study).  Any clinically significant deviations from baseline vital 
signs which are deemed clinically significant in the opinion of the Investigator are recorded as 
an AE. 
Vital signs and body weight should be recorded according to the Time and Events Schedule 
and include: body temperature, heart rate, respiratory rate, and blood pressure [systolic and 
diastolic blood pressure]. 
8.9.3.5 Clinical Laboratory Evaluations 
All blood laboratory test collections must be performed prior to study drug dosing (where 
other exclusions do not apply). Blood specimens for hematology and serum chemistry will be 
collected, and results obtained by local laboratories, except for the pharmacokinetic and 
genotyping samples. These samples will be sent to external labs for analysis of 
Levosimendan, OR-1855 and OR-1896 metabolites. 
 
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures.  Reference ranges are supplied by the laboratory and used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes.  The 
Investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant (NCS) or clinically significant (CS).  


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Abnormal clinical laboratory values, which are unexpected or not explained by the subject’s 
clinical condition may be, at the discretion of the Investigator or Sponsor, repeated until 
confirmed, explained, or resolved as soon as possible.   
Blood samples for hematology and serum chemistry will be taken at the time points detailed in 
the Time and Events Schedule. The investigator must review the laboratory report, document 
this review, and record any clinically relevant changes occurring during the study in the adverse 
event section of the eCRF. The following tests may be performed by the local laboratories and 
results entered into the eCRF, as shown in the Time and Events Schedule: 
Hematology and Coagulation Panel 
Hematocrit 
Hemoglobin 
White blood cell (WBC) count with differential 
Platelet count 
Prothrombin time 
Partial thromboplastin time 
Serum Chemistry Panel 
Sodium 
Potassium 
Bicarbonate 
Blood urea nitrogen (BUN) 
Creatinine 
8.9.3.6 Pregnancy Test  
For female subjects with childbearing potential, a urine or serum pregnancy test will be 
performed at the Screening Visit. Results must be available before study drug administration. 
Additional serum or urine pregnancy testing may be performed as required by local regulations 
(if performed, pregnancy tests must be negative for subjects to continue in the study). 
8.9.3.7 Electrocardiogram 
Subjects should have a 12-lead ECG performed at Screening and Week 6. ECGs should be 
performed prior to administration of study drug (where applicable). Abnormal ECGs may be 
repeated at the Investigator’s discretion. 
8.9.3.8 Clinical Pharmacology Assessments 
Pharmacokinetic sampling will occur at the Day 0 and Week 6 visits. These samples will be 
sent to a central laboratory for testing. The name and address of the clinical pharmacology 
laboratory used in this study will be maintained in the Investigator’s files at each site. 


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Complete instructions for sample processing, handling and shipment will be provided in the 
Laboratory Manual. 
8.9.3.9 Pharmacogenomic Assessments 
Genetic sampling will occur at the Day 0 visit. The purpose of this sample is to determine 
acetylation status (rapid, slow) and will not be used for further research. 
These samples will be sent to a central laboratory for testing. The name and address of the 
pharmacogenomic laboratory used in this study will be maintained in the Investigator’s files at 
each site. 
Subjects will provide an additional blood sample at Day 0.  Donation of samples is optional, 
has no impact on participation in the main study.  To ensure subject confidentiality samples 
will be stored and analyzed in a de-identified format.   
Subjects have the right to withdraw consent from this additional component, with no impact on 
participation in the main study. Any results generated will not be made available, unless 
required to do so by law.  Subjects can request results of any analysis on their samples, although 
it won’t be possible to interpret these.  No record of participation in this pharmacogenomics 
portion of the protocol, or any results derived from it, should be recorded in the subjects’ 
medical records.  A record of participation in the pharmacogenomics portion of the protocol 
will, however, be captured in the study-specific source documentation records or eCRF. 
Complete instructions for sample processing, handling and shipment will be provided in the 
Laboratory Manual. 
8.9.3.10 Quality of Life Assessments 
A six-point Likert scale will be provided to subjects to complete at the Week 3 Office Visit and 
the Week 6 Visit. 
8.10 
Retention of Testing Samples 
Samples will be retained for at least 5 years following the date of the New Drug Application 
(NDA) or supplemental NDA approval or if the Investigational New Drug (IND) is 
discontinued, at least 5 years following the date of completion of the study. 


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9. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
9.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can, therefore, be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1994).   
All AEs are collected from the time the informed consent is signed until the subject discontinues 
or until Week 6 (whichever is first) and are to be recorded on the appropriate AE pages in the 
eCRF and in source documents. AEs will continue to be followed and collected during the 
Open-Label phase of the trial.  Where possible, a diagnosis, rather than a list of symptoms, 
should be recorded.  If a diagnosis has not been made, then each symptom should be listed 
individually.  In addition to untoward AEs, unexpected benefits outside the investigational 
product indication should also be captured on the AE eCRF. 
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), an outcome is reached, stabilization (the Investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained regardless of whether the subject is still participating in the study.  When appropriate, 
medical tests and examinations are performed so that resolution of event(s) can be documented. 
9.1.1 
Severity Categorization 
The severity of AEs must be recorded during the event including the start and stop dates for 
each change in severity.  An event that changes in severity should be captured as a new event.  
Worsening of pre-treatment events, after initiation of investigational product, must be recorded 
as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing 
of investigational product, but the dyspepsia becomes severe and more frequent after first dose 
of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF). 
The medical assessment of severity is determined by using the following definitions: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living.  
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research subject. 


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Severe: 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
9.1.2 
Relationship Categorization 
A Physician/Investigator must make the assessment of relationship to investigational product 
for each AE.  The Investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product.  If 
there is no valid reason for suggesting a relationship, then the AE should be classified as ‘not 
related’.  Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and the 
occurrence of the AE, then the AE should be considered ‘related’.  The causality assessment 
must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship between the event and the administration 
of the investigational product is compelling and/or follows a known 
or suspected response pattern to that product, and the event cannot 
be explained by the subject’s medical condition, other therapies, or 
accident. 
Not Related 
No 
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event. 
9.1.3 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae  
• Recovering/Resolving 
• Unknown 
9.1.4 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs if they are within the normal 
day-to-day fluctuation or expected progression of the disease.  However, significant worsening 
of the symptoms should be recorded as an AE. 


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Adverse events should not be recorded in the eCRF if they are represented by any of the 
following: 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
however, the condition that required the procedure is considered an adverse event if the 
situation developed or worsened after enrollment into the study. 
Pre-existing diseases or baseline conditions present or detected at the start of the study that 
do not worsen. 
Situations where an untoward medical occurrence has not taken place (e.g., hospitalization 
for elective surgery, social or convenience admissions). 
9.1.5 
Study-specific Events of Interest 
Duration, course, and any medical intervention or dose adjustment will be captured in the 
eCRF. All study-specific events of interest should also be assessed for serious adverse event 
criteria (refer to section 9.2.3) and reported on the appropriate eCRF.   
Hypotension 
Since there is no single blood pressure measurement that will define hypotension for all study 
subjects, hypotension is to be recorded as an event of interest if the observed decrease in blood 
pressure was more than what the investigator anticipated.  
In the conscious subject, whenever hypotension is recorded as an adverse event, it is to be 
classified as either a significant decrease in SBP or sufficiently low blood pressure defined as 
 80 mmHg. 
Atrial Fibrillation 
New-onset of persistent atrial fibrillation requiring intervention.  
Other Clinically Significant Arrhythmias  
Except for new-onset atrial fibrillation, clinically significant arrhythmias will be defined as any 
rhythm that requires medical intervention such as pacing, or the addition, removal, or dose 
adjustment of any drugs in an attempt to treat the abnormal rhythm.  
Aborted Resuscitated Death 
The incidence of survival following a cardiac arrest. 
Stroke 


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Stroke will be defined as a new the rapid onset of a new neurological deficit of cerebrovascular 
cause that persists beyond 24 hours (non-fatal) or is interrupted by death within 24 hours (any) 
with evidence of new neurological lesion on imaging modalities. 
9.1.6 
Clinical Laboratory Evaluations 
A change in the value of a clinical laboratory investigation can represent an AE if the change 
is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value or a further worsening of an 
already abnormal value.  When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing 
treatment or after the end of treatment with the investigational product, and the range of 
variation of the respective parameter within its reference range, must be taken into 
consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed until 
the values return to within the reference range or until a plausible explanation (e.g., concomitant 
disease) is found for the abnormal clinical laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory parameter is clinically significant and 
therefore represents an AE. 
9.1.7 
Pregnancy 
All pregnancies are to be reported from the time first infusion of study drug is received until 
the subject discontinues the study. 
Any report of pregnancy for any female study participant must be reported within 24 hours to 
the Medpace Pharmacovigilance Department using the Medpace Pregnancy Report Form.   
The female study participant must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the Investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the provided SAE form.  Note:  An elective 
abortion is not considered an SAE. 
In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the provided SAE form as well as the Pregnancy Report 


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Form.  The test date of the first positive serum/urine HCG test or ultrasound result will 
determine the pregnancy onset date. 
In animal studies, levosimendan was not teratogenic, but it caused a generalized reduction in 
the degree of ossification in rat and rabbit fetuses with anomalous development of the 
supraoccipital bone in the rabbit. When administered before and during early pregnancy, 
levosimendan reduced fertility (decreased the number of corpora lutea and implantations) and 
exhibited developmental toxicity (decreased pups per litter and increased the number of early 
resorptions and post-implantation losses) in the female rat. The effects were seen at clinical 
exposure levels. 
9.1.8 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
Sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 9.2.  Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than one category. 
• Abuse – Persistent or sporadic intentional intake of the investigational product when used 
for a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.  
• Misuse – Intentional use of the investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).  
• Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose. 
• Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product.  For studies, medication errors are reportable to the Sponsor 
only as defined below. 
Cases of subjects missing doses of product are not considered reportable as medication errors.  
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of an expired product should be considered as a reportable 
medication error.  
To prevent possible medication errors or miscalculations, refer to Attachment 1 of this protocol 
before administration of study drug 


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9.2 
Serious Adverse Event Procedures 
9.2.1 
Reference Safety Information 
The reference for safety information for this study is the Investigator’s Brochure/Summary of 
Product Characteristics/SmPC which the Sponsor has provided to all Investigators. 
9.2.2 
Reporting Procedures 
Initial Reports 
All SAEs must be reported to Medpace Clinical Safety within 24 hours of the knowledge of 
the occurrence.  
 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria 
and it is not possible to access the EDC system, send an email to Medpace Safety at medpace-
safetynotification@medpace.com or call the Medpace SAE hotline (phone number listed 
below), and fax/email the completed paper SAE form to Medpace (contact information listed 
below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
 
 
 
 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
subject dies. 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE 
form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., subject discharge summary or autopsy reports) to Medpace Clinical 
Safety via fax or e-mail. If it is not possible to access the EDC system, refer to the procedures 
outlined above for initial reporting of SAEs.  
 
Safety Contact Information: 
Medpace Clinical Safety 
 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, dial “3” or +1-513-579-9911, dial “3” 
Facsimile: +1-866-336-5320 or +1-1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 
 


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Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless they result in an SAE.  
9.2.3 
Serious Adverse Event Definition 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital abnormality/birth defect 
• Is an important medical event; Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in subject 
hospitalization; or the development of drug dependency or drug abuse.   
Hospitalizations, which are the result of elective or previously scheduled surgery for pre-
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs.  For example, admission for a previously scheduled ventral hernia repair 
would not be classified as an SAE.  
However, complication(s) resulting from hospitalization for an elective or previously scheduled 
surgery that meets serious criteria must be reported as SAE(s). 
9.2.4 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject prior to study entry or leading 
up to the onset date of the SAE or following the resolution date of the SAE, must be recorded 
as an AE, if appropriate. 


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9.2.5 
Fatal Outcome 
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date.  For all other events ongoing at time of death that did not contribute to the subject’s death, 
the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product). 
9.2.6 
Regulatory Agency, Institutional Review Board, and Site Reporting 
The Sponsor is responsible for notifying the relevant regulatory authorities/US central 
Institutional Review Boards (IRBs) of related, unexpected SAEs. 
In addition, the Sponsor (or designee) is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the program.   
The Investigator is responsible for notifying the local IRB, or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
9.2.7 
Serious Adverse Event Collection Timeframe 
All SAEs (regardless of relationship to study) are collected from the time the subject signs 
informed consent until the subject discontinues the study or Week 6 (whichever comes first) 
and must be reported to the Medpace Pharmacovigilance Department within 24 hours of the 
first awareness of the event.  
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the Investigator at any interval after the study has completed must be reported to the Med Pace 
Pharmacovigilance Department within 24 hours of the first awareness of the event. 
SAEs will be collected for subjects who continue to receive study drug in the Open-Label phase 
of the study, post Week 6, until they discontinue use of Levosimendan for purposes related to 
this protocol. 
10. 
DATA MANAGEMENT AND STATISTICAL METHODS 
10.1 Data Collection 
The Investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  


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When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the Investigator’s Meeting (if applicable).  It is expected that site personnel will 
complete the eCRF entry within five business days of the subject’s visit. 
10.2 Clinical Data Management 
Data collected. eCRF will follow certain pre-set standards. Quality control and data validation 
procedures are applied to ensure the validity and accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification 
are to be communicated to the site for resolution.  Only authorized personnel will make 
corrections to the clinical database, and all corrections are to be documented in an auditable 
manner. 
Hemodynamic data recorded by clinical staff during the required right heart catheterization 
measurements will undergo a central adjudication (blinded by patient, treatment, time, and site) 
by reviewing the electronic tracing captured during right heart catheterization and provided by 
the clinical site.   The adjudicated data will be used in the final data analyses.    
 
10.3 Statistical Analysis Process 
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to unblinding to preserve the integrity of 
the statistical analysis and study conclusions.  All statistical analyses will be performed after 
the database is locked and unblinded.  Statistical analyses will be performed using Version 9.33 
or higher of SAS (SAS Institute, Cary, NC 27513).  
10.4 Selection of Subjects to be Included in the Analyses 
Screened Set – The set of subjects who have signed informed consent. 
Enrolled Set – Subjects who have signed informed consent and met open-label lead-in 
inclusion-enrollment criteria.  
Randomized Set – Enrolled subjects who met the inclusion-randomization criterion as 
responders to levosimendan for whom a randomization number has been assigned. 
Safety Analysis Set – Enrolled/Randomized subjects who received any study drug  
Full Analysis Set – Randomized subjects who received any study drug and completing the 
study with Week 6 office visit. 


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Per-Protocol Set – Subjects in the Full Analysis Set who have completed the final scheduled 
primary assessment for the study and do not have pre-defined major protocol deviation. 
Pharmacokinetic Set – Subjects in the Full Analysis Set for whom the primary 
pharmacokinetic data is considered sufficient and interpretable. 
10.5 Subject Disposition 
Subjects in each analysis set, as well as subjects who complete the study, and subjects who 
prematurely discontinue from the study will be summarized by treatment group using 
descriptive statistics.  In addition, for subjects who prematurely discontinue from the study, the 
reasons for discontinuation will be summarized by treatment group.  Note:  Subjects who 
discontinue the study prior to the Week 6 office visit will be replaced to ensure 18 randomized 
subjects in both arms (levosimendan, placebo) have completed the study for the primary 
analysis. 
10.6 Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the Safety Analysis Set and Full Analysis Set.   
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups at baseline.  Continuous variables such as subject age, weight, height, and 
body mass index (BMI) will be summarized using number of observations, mean, standard 
deviation, median, minimum, and maximum values.  Categorical variables such as subject sex 
and race will be summarized using number of observations and percentages for each category.   
Medical history will be summarized by treatment group using the number of observations and 
percentages of subjects reporting each category. 
10.7 Investigational Product Exposure  
Summary statistics for the duration of exposure to investigational product will be presented by 
treatment group.  The number of subjects receiving each dose will be summarized by treatment 
group and by visit in the study.  Compliance rates will be summarized by treatment group at 
each visit. 
10.8 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary.  Prior and concomitant medications will be listed and summarized by preferred 
drug name and treatment group. 


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10.9 Efficacy Analyses 
All efficacy analyses will be based on the Full Analysis Set and all statistical tests will be 2-
sided hypothesis tests performed at the 5% level of significance.  Also, all confidence intervals 
will be 2-sided 95% confidence intervals, unless stated otherwise. 
10.9.1 Primary Efficacy Variable 
The primary efficacy variable is defined as the change from baseline PCWP with bicycle 
exercise (25 watts) at 6 weeks.   The baseline PCWP with bicycle exercise (25 watts) is defined 
as the value obtained prior to lead-in study drug infusion on Day 0.  
The primary efficacy analysis will be conducted over the Full Analysis Set.  The PCWP will be 
analyzed using an analysis of covariance (ANCOVA) model with change from baseline to 
Week 6 in PCWP as dependent variable, treatment group and analysis site as factors.   
For patients who withdraw before Week 6 endpoint, multiple imputation methods with missing 
at random and missing not at random will be used.  A sensitivity analysis will include an 
adjustment for baseline.   An additional analysis will be performed on the Full Analysis Set that 
met recruitment criteria and received all weekly infusions, the Per-Protocol Set. 
10.9.2 Secondary Efficacy Variables 
The following secondary variables will be assessed in this study. 
• 
Change in Cardiac Index at rest and with exercise at Week 6 
• 
Change in PVR effect at rest and with exercise at Week 6 
• 
Change in PCWP when supine and legs elevated at Week 6 
• 
Patient global assessment (based on a six-point Likert scale) at Week 6  
• 
Exercise duration 6-min walk test at Week 6  
• 
Physician’s Assessment of Functional Class 
• 
Clinical Events:  Death and hospitalizations  
 
Analyses will be performed on the Full Analysis Set.  Hemodynamic responses during the 
initial lead-in infusion will be summarized using descriptive statistics for all subjects 
receiving levosimendan and in PH-HFpEF strata.  The hemodynamic variables will be 
analyzed using the same ANCOVA model as the primary endpoint.   A sensitivity analysis 
will include an adjustment for baseline.   All secondary analyses will be performed in the Full 


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Analysis Set.   Exercise tolerance differences will be tested using an ANOVA with effects for 
treatment and investigative site.  Treatment differences in the subjects’ response identified by 
Likert Scale will be analyzed by a Mann–Whitney–Wilcoxon test.   
10.9.3 Exploratory Efficacy Variables 
• 
Change in echo measurements of RV size and TAPSE  
A description of the analyses will be included in the SAP.  
10.10 
Safety Analyses 
Adverse events will be coded using MedDRA.  The number of events, incidence, and 
percentage of treatment-emergent adverse events (TEAE) will be calculated overall, by system 
organ class (SOC), and by preferred term.  Treatment-emergent adverse events will be further 
summarized by severity and relationship to the investigational product.  Adverse events related 
to the investigational product, AEs leading to withdrawal, SAEs, and deaths will be 
summarized/listed. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit.  Potentially clinically important findings will also be summarized or listed. 
10.11 
Pharmacokinetic Collection and Analyses 
Pharmacokinetic samples will be collected post-infusion (24+2 hrs.) post Lead-in infusion and 
at the Week 6 visit. Analysis will occur via a central laboratory.  
10.12 
Sample Size Calculation and Power Considerations 
The sample size was estimated for the primary comparison of levosimendan and placebo using 
SAS (v9.4) for windows procedure PROC POWER.   
A total of 36 randomized subjects (at 1:1 levosimendan vs. placebo) will provide 80% power 
to detect the difference at two-sided 0.05 level, assuming an SD of 5 mmHg in PCWP and a 
treatment difference of ≥4.9 mmHg. 
Randomized subjects that have not received study drug weekly through Week 5 and returned 
for evaluation on Week 6 will be replaced to ensure 18 subjects have completed in each study 
group.  
11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, and local 
ethical and legal requirements.   


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11.1 
Sponsor’s Responsibilities 
11.1.1 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations and ICH Good Clinical Practice (GCP) Guideline E6 (1996). 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the Sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
inter/national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The Sponsor ensures that Local Regulatory Authority requirements are met before the start of 
the study.  The Sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any Regulatory Authority approvals required prior 
to release of investigational product for shipment to the site. 
11.1.2 
Public Posting of Study Information 
The Sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating Investigators’ names 
and contact information.  
11.1.3 
Study Suspension, Termination, and Completion 
The Sponsor may suspend or terminate the study or part of the study at any time for any reason.  
If the study is suspended or terminated, the Sponsor will ensure that applicable regulatory 
agencies and IRBs are notified as appropriate.  Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly. 
11.2 
Investigator’s Responsibilities 
11.2.1 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (R2) 2016, and applicable regulatory requirements and guidelines. 
It is the Investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to committing to participate in this study.  The 
Investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 


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The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. Curriculum vitae for Investigators and sub-
investigators are provided to the study Sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the Investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A Coordinating Principal Investigator is appointed to review the final Clinical Study Report for 
multi-site studies.  Agreement with the final Clinical Study Report is documented by the signed 
and dated signature of the Coordinating Principal Investigator, in compliance with ICH 
Guidance E3 (1995).  
11.2.2 
Protocol Adherence and Investigator Agreement 
The Investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The Investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an Investigator Agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the Investigator suspends or terminates the study at their site, the Investigator will promptly 
inform the Sponsor and the IRB and provide them with a detailed written explanation.  The 
Investigator will also return all investigational product, containers, and other study materials to 
the Sponsor.  Upon study completion, the Investigator will provide the Sponsor, IRB, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the Sponsor, applicable CRO, Investigator, or for 
multi-site studies, the Coordinating Principle Investigator according to national provisions and 
will be documented in the Investigator Agreement. 
11.2.3 
Documentation and Retention of Records 
11.2.3.1 Case Report Forms 
The electronic Case Report Form (eCRF) is supplied by Medpace and should be handled in 
accordance with instructions from the Sponsor.  
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  Case Report Forms must be 
completed by the Investigator or designee as stated in the site delegation log.  All data will have 
separate source documentation; no data should be recorded directly onto the eCRF. 
All data sent to the Sponsor must be endorsed by the Investigator.  


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The CRA/Study Monitor will verify the contents against the source data per the Monitoring 
Plan.  If the data are unclear or contradictory, queries are sent for corrections or verification of 
data. 
11.2.3.2 Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but is not limited to: subject’s 
medical file, subject quality of life assessments, original clinical laboratory reports, and 
histology and pathology reports. 
All key data must be recorded in the subject’s medical records. 
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The CRA/Study Monitor (and auditors, IRB or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the Sponsor or its representatives, national or local 
regulatory authorities, or the IRB having access to source data (e.g., subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).   
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (e.g., the US Food 
and Drug Administration [FDA], European Medicines Agency [EMA], UK Medicines and 
Healthcare Products Regulatory Agency [MHRA]) or an auditor).   
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor.   
11.2.3.3 Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
US national and local regulatory authorities), the EMA, the MHRA, other regulatory 
authorities, the Sponsor or its representatives, and the IRB for each site. 
11.2.3.4 Financial Disclosure 
The Investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the value of the compensation for conducting the study could be 
influenced by the outcome of the study.  The following information is collected: any significant 
payments from the Sponsor or subsidiaries such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation or honoraria; any 


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proprietary interest in investigational product; any significant equity interest in the Sponsor or 
subsidiaries as defined in 21 CFR 54 2(b) (1998). 
In consideration of participation in the study, the Sponsor pays the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator agreement. 
11.3 
Ethical Considerations 
11.3.1 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or 
the subject’s legally-authorized representative as applicable is requested to sign the Informed 
Consent Form (ICF) or a certified translation, if applicable after the subject has received and 
read (or been read) the written subject information and received an explanation of what the 
study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities.  A copy of the informed consent 
documentation (i.e., a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally-authorized representative as 
applicable.  If applicable, it is provided in a certified translation of the local language.  Signed 
consent forms must remain in each subject’s study file and must be available for verification at 
any time. 
The Investigator provides the Sponsor with a copy of the consent form which was reviewed by 
the IRB and which received their favorable opinion/approval.  A copy of the IRB’s written 
favorable opinion/approval of these documents must be provided to the Sponsor, prior to the 
start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., Sponsor or Coordinating 
Principal Investigator) is responsible for this action.  Additionally, if the IRB requires 
modification of the template ICF provided by the Sponsor, the documentation supporting this 
requirement must be provided to the Sponsor. 
11.3.2 
Institutional Review Board  
It is the responsibility of the Investigator to submit this protocol, the informed consent 
document (approved by the Sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB for review, and all must be approved prior 
to site initiation. 
Responsibility for coordinating with IRBs is defined in the Investigator Agreement. 
Prior to implementing changes in the study, the Sponsor and the IRB must approve any 
revisions of any revised informed consent documents and amendments to the protocol unless 
there is a subject safety issue. 


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Investigational product supplies will not be released until the Sponsor has received written IRB 
approval of and copies of revised documents. 
The Investigator is responsible for keeping the IRB appraised of the progress of the study and 
of any changes made to the protocol, but in any case, at least once a year.  The Investigator 
must also keep the local IRB informed of any serious and significant AEs. 
11.4 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  A site that is not a Covered Entity as defined by HIPAA must provide documentation 
of this fact to the Sponsor. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the Sponsor and/or its representatives 
review their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate 
the data on behalf of the Sponsor; third parties with whom the Sponsor may develop, register, 
or market levosimendan; national or local regulatory authorities; and the IRB(s) which gave 
approval for the study to proceed.  The Sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, 
and guidelines to maintain the confidentiality of subjects' identities. 
Subjects are assigned a unique identifying number.  However, their initials and date of birth 
may also be collected and used to assist the Sponsor to verify the accuracy of the data, for 
example, to confirm that laboratory results have been assigned to the correct subject.   
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies to 
the countries where this study is conducted.  The purpose of any such transfer would include: 
to support regulatory submissions, to conduct new data analyses to publish or present the study 
results or to answer questions asked by regulatory or health authorities. 
11.5 
Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor, in advance of submission.  The 
review is aimed at protecting the Sponsor’s proprietary information existing either at the date 
of the commencement of the study or generated during the study. 
 


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12. 
REFERENCES 
1. Oktay AA, Rich JD, Shah SJ (2013) The emerging epidemic of heart failure with preserved ejection fraction. 
Curr Heart Fail Rep 10(4):401–410 
2. Oudiz RJ (2007). Pulmonary hypertension associated with left-sided heart disease. Clin Chest Med 28(1):233–
241, 
3. Hoeper, Marius M., et al. "A global view of pulmonary hypertension." The Lancet Respiratory Medicine 4.4 
(2016): 306-322 
4. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, et. al. (2009) Guidelines for the diagnosis and 
treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary 
Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), 
endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30(20):2493–
2537 
5. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, et.al. (2009) ACCF/AHA 2009 expert 
consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation 
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with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary 
Hypertension Associati.Circulation 119(16):2250–2294. 
6. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. (2009) Updated clinical 
classification of pulmonary hypertension. J Am Coll Cardiol 54(1 Suppl):43–54. 
7. D. Dixon, A. Trivedi, S. Shah. Combined post- and pre-capillary pulmonary hypertension in heart failure with 
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8. S. Shaw, D.Kitzman, B. Borlaug, L.van Heerebeek, et al.  Phenotype-Specific Treatment of Heart Failure 
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0.1161/CIRCULATIONAHA.116.021884 
9. Gorter TM, van Veldhuisen DJ, Bauersachs J, Borlaug BA, Celutkiene J, et al.  Right heart dysfunction and 
failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on 
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10. Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, et al. (2004) Hospitalization for heart failure in 
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recombinant human cardiac troponin C. A molecular modeling, fluorescence probe, and proton nuclear 
magnetic resonance study. J Biol Chem. 269 (46): 28584-90. 
14. Sorsa T, Pollesello P, and Solaro RJ (2004) The contractile apparatus as a target for drugs against heart 
failure: interaction of levosimendan, a calcium sensitizer, with cardiac troponin c. Mol Cell Biochem. 266 
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15. Yokoshiki H, Katsube Y, Sunagawa M and Sperelakis N (1997) Levosimendan, a novel Ca2+ sensitizer, 
activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 333 (2-3): 249-
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16. Pataricza J, Hohn J, Petri A, et al. (2000) Comparison of the vasorelaxing effect of cromakalim and the new 
inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol. 52 (2): 213-7. 
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367-74. 
18. Erdei N, Papp Z, Pollesello P, et al. (2006) The levosimendan metabolite OR-1896 elicits vasodilation by 
activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 148 (5): 696-702. 
19. Maytin M and Colucci WS (2005) Cardioprotection: a new paradigm in the management of acute heart 
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20. Pollesello P and Papp Z (2007) The cardioprotective effects of levosimendan: preclinical and clinical 
evidence. J Cardiovasc Pharmacol. 50 (3): 257-63. 
21. du Toit EF, Genis A, Opie LH, et al. (2008) A role for the RISK pathway and K(ATP) channels in pre- and 
post-conditioning induced by levosimendan in the isolated guinea pig heart. Br J Pharmacol. 154 (1): 41-50. 
22. Louhelainen, M., S. Merasto, P. Finckenberg, E. Vahtola, et. al.  Effects of the calcium sensitizer OR-1896, a 
metabolite of levosimendan, on post-infarct heart failure and cardiac remodeling in diabetic Goto-Kahkizaki 
rats.  British Journal of Pharmacology (2010), 160, 142–152.  
23. Erdei N, Papp Z, Pollesello P, et al. (2006) The levosimendan metabolite OR-1896 elicits vasodilation by 
activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 148 (5): 696-702. 
24. Szilagyi S, Pollesello P, Levijoki J, et al. (2004) The effects of levosimendan and OR-1896 on isolated 
hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol. 486 
(1): 67-74.  
25. Banfor PN, Preusser LC, Campbell TJ, et al. (2008) Comparative effects of levosimendan, OR- 1896, OR-
1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in 
dogs. Am J Physiol Heart Circ Physiol. 294 (1): H238-48. 
26. Louhelainen M, Merasto S, Finckenberg P, et al. (2009) Effects of calcium sensitizer OR-1986 on 
cardiovascular mortality and myocardial remodeling in hypertensive Dahl/Rapp rats. J Physiol Pharmacol. 
60 (3): 41-7. 
27. Segreti JA, Marsh KC, Polakowski JS and Fryer RM (2008) Evoked changes in cardiovascular function in 
rats by infusion of levosimendan, OR-1896 [(R)-N-(4-(4-methyl-6-oxo-1,4,5,6- tetrahydropyridazin-3-
yl)phenyl)acetamid e], OR-1855 [(R)-6-(4-aminophenyl)-5-methyl- 4,5-dihydropyridazin-3(2H)-one], 
dobutamine, and milrinone: comparative effects on peripheral resistance, cardiac output, dP/dt, pulse rate, 
and blood pressure. J Pharmacol Exp Ther. 325 (1): 331-40. 
28. Kivikko M, Lehtonen L and Colucci WS (2003) Sustained hemodynamic effects of intravenous levosimendan. 
Circulation. 107 (1): 81-6. 
29. Follath F, Cleland JG, Just H, et al. (2002) Efficacy and safety of intravenous levosimendan compared with 
dobutamine in severe low-output heart failure (the LIDO study): a randomized double-blind trial. Lancet. 360 
(9328): 196-202. 


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30. Slawsky MT, Colucci WS, Gottlieb SS, et al. (2000) Acute hemodynamic and clinical effects of levosimendan 
in subjects with severe heart failure. Study Investigators. Circulation. 102 (18): 2222-7.  
31. Nieminen MS, Akkila J, Hasenfuss G, et al. (2000) Hemodynamic and neurohumoral effects of continuous 
infusion of levosimendan in subjects with congestive heart failure. J Am Coll Cardiol. 36 (6): 1903-12.  
32. Lilleberg J, Nieminen MS, Akkila J, et al. (1998) Effects of a new calcium sensitizer, levosimendan, on 
haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass 
grafting. Eur Heart J. 19 (4): 660-8.  
33. Ukkonen H, Saraste M, Akkila J, et al. (2000) Myocardial efficiency during levosimendan infusion in 
congestive heart failure. Clin Pharmacol Ther. 68 (5): 522-31.   
34. Packer M, Colucci W, Fisher L, et al. (2013) Effect of Levosimendan on the Short-Term Clinical Course of 
Patients With Acutely Decompensated Heart Failure. JCHF. 1 (2): 103-11.   
35. Mebazaa A, Nieminen MS, Packer M, et al. (2007) Levosimendan vs. dobutamine for subjects with acute 
decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 297 (17): 1883-91.   
36. Lilleberg J, Laine M, Palkama T, et al. (2007) Duration of the haemodynamic action of a 24-h infusion of 
levosimendan in subjects with congestive heart failure. Eur J Heart Fail. 9 (1): 75-82.   
37. Kivikko M, Lehtonen L and Colucci WS (2003) Sustained hemodynamic effects of intravenous levosimendan. 
Circulation. 107 (1): 81-6.  
38. Mebazaa A, Nieminen MS, Filippatos GS, et al. (2009) Levosimendan vs. dobutamine: outcomes for acute 
heart failure subjects on beta-blockers in SURVIVE. Eur J Heart Fail. 11 (3): 304-11. 
39. Comín-Colet, J. "Multicenter, double-blind, randomized, placebo-controlled trial evaluating the efficacy and 
safety of intermittent levosimendan in outsubjects with advanced chronic heart failure: the LION Heart 
Study." Late Breaking Trials II: Heart Failure Management/Heart FAILURE 2015 Congress of the ESC-HFA. 
2015. 
40. Nieminen, Markku S., et al. "Oral levosimendan in subjects with severe chronic heart failure—the PERSIST 
study." European journal of heart failure 10.12 (2008): 1246-1254. 
41. Hosenpud, Jeffrey D. "Levosimendan, a novel myofilament calcium sensitizer, allows weaning of parenteral 
inotropic therapy in subjects with severe congestive heart failure." The American journal of cardiology 83.12 
(1999): 9-11. 
42. Michaels AD, McKeown B, Kostal M, Vakharia KT, Jordan MV, Gerber IL, Foster E, Chaterjee K. Effects 
of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and 
myocardial oxygen uptake. Circulation 2005;111:1504–9. 
43. Grossini E, Caimmi PP, Molinari C, Teodori G, Vacca G. Hemodynamic effect of intracoronary 
administration of levosimendan in the anesthetized pig. J Cardiovasc Pharmacol 2005;46:333–42. 
44. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent 
levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998;98: 
2141–2147 
45. De Luca L, Sardella G, Proietti P, Battagliese A, Benedetti G, Di Roma A, Fedel F. Effects of levosimendan 
on left ventricular diastolic function after primary angioplasty for acute anterior myocardial infarction: a 
Doppler echocardiographic study. J Am Soc Echocardiogr. 2006 Feb;19(2):172-7. 


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46. Altenberger J, Parissis JT, Costard-Jaeckle A, et al. Efficacy and safety of the pulsed infusions of 
levosimendan in outsubjects with advanced heart failure (levorep) study: a multicentre randomized trial. Eur 
J Heart Fail. 2014;16:898–906. 
47. Comin-Colet J, N. Manito, J. Servia-Cubero, J. Delgado, et al. Efficacy and safety of intermittent intravenous 
outsubject administration of levosimendan in subjects with advanced heart failure: the LION-HEART 
multicentre randomized trial.  European Journal of Heart Failure (2018) doi:10.1002/ejhf.1145. 
48. García-González MJ, et al.; LAICA Study Investigators. Efficacy and safety of intermittent. Paper presented 
at: European Society of Cardiology–Heart Failure Association Congress; May 21, AU9 2016; Florence, Italy. 
49. Szilagyi S, Pollesello P, Levijoki J, Kaheinen P, Haikala H, Edes I et al. (2004). The effects of levosimendan 
and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea 
pig. Eur J Pharmacol 486: 67–74 
50. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: 
Guidelines for the Six-minute Walk Test. Am J Respir Crit Care Med. 2002;166(1):111-7. 
51. Kleber FX, Bollmann T, Borst MM, et al. Repetitive dosing of intravenous levosimendan improves pulmonary 
hemodynamics 
in patients with 
pulmonary hypertension: Results of a pilot study. J Clin 
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52. Hoeper M, Badesch DB, et. al. Definitions and Diagnosis of Pulmonary Hypertension. J Am Coll Cardiol 
2013;62: D42–50 
 
 


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13. 
APPENDICES 
 
13.1 
APPENDIX 1: Summary of Changes to Previous Protocol Amendments 
Revisions included in Amendment 3 to the protocol, dated 15 May 2019 (Version 4.0) 
 
 
Page 
(redline 
version) 
Section 
Revisions Made 
(rationale for protocol revisions) 
 
Legend:  unaltered text, deleted text, new text 
 
 
 
Please Note:  Administrative changes are shaded 
 
Global Change 
Revised reference to Protocol amendment and date: Version 4.0, 15 
May 2019 
 
12 
Enrollment 
Criteria: 
(revised qualifying hemodynamic criteria to clarify the values may be 
observed at rest or with legs up at baseline right heart catheter (Lead-
In) 
 
3. WHO Group 2 Pulmonary Hypertension subjects with heart 
failure and preserved ejection fraction as defined by:  
a. Mean pulmonary arterial pressure (mPAP) >35 mmHg at 
rest or with legs up (at baseline right heart catheter, Lead-
In) 
b. Pulmonary capillary wedge pressure (PCWP) ≥20 mmHg at 
rest or with legs up (at baseline right heart catheter, Lead-
In) 
12 
Enrollment 
Criteria: 
(the qualifying range of six-minute walk test at baseline was expanded 
as the initial range was determined to be too restrictive and limited 
enrollment of patients that would otherwise qualify) 
 
5.   Ability to walk at least 100 50 meters, but not more than 
400 550 meters in a six-minute walk test. 
12 
Enrollment 
Criteria: 
(deleted the last phrase to elimate any confusion in the criterion. The 
only delivery route for oxygen is nasal cannula.) 
 
6.  Long term oxygen treatment (if applicable) must be stable 
for 30 days prior to enrollment, including delivery route and 
dose. 


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12 
Enrollment 
Criteria: 
(added to allow modification of antihypertensives medications prior to 
enrollment) 
 
7.  Subjects on a chronic medication or therapy for any 
underlying cardiac condition must be on a stable dose for ≥30 
days prior to randomization, with the exception of diuretics and 
antihypertensive medication for blood pressure control which 
may be discontinued if deemed appropriate. 
12 
Enrollment 
Criteria: 
(added Note to clarify interpretation of the term ”stable” as used in 
Inclusion Crierion 6-8.) 
 
Note:  With regard to Inclusion Criteria 6-8, “stable” refers to changes 
in oxygenation therapy or medications no greater than a 100% increase 
or a 50% decrease, as needed to optimize the patient. 
13 
Exclusion 
Criteria: 
(clarified that a negative stress test applies to previous CABG cardiac 
surgery patients) 
 
 1. 
Previous PCI or cardiac surgery (CABG/valve) unless 
documented to have a negative stress test within the last 12 months. 
13 
Exclusion 
Criteria: 
(reduced the period required since surgical correction of congenital 
disease with pre and post tricuspid shunts) 
 
5. 
Congenital heart disease other than surgically corrected pre and 
post tricuspid shunts for at least 10 5 years 
13 
Exclusion 
Criteria: 
(removed redundancy in text) 
 
6. 
Symptomatic coronary artery disease and/or CAD based on a 
positive stress test. 
13 
Exclusion 
Criteria: 
(expanded to incorporate published standards for obstructive and 
restrictive lung disease in obese patients that are otherwise eligible for 
the study)    
 
8. Patients diagnosed with pulmonary hypertension secondary to 
associated with clinically significant lung disease at the time of initial 
diagnosis, or patients with a congenital defect of the lung, patients with 
severe obstructive lung disease (FEV1 <60% of predicted), or patients 
with severe restrictive lung disease (FVC of <70% of predicted). 
a.  Clinically significant obstructive lung disease is defined as 
FEV1/FVC <60% of predicted, unless a high resolution chest 
CT scan shows no more than mild areas of emphysematous 
changes. 
b.  Clinically significant restrictive lung disease is defined as 
disease a FVC of <60% of predicted, unless a high resolution 
chest CT scan shows no more than mild areas of interstitial lung 
disease or pulmonary fibrosis. 
 


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13 
Exclusion 
Criteria: 
(expanded weight range to include those patients between 135 and 150 
kg that can be effectively managed on the cath lab table) 
 
13.  Weight >135150 kg 
17 
Footnotes for 
Time and Events 
Schedule 
(corrected typographical error in Weeks 2, 3, 4, 5, and 6 vist window) 
 
11. Visits at Weeks 2, 3, 4, 5, and 6 should occur within +2448 hours of the 
scheduled visit (section 8.4). 
27 
4.1 Inclusion 
Criteria 
Enrollment 
Criteria: 
(revised qualifying hemodynamic criteria to clarify the values must be 
observed at rest or with legs up at basleine (Lead-In) 
 
3. WHO Group 2 Pulmonary Hypertension subjects with heart 
failure and preserved ejection fraction as defined by:  
a. Mean pulmonary arterial pressure (mPAP) >35 mmHg at 
rest or with legs up (at baseline right heart catheter, Lead-
In) 
b. Pulmonary capillary wedge pressure (PCWP) ≥20 mmHg at 
rest or with legs up (at baseline right heart catheter, Lead-In) 
27 
4.1 Inclusion 
Criteria 
Enrollment 
Criteria: 
(the qualifying range of six-minute walk test at baseline was expanded 
as the initial range was determined to be too restrictive and limited 
enrollment of patients that would otherwise qualify) 
 
5. Ability to walk at least 100 50 meters, but not more than 400 550 
meters in a six-minute walk test. 
27 
4.1 Inclusion 
Criteria 
Enrollment 
Criteria: 
(deleted the last phrase to elimate any confusion in the criterion;  the 
only delivery route for oxygen is nasal cannula) 
 
6.  Long term oxygen treatment (if applicable) must be stable for 30 
days prior to enrollment, including delivery route and dose. 
28 
4.1 Inclusion 
Criteria 
Enrollment 
Criteria: 
(added to allow modification of antihypertensives medications prior to 
enrollment) 
 
7.  Subjects on a chronic medication or therapy for any underlying 
cardiac condition must be on a stable dose for ≥30 days prior to 
randomization, with the exception of diuretics and antihypertensive 
medication for blood pressure control which may be discontinued if 
deemed appropriate. 
28 
4.1 Inclusion 
Criteria 
Enrollment 
Criteria: 
(added Note to clarify interpretation of the term ”stable” as used in 
Inclusion Crierion 6-8.) 
 
Note:  With regard to Inclusion Criteria 6-8, “stable” refers to changes 
in oxygenation therapy or medications no greater than a 100% increase 
or a 50% decrease, as needed to optimize the patient. 
28 
4.2 Exclusion 
Criteria 
(clarified that a negative stress test applies to previous CABG cardiac 
surgery patients) 


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 1. 
Previous PCI or cardiac surgery (CABG/valve) unless 
documented to have a negative stress test within the last 12 months. 
28 
4.2 Exclusion 
Criteria 
(reduced the period required since surgical correction of congenital 
disease with pre and post tricuspid shunts) 
 
5. 
Congenital heart disease other than surgically corrected pre and 
post tricuspid shunts for at least 10 5 years 
28 
4.2 Exclusion 
Criteria 
(removed redundancy in text) 
 
6. 
Symptomatic coronary artery disease and/or CAD based on a 
positive stress test. 
29 
4.2 Exclusion 
Criteria 
(expanded to incorporate published standards for obstructive and 
restrictive lung disease in obese patients that are otherwise eligible for 
the study)    
 
8. Patients diagnosed with pulmonary hypertension secondary to 
associated with clinically significant lung disease at the time of initial 
diagnosis, or patients with a congenital defect of the lung, patients with 
severe obstructive lung disease (FEV1 <60% of predicted), or patients 
with severe restrictive lung disease (FVC of <70% of predicted). 
a.  Clinically significant obstructive lung disease is defined as 
FEV1/FVC <60% of predicted, unless a high resolution chest 
CT scan shows no more than mild areas of emphysematous 
changes. 
b.  Clinically significant restrictive lung disease is defined as 
disease a FVC of <60% of predicted, unless a high resolution 
chest CT scan shows no more than mild areas of interstitial lung 
disease or pulmonary fibrosis. 
 
29 
4.2 Exclusion 
Criteria 
(expanded weight range to include those patients between 135 and 150 
kg that can be effectively handeled on the cath lab table) 
 
13.  Weight >135150 kg 
36 
7.5.5 
Blinding 
the Treatment 
Assignment 
(deleted text in conflict with previous sentence) 
 
It is not required to use the protective sheath during the Lead-In 
infusion. 
44 
8.4 
Weeks 2-
5 (Weekly 
Infusion Visits 2, 
3, 4, and 5) 
(added window to vital sign measurements at 2 hours and 24 hours at 
weekly infusion visits) 
 
•  Measure vital signs prior to starting the infusion, after the first 2 hours 
(±30 min), and after 24 hours (±30 min). 
 
 
 


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Revisions included in Amendment 2 to the protocol, dated 25 January 2019 (Version 3.0) 
 
Page 
(redline 
version) 
Section 
Revisions Made 
(rationale for protocol revisions) 
 
Legend:  unaltered text, deleted text, new text 
 
 
 
Please Note:  Administrative changes are shaded 
 
Global Change 
Revised reference to Protocol amendment and date: Version 3.0, 25 
January 2019 
 
12 
Enrollment 
Criteria: 
(deleted reference to NHYA Subclass II”b” as the distinction is not 
universally accepted, raising questions of interpretation) 
 
3. WHO Group 2 Pulmonary Hypertension subjects with heart failure 
and preserved ejection fraction as defined by: 
 
c. NYHA Class IIb  or III 
 
13 
Exclusion 
Criteria: 
(added allowance for patients with history of previous PCI or cardiac 
surgery if there is documentation of a negative stress test in last 12 
months.) 
 
1. 
Previous PCI or cardiac surgery (CABG/valve)  unless 
documented to have negative stress test within the last 12 months. 
   
13 
Exclusion 
Criteria: 
(expanded to further clarify clinically significant lung disease) 
 
8. 
History of symptomatic COPD, restrictive lung disease, 
congenital defect of the lung, or other clinically significant lung disease 
Patients diagnosed with pulmonary hypertension secondary to lung 
disease at the time of initial diagnosis, patients with a congenital defect 
of the lung, patients with severe obstructive lung disease (FEV1 <60% 
of predicted), or patients with severe restrictive lung disease (FVC of 
<70% of predicted). 
 
 
13 
Exclusion 
Criteria: 
(clarified to note ”symptomatic” elevation in SBP to be consistent with 
Appendix 5: Cardiac Event Recommendations and Management in the 
protocol, page 81) 
 


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14. Symptomatic low  Ssystolic blood pressure (SBP) that cannot be 
managed to ensure SBP > 100 mmHg at initiation of study drug  
 
 
13 
Exclusion 
Criteria: 
(clarified to note ”symptomatic” elevation in HR to be consistent with 
Appendix 5: Cardiac Event Recommendations and Management in the 
protocol, page 81) 
 
15. Heart rate ≥100 bpm with study drug, symptomatic and  persistent 
for at least 10 minutes at Lead-in. 
 
13 
Exclusion 
Criteria: 
(revised the length of time a patients must be off vasodilator therapy 
prior to randomization, as these drugs have short half-lives) 
23. Concomitant administration of pulmonary vasodilator therapy, or 
taken within 30 14 days of randomization. 
16 
TIME AND 
EVENTS 
SCHEDULE  
Lead-In Infusion, 
Day 0 (Visit 1) 
(added to ensure lead-in dose based on a current body weight) 
Added “X” in ”Lead In” column for “Body Weight” 
16 
TIME AND 
EVENTS 
SCHEDULE  
Lead-In Infusion, 
Week 6 
(revised time window for Week 6 visit window as per the 
Administrative Letter 2.0, dated 5 November 2018; 
The timing of the Week 6 visit was revised to allow flexibility for cath 
lab scheduling.  Rather than have the visit at the END of Week 6, the 
revised visit window recommends 3-6 days following completion of the 
Week 5 infusion to ensure that final hemodynamic measurements in the 
cath lab will be made during a period that coincides with the usual range 
in plasma levels of levosimendan’s active metabolite, OR-1896.  ) 
 
Week 6 
(+ 48 hrs. 3 -6 days following completion of the Week 5 infusion.) 
 
 
 
27 
Enrollment 
Criteria: 
(deleted reference to NHYA Subclass II”b” as the distinction is not 
universally accepted, raising questions of interpretation) 
 


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Protocol TNX-LVO-04 
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TNX-LVO-04; Version 4.0   15 May 2019  
3. WHO Group 2 Pulmonary Hypertension subjects with heart failure 
and preserved ejection fraction as defined by: 
 
c. NYHA Class IIb  or III 
27 
4.2  Exclusion 
Criteria 
(added allowance for patients with history of previous PCI or cardiac 
surgery if there is documentation of a negative stress test in last 12 
months.) 
 
1. Previous PCI or cardiac surgery (CABG/valve) unless documented to 
have a negative stress test within the last 12 months . 
28 
4.2  Exclusion 
Criteria 
(expanded to further clarify clinically significant lung disease) 
 
8. History of symptomatic COPD, restrictive lung disease, congenital 
defect of the lung, or other clinically significant lung disease 
Patients diagnosed with pulmonary hypertension secondary to lung 
disease at the time of initial diagnosis, patients with a congenital defect 
of the lung, patients with severe obstructive lung disease (FEV1 <60% 
of predicted), or patients with severe restrictive lung disease (FVC of 
<70% of predicted). 
 
28 
4.2  Exclusion 
Criteria 
(clarified to note ”symptomatic” elevation in SBP to be consistent with 
Appendix 5: Cardiac Event Recommendations and Management in the 
protocol, page 81) 
 
14. Symptomatic low Ssystolic blood pressure (SBP) that cannot be 
managed to ensure SBP > 100 mmHg at initiation of study drug  
 
28 
4.2  Exclusion 
Criteria 
(clarified to note ”symptomatic” elevation in HR to be consistent with 
Appendix 5: Cardiac Event Recommendations and Management in the 
protocol, page 81) 
 
15. Heart rate ≥100 bpm with study drug, symptomatic and persistent 
for at least 10 minutes at Lead-in. 
 
29 
4.2 Exclusion 
Criteria 
(revised the length of time a patients must be off vasodilator therapy 
prior to randomization, as these drugs have short half-lives) 
23. Concomitant administration of pulmonary vasodilator therapy, or 
taken within 30 14 days of randomization. 
 
36 
7.5.5 Blinding the 
Treatment 
Assignment 
 
(Clarification to ensure the patient is consistently blinded to the 
appearance of administered study drug.) 
 


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Protective sheaths for the infusion line and bag will be used to protect 
the study drug from UV light and are required to be used at Lead-In and  
during the Week 2 through 5 infusion visits. It is not required to use the 
protective sheath during the Lead-In infusion. 
40 
8.1  Screening 
Visit (< 28 Days 
prior to Day 0) 
(added to ensure lead-in dose based on a current body weight) 
• 
Body weight 
 
44 
8.6 Week 6 (Visit 
6) 
(revised time window for Week 6 visit window as per the 
Administrative Letter 2.0, dated 5 November 2018; 
The timing of the Week 6 visit was revised to allow flexibility for cath 
lab scheduling.  Rather than have the visit at the END of Week 6, the 
revised visit window recommends 3-6 days following completion of the 
Week 5 infusion to ensure that final hemodynamic measurements in the 
cath lab will be made during a period that coincides with the usual range 
in plasma levels of levosimendan’s active metabolite, OR-1896. ) 
 
Visits at Week 6 should be performed within +48 hours of the scheduled 
visit3-6 days following completion of the Week 5 infusion. 
 
58 
10.2 Clinical 
Data 
Management 
(added clarification that final analysis will be performed on 
hemodynamic data that have been adjudicated by a central reader) 
Hemodynamic data recorded by clinical staff during the required right 
heart catheterization measurements will undergo a central adjudication 
(blinded by patient, treatment, time, and site) by reviewing the 
electronic tracing captured during right heart catheterization and 
provided by the clinical site.   The adjudicated data will be used in the 
final data analyses.    
 
 
 
 
 
 


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Protocol TNX-LVO-04 
Version: 4.0 
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TNX-LVO-04; Version 4.0   15 May 2019  
Revisions Amendment 1 to the protocol dated 10 July 2018 (Version 2.0) 
 
Page 
(redline 
version) 
Section 
Revisions Made 
 
(rationale for protocol revisions) 
 
Legend:  unaltered text, deleted text, new text 
 
 
 
Please Note:  
administrative changes are shaded 
Global Change 
Revised reference to Protocol amendment and date: version 2.0, 10 July 
2018 
16 
Time and Events 
Schedule 
 
(added body weight measurement at Interim Office Visit to allow 
modification of weight based dosing during trial) 
Body Weight added during Interim Office Visit. 
17 
Footnotes 
for 
Time and Events 
Schedule 
(added to identify requirements for safety follow-up on subjects that 
receive an open-label lead-in dose who are NOT randomized, and the 
general requirements for safety follow-up of patients who terminate the 
study early.) 
 
15. 
Subjects who receive levosimendan during the Lead-In dose but 
are not randomized into the trial, will be followed for safety for 2 weeks 
post end of 24-hour infusion. A phone contact will be made to the 
subject at 24 hours, 7 days, and 14 days post infusion by investigational 
site personnel to assess adverse events. Please see section 8.7 for further 
details regarding subjects who terminate the study early. 
39 
8. 
STUDY 
PROCEDURES 
(added to clarify designation of study “Week” relative to initial dose in 
Open Label Lead-In) 
Visits for Week 2 through Week 6 should be calculated based on the 
date of the Lead-in infusion (not the date of randomization). 
41 
8.2 
Day 
0 
(Lead-in 
Infusion, Visit 1) 
(added reference to Attachment 6 that includes an added summary of 
right heart catheter measurement procedures in the cath label) 
• 
Venous sheath placement for right heart catheterization. The 
sheath will remain following the baseline study, and the patient will be 
hospitalized where they will receive the 24-hour levosimendan infusion 
(preferably through the venous sheath). The sheath will then be used for 
access for the right heart catheterization study following the 24-hour 
levosimendan infusion, and then removed (see Attachment 6). 


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15 May 2019  
Protocol TNX-LVO-04 
Version: 4.0 
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TNX-LVO-04; Version 4.0   15 May 2019  
42 
 
(added to clarify baseline right heart catherization should be performed 
prior to levosimendan infusion) 
• 
Right heart catheterization measurements: baseline (prior to 
levosimendan infusion) and post 24-hour infusion 
 
 
(added to specify follow-up in patients who receive the lead-in 
levosimendan dose, but are NOT randomized) 
Subjects who do not respond to levosimendan based on hemodynamic 
measurements as defined in Section (7.5.3) will be withdrawn from 
screening. These subjects will be followed for safety, as outlined in 
section 8.7. 
42 
8.3 
Day 
0 
(Double-blind 
Randomization, 
Visit 1) 
(added to specify follow-up in patients who receive the Lead-in 
levosimendan dose, but are NOT randomized) 
Follow-Up in patients that are not randomized: Subjects that receive 
levosimendan during the Lead-In dose, but are not randomized into the 
trial, will followed for 2 weeks.  Phone contact will be made with the 
subject by the investigational staff at 24 hours (+ 24 hours), 7 (+2) days, 
and 14 (+2) days post Lead-In infusion. 
 
8.4 
Weeks 2-
5 
(Weekly 
Infusion Visits 2, 
3, 4, and 5) 
(added to clarify designation of study “Week” relative to initial dose in 
Open Label Lead-In) 
Visits for Weeks 2-5 should be calculated based on the date of the Lead-
in infusion. 
43 
8.5 
Interim 
Office 
Visit 
(Between Weeks 
3 and 4) 
(added body weight measurement to allow for adjustment of weight-
based dosing during the study, and the requirement to provide subjects 
with the cardiac monitoring patch for in-home application during Week 
5) 
• 
Body weight 
• 
Dispense cardiac monitoring patch 
 
8.6 
Week 
6 
(Visit 6) 
(added reference to Attachment 6 that includes an added summary of 
right heart catheter measurement procedures in the cath label) 
• 
Right heart catheterization at rest and with exercise (see section 
8.9.2 and Attachment 6) 
44 
8.7 
Early 
Termination 
(added to specify follow-up for safety in those patients that terminate 
participation in the study prior to Week 6.) 
If a subject terminates the study prematurely, all procedures listed in the 
Week 6 visit should be performed as soon as possible.  The RHC, 
echocardiogram, and 6MWT do not need to be performed for subjects 
who terminate the study early. 
Subjects will be followed for safety for 2 weeks. A phone contact will 
be made with the subject at 24 hours, (+24 hours) 7 days (±2 days), and 


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Version: 4.0 
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14 days (±2 days) post infusion by investigational site personnel to 
assess adverse events.  
If a subject discontinues greater than 24 hours after their prior infusion, 
the 24-hour phone contact does not need to be performed and the next 
phone contact beginning at 7 days should be completed. 
 
8.8 
Open 
Label Extension 
(added to specify follow-up for safety in those patients that terminate 
participation in the study prior to Week 6.) 
If a subject decides not to continue in the open label protocol after Week 
6, safety follow up phone call procedures listed in section 8.7 should be 
followed. 
45 
8.9.2 
Efficacy 
Measures 
Right 
Heart 
Catheterization 
(added to specify the sequence of positions/exercise sequence for 
measurements recorded via right heart catheterization at Day 0 (pre-and 
post- infusion) and Week 6) 
Measurements will be recorded via RHC in the following sequence: as 
the subject is supine, legs elevated, and supine with bicycle exercise (25 
watts).  See Attachment 6 for procedure. 
47 
8.9.3.5 Clinical 
Laboratory 
Evaluations 
(added to specify that PK analyses will include Levosimendan and the 
metabolites, OR-1855 and OR-1896) 
All blood laboratory test collections must be performed prior to study 
drug dosing (where other exclusions do not apply). Blood specimens for 
hematology and serum chemistry will be collected, and results obtained 
by local laboratories, except for the pharmacokinetic and genotyping 
samples. These samples will be sent to external labs for analysis of 
Levosimendan, OR-1855 and OR-1896 metabolites. 
 
 
 
 
 
 
 
 


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Protocol TNX-LVO-04 
Version: 4.0 
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TNX-LVO-04; Version 4.0   15 May 2019  
14. 
ATTACHMENTS 
 
 
 


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Version: 4.0 
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TNX-LVO-04; Version 4.0   15 May 2019  
14.1 
ATTACHMENT 1: Study Drug Dose and Dosing Table 
Preparation of the infusion 
Levosimendan/placebo infusion for the 24-hour infusion (±30 min) is prepared as 
follows: 
1) for subjects < 85 kg by adding one (1) 5 mL vial of levosimendan/placebo 
infusion concentrate to one 250 mL infusion bag or bottle of 5% Dextrose or 
0.9% Normal Saline. 
2) for subjects  85 kg by adding two (2) 5 mL vials of levosimendan/placebo 
infusion concentrate to one 500 mL infusion bag or bottle of 5% Dextrose or 
0.9% Normal Saline.  
The concentration of the diluted infusion is about 50 µg/mL (12.5mg/255mL in a 
250mL bag; 25mg/510mL in a 500mL bag). 
The diluted infusion is administered intravenously by a peripheral or central route. 
No other treatments should be administered via the same line.  
The dosing regimen 
1) During the Lead-In Phase, a continuous infusion of 0.10 µg/kg/min is 
administered over 24 hours (±30) 
2) During Weeks 2 and 3, a continuous infusion of 0.075 µg/kg/min is administered 
over 24 hours (±30) 
3) During Weeks 4 and 5, a continuous infusion of 0.10 µg/kg/min is administered 
over 24 hours (±30)  
On completion of the 24-hour infusion period, the study drug infusion is switched off 
abruptly. 
Placebo is diluted and infused intravenously according to the same schedule as 
levosimendan. 
 
 
 
 
 


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TNX-LVO-04; Version 4.0   15 May 2019  
Infusion Rates 
The table below provides detailed infusion rates (for given subject weight as mL/h) for the 
different infusion rates of a 50 µg/mL preparation of levosimendan/placebo infusion.  
Patient’s 
weight (kg) 
Infusion rate (mL/h) 
 
0.10 µg/kg/min 
0.075 µg/kg/min 
0.05 µg/kg/min 
40-44 
5 
4 
2 
45-49 
5 
4 
3 
50-54 
6 
5 
3 
55-59 
7 
5 
3 
60-64 
7 
6 
4 
65-69 
8 
6 
4 
70-74 
8 
7 
4 
75-79 
9 
7 
5 
80-84 
10 
8 
5 
85-89 
10 
8 
5 
90-94 
11 
8 
5 
95-99 
11 
9 
6 
100-104 
12 
9 
6 
105-109 
13 
10 
6 
110-114 
13 
10 
7 
115-119 
14 
11 
7 
120-124 
14 
11 
7 
125-129 
15 
12 
8 
130-134 
16 
12 
8 
135-139 
16 
13 
8 
140-144 
17 
13 
8 
145-149 
17 
13 
9 
150-154 
18 
14 
9 
155-159 
19 
14 
9 
160-164 
19 
15 
10 
165-169 
20 
15 
10 
 
Example for calculating infusion rates if weight is not indicated on the table above: 
o For a subject weighing 38 kg subject: 
o μg/kg/min infusion rate: 0.1 x 38 ÷ 50 x 60 = 5 mL/h 
o 0.075 μg/kg/min infusion rate: 0.075 x 38 ÷ 50 x 60 = 3 mL/h 
Dose reductions: 
Patients receiving 0.10 μg/kg/min should be reduced to 0.075 μg/kg/min and patients receiving 
0.075 μg/kg/min should be reduced to 0.05 μg/kg/min. Reductions below 0.05 μg/kg/min are 
not permitted. 
 


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14.2 
ATTACHMENT 2: Diagnosis of Pulmonary Hypertension  
To be considered for inclusion into this trial, all patients presenting with PH must have undergone a 
clinical evaluation to determine the etiology, based on the WHO Clinical Classification (52) as outlined 
in the figure below.                                      
 
 
 
 
 
 
 
 
 


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TNX-LVO-04; Version 4.0   15 May 2019  
14.3 
ATTACHMENT 3: Child-Pugh Classification 
Scoring System 
The score employs five clinical measures of liver disease.1 Each measure is scored 1-3, 
with 3 indicating most severe derangement. 
Measure 
1 point 
2 points 
3 points 
Total bilirubin 
μmol/l (mg/dl) 
<34 (2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/l 
>35 
28-35 
<28 
PT INR 
<1.7 
1.71-2.30 
> 2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic 
encephalopathy 
None 
Grade I-II (or 
suppressed with 
medication) 
Grade III-IV (or 
refractory) 
Different textbooks and publications use different measures. Some older reference 
works substitute PT prolongation for INR. 
In primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), the 
bilirubin references are changed to reflect the fact that these diseases feature high 
conjugated bilirubin levels. The upper limit for 1 point is 68 μmol/l (4 mg/dl), and the 
upper limit for 2 points is 170 μmol/l (10 mg/dl). 
Classification designation 
Chronic liver disease is classified as Child-Pugh class A to C, employing the added 
score from above. 
Points Class 
5-6 
A 
7-9 
B 
10-15 C 
 
Reference 
1. 
Pugh RN et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 
60(8):646-9. 


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14.4 
ATTACHMENT 4: Likert Scale 
Since starting the medication, 
please rate the symptoms listed 
below by circling your choice: 
 
Much Worse 
Somewhat 
Worse 
No Different 
Somewhat 
Better 
Much Better 
1. Shortness of breath 
1 
2 
3 
4 
5 
2. Fatigue/tiredness 
1 
2 
3 
4 
5 
3. Swelling in ankles or 
legs 
1 
2 
3 
4 
5 
4. Walking upstairs or up 
hill 
1 
2 
3 
4 
5 
5. Ability to do daily 
activities 
1 
2 
3 
4 
5 
6. Overall sense of well 
being 
1 
2 
3 
4 
5 


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14.5 
ATTACHMENT 5: Cardiac Event Recommendations and Management 
Changes in BP or HR that could represent a significant safety concern should be reported to 
the treating physician (24-hour medical hotline). 
If the subject meets any of the dose-limiting event criteria (see section 7.5.4), the following 
actions on study drug infusion should be undertaken: 
1. Blood pressure (systolic) management prior to enrollment 
a. Minimum allowed BP 100 mmHg systolic  
i. If <120 on antihypertensive meds, recommend reduce or discontinue 
ii. If >120 on antihypertensive meds, no change. 
2. Low blood pressure (systolic <100) management during trial without symptoms 
a. On diuretics 
i. With edema = no change 
ii. No edema = reduce or withdraw 
b. On antihypertensive meds 
i. Reduce/withdraw 
c. On no diuretics or antihypertensive meds 
i. No symptoms = observe 
ii. BP <90 = reduce levosimendan/placebo dose 
3. Symptomatic low BP management 
a. Follow recommendations of asymptomatic scenario (above), and 
i. BP <100 mild symptoms = levosimendan/placebo dose reduction 
ii. BP <100 severe symptoms = IV phenylephrine and 
levosimendan/placebo dose reduction 
iii. BP <90 on lowest dose = discontinue study 
4. Sinus tachycardia at rest during the infusion 
a. HR >110 = repeat three times per protocol and obtain BP to validate 
b. HR >110 without symptoms = in the absence of hypotension (above), observe 
c. HR >110 with symptoms of worsening dyspnea in the absence of hypotension 
(above) = levosimendan/placebo dose reduction 
d. HR >120 (validated) without symptoms = obtain EKG do determine if sinus 
tachycardia or atrial-fibrillation. (If HR>120 during the weekly home infusion, 
the treating physician who is available 24 hours.) 
i. If sinus tachycardia = levosimendan/placebo dose reduction or 
withdraw 
ii. If atrial fibrillation = heart rate drug management 
e. Persistent HR>120 despite any/all above measures = discontinue study 


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TNX-LVO-04; Version 4.0   15 May 2019  
14.6 
ATTACHMENT 6: Procedure for Right Heart Catheterization at Rest and 
With Exercise 
1. A venous sheath will be placed in the jugular vein percutaneously under ultrasonic 
imaging guidance. 
2. A Swan-Ganz catheter will be inserted and advanced into the pulmonary artery with 
measurements of the mean RA pressure and RV systolic and diastolic pressures. 
3. When the catheter is in the pulmonary artery, the following hemodynamic measures 
will be recorded after 5 minutes of stabilization: 
 
• Heart Rate 
• Cuff blood pressure 
• Pulse oximetry 
• PA pressure at end expiration (systolic, diastolic, mean) 
• Mean PCWP at end expiration 
• Thermodilution cardiac output 
• PA oxygen saturation 
 
4. The patient will have their legs placed on the bicycle ergometer in the resting position 
with a repeat of the following hemodynamic measures after 5 minutes of stabilization: 
 
• Heart Rate 
• Cuff blood pressure 
• Pulse oximetry 
• PA pressure at end expiration (systolic, diastolic, mean) 
• Mean PCWP at end expiration 
• Thermodilution cardiac output 
• PA oxygen saturation 
 
5. Supine bicycle exercise will be conducted at 25 watts, with the duration of the exercise 
recorded and noted. The patient will be instructed to pedal at 60 rpm. A final 
measurement will be made after 3 minutes of steady state exercise which will include 
the following:  
 
• Heart Rate 
• Cuff blood pressure 
• Pulse oximetry 
• PA pressure at end expiration (systolic, diastolic, mean) 
• Mean PCWP at end expiration 
• Thermodilution cardiac output 
• PA oxygen saturation 
 
 


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Version: 4.0 
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NOTE: For patients who develop such dyspnea that they feel unable to continue the entire 3 
minutes, the final hemodynamic measurements will be made at such time and noted.  The 24-
hour follow-up study, and the Week 6 follow-up study will also be made at the same time 
interval, even if the patient does not develop dyspnea. 
 
Any deviation from this procedure requires prior approval from the Sponsor. 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A Double-Blind, Randomized, Placebo-Controlled Study of 
Levosimendan in Pulmonary Hypertension Patients with 
Heart Failure and Preserved Left Ventricular Ejection 
Fraction (PH-HFpEF) 
Protocol Number: 
TNX-LVO-04 
Protocol Version/Date: 
Version 4.0, 15 May 2019 
Investigational Product: 
Levosimendan (Simdax) Injection 
 
 
Sponsor: 
Tenax Therapeutics, Inc. 
One Copley Parkway 
Morrisville, NC 27560 
 
 
SAP Version/Date: 
Version 2.0, 18 May 2020 
 
 
 
CONFIDENTIAL 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. 
In any event, persons to whom the information is disclosed must be informed that the information is 
privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied to you that is indicated as privileged or confidential. 


Tenax Therapeutics, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
TNX-LVO-04 
 
Version 2.0, 18 May 2020 
Page 2 of 16 
 
SIGNATURE PAGE 
 
Protocol Title: 
A Double-Blind, Randomized, Placebo-Controlled Study of 
Levosimendan in Pulmonary Hypertension Patients with Heart 
Failure and Preserved Left Ventricular Ejection Fraction (PH-
HFpEF) 
Protocol Number: 
TNX-LVO-04 
SAP Version/Date: 
Version 2.0, 18 May 2020 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 
Date 
 
 
 
 
 
 
Ran Fu, PhD 
Biostatistician 
Medpace, Inc. 
 
 
 
 
 
 
 
 
Reinilde Heyrman, MD 
Vice-President, Medical Department 
Medpace, Inc. 
 
 
 
 
 
 
 
 
Kevin Crawford, MS 
Associated Director, Clinical Operations 
Tenax Therapeutics, Inc 
 
 
 
 
 
 
 
 
Douglas Hay, PhD 
SVP, Regulatory Affairs 
Tenax Therapeutics, Inc 
 
 


Tenax Therapeutics, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
TNX-LVO-04 
 
Version 2.0, 18 May 2020 
Page 3 of 16 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
09 March 2020 
Original signed version 
2.0 
18 May 2020 
Update the Per-Protocol Set definition 
 
 


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Statistical Analysis Plan 
TNX-LVO-04 
 
Version 2.0, 18 May 2020 
Page 4 of 16 
 
TABLE OF CONTENTS 
1 
Introduction ........................................................................................................................................ 7 
2 
Study Overview .................................................................................................................................. 7 
2.1 
Study Objectives ......................................................................................................................... 7 
2.1.1 
Primary Objectives .............................................................................................................. 7 
2.1.2 
Secondary Objectives .......................................................................................................... 7 
2.1.3 
Exploratory Objectives ........................................................................................................ 7 
2.2 
Study Design ............................................................................................................................... 7 
2.2.1 
Overview ............................................................................................................................. 7 
2.2.2 
Blinding .............................................................................................................................. 8 
2.2.3 
Sample Size Calculation and Power Considerations ........................................................... 9 
2.3 
Study Endpoints .......................................................................................................................... 9 
2.3.1 
Primary Efficacy Endpoint .................................................................................................. 9 
2.3.2 
Secondary Efficacy Endpoints ............................................................................................ 9 
2.3.3 
Exploratory Efficacy Endpoint ............................................................................................ 9 
2.3.4 
Safety Endpoints ................................................................................................................. 9 
3 
Statistical Methodology .................................................................................................................... 10 
3.1 
General Considerations ............................................................................................................. 10 
3.1.1 
Study Day.......................................................................................................................... 10 
3.1.2 
Definition of Baseline ....................................................................................................... 10 
3.1.3 
Analysis Visit Windows .................................................................................................... 10 
3.1.4 
Summary Statistics ............................................................................................................ 10 
3.1.5 
Handling of Dropouts and Missing Data ........................................................................... 10 
3.2 
Analysis Populations ................................................................................................................. 11 
3.2.1 
Screened Set ...................................................................................................................... 11 
3.2.2 
Enrolled Set ....................................................................................................................... 11 
3.2.3 
Randomized Set ................................................................................................................ 11 
3.2.4 
Safety Analysis Set ........................................................................................................... 11 
3.2.5 
Full Analysis Set ............................................................................................................... 11 
3.2.6 
Per-Protocol Set ................................................................................................................ 11 
3.2.7 
Pharmacokinetic Set .......................................................................................................... 11 
3.3 
Subject Data and Study Conduct ............................................................................................... 11 
3.3.1 
Subject Disposition ........................................................................................................... 11 
3.3.2 
Protocol Deviations ........................................................................................................... 12 
3.3.3 
Demographic and Baseline Characteristics ....................................................................... 12 
3.3.4 
Medical History ................................................................................................................. 12 
3.3.5 
Concomitant Medications.................................................................................................. 12 
3.3.6 
Study Duration and Drug Exposure ................................................................................... 13 
3.4 
Efficacy Assessment ................................................................................................................. 13 
3.4.1 
Primary Efficacy Endpoints .............................................................................................. 13 


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3.4.2 
Secondary Efficacy Endpoints .......................................................................................... 14 
3.4.3 
Exploratory Efficacy Endpoints ........................................................................................ 14 
3.5 
Pharmacokinetic Assessment .................................................................................................... 14 
3.6 
Safety Assessment..................................................................................................................... 14 
3.6.1 
Adverse Events ................................................................................................................. 14 
3.6.2 
Clinical Laboratory Tests .................................................................................................. 15 
3.6.3 
Vital Signs ......................................................................................................................... 15 
3.6.4 
Electrocardiograms ........................................................................................................... 15 
3.6.5 
Cardiac Monitoring ........................................................................................................... 15 
3.6.6 
Other Safety Parameters .................................................................................................... 15 
4 
Interim Analysis................................................................................................................................ 16 
5 
Changes from Protocol-Specified Statistical Analyses ..................................................................... 16 
6 
Programming Specifications ............................................................................................................. 16 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
ANCOVA  
Analysis of Covariance  
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI  
Body Mass Index  
BUN 
Blood Urea Nitrogen 
CSR 
Clinical Study Report 
COVID-19 
Coronavirus Disease 2019 
eCRF  
Electronic Case Report Form  
ECG  
Electrocardiogram  
HFpEF  
Heart Failure with Preserved Ejection Fraction  
IRT 
Interactive Response Technology 
LLN 
Lower Limit of Normal 
LV 
Left Ventricular 
MedDRA 
Medical Dictionary for Regulatory Activities 
NYHA 
New York Heart Association 
PAP 
Pulmonary Artery Pressure 
PCWP 
Pulmonary Capillary Wedge Pressure 
PH 
Pulmonary Hypertension 
PK 
Pharmacokinetic 
PVR 
Pulmonary Vascular Resistance 
RAP 
Right Atrial Pressure 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHODrug 
World Health Organization Drug 
 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical methods to 
be implemented for the analysis of data from the study with protocol number TNX-LVO-04. The SAP will 
be finalized prior to database lock. Any deviations from the SAP after database lock will be documented in 
the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objectives 
This study will evaluate the efficacy and safety of intermittent (weekly) levosimendan infusions in 
hemodynamic improvement with exercise in Pulmonary Hypertension with Heart Failure and Preserved 
Ejection Fraction (PH-HFpEF) subjects. 
2.1.2 Secondary Objectives 
The study will evaluate the effectiveness of intermittent (weekly) levosimendan infusions in improving the 
following: 
• 
Change in Cardiac Index at rest and with exercise at Week 6 
• 
Change in pulmonary vascular resistance (PVR) effect at rest and with exercise at Week 6 
• 
Change in pulmonary capillary wedge pressure (PCWP) when supine and legs elevated at Week 6 
• 
Patient global assessment (based on a six-point Likert scale) at Week 6 
• 
Exercise duration 6-min walk test at Week 6 
• 
Physician’s Assessment of Functional Class 
• 
Clinical Events: Death and hospitalizations 
o All cause hospitalizations 
o Hospitalizations attributed to any abnormality in cardiac and/or pulmonary status.  
2.1.3 Exploratory Objectives 
Baseline echocardiographic measurements of right ventricle (RV) and left ventricle (LV) function to predict 
favorable response to levosimendan therapy. 
2.2 Study Design 
2.2.1 Overview 
This study will be conducted at approximately 20-25 sites in the United States. The Phase 2 study of 
levosimendan in PH-HFpEF subjects has been designed in two phases (Figure 1). The study will recruit 
male and female subjects meeting identified enrollment criteria for PH-HFpEF into the lead-in open label 
phase to identify “responders” to levosimendan intravenous infusion of at 0.10 μg/kg/min for 24 hours ±30 
min. Subjects that have clinically relevant responses to levosimendan will be randomized to levosimendan 
or placebo (1:1) and receive intermittent (weekly) study drug infusions (Week 2-5). The first 36 subjects 
who demonstrate a ≥4mmHg reduction in PCWP from baseline measured at bicycle exercise (25 watts) 
with no more than a 10% decrease from baseline in cardiac index will be classified as a “responder” to the 


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lead-in levosimendan dose and be randomized to the double-blind phase of the study. Patients who do not 
tolerate the initial levosimendan infusion due to excessive hypotension or tachycardia will be dropped from 
eligibility. In the double-blinded phase, patients will be randomized to levosimendan or placebo and receive 
a weekly dose of study drug intravenously at 0.075 μg/kg/min for 24 hours ±30 min and if tolerated titrated 
to 0.10 μg/kg/min for 24 hours ±30 min at Week 4. The infusion rate of study drug may be decreased or 
interrupted as clinically warranted if the subject has hypotension, tachycardia, or signs or symptoms 
consistent with hypovolemia (e.g., low systolic blood pressure [SBP], decreasing urine output with rising 
blood urea nitrogen [BUN] and serum creatinine) Record the time of discontinuation or down titration. 
Patients should be monitored closely until clinically stable. See Protocol Attachment 1 for infusion rates 
and instructions on dose adjustments. Patients will be evaluated Week 6 to determine the efficacy and safety 
of levosimendan. Randomized subjects that have not received study drug weekly through Week 5 and 
returned for evaluation on Week 6 will be replaced to ensure 18 subjects have completed in each study 
group. 
If a subject terminates the study prematurely, procedures listed in the Week 6 visit should be performed as 
soon as possible. The RHC, echocardiogram, and 6-minute walk test (6MWT) do not need to be performed 
for subjects who terminate the study early. Subjects will be followed for safety for 2 weeks after early 
termination. A phone contact will be made with the subject at 24 hours (+ 24 hours), 7 days (+ 2 days), and 
14 days (+ 2 days) post infusion by investigational site personnel to assess any new or ongoing adverse 
events. If a subject discontinues greater than 24 hours after their prior infusion, the 24-hour phone contact 
does not need to be performed and the next phone contact beginning at 7 days should be completed. The 
vital status of all subjects will be collected at the end of the trial, regardless of reason for discontinuation. 
Refer to Protocol for the time and events schedule of the study procedures. 
Figure 1: Study Design Flow Chart 
 
2.2.2 Blinding 
The blind is maintained by the use of matching placebo.  


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All subjects are to remain blinded until all subjects have completed the study (defined as Week 6) and the 
database is locked. The protocol specifies that the blind could be broken only if specific emergency 
treatment would be dictated by knowing the treatment status of the subject. In such cases, the investigator 
must contact the sponsor or designee. Please consult the Pharmacy Manual for unblinding procedures 
should the sponsor or designee be unavailable. The sponsor must be informed as soon as possible. The date, 
time, and reason for the unblinding must be documented in the appropriate section of the electronic Case 
Report Form (eCRF) and in the source document. 
2.2.3 Sample Size Calculation and Power Considerations 
The sample size was estimated for the primary comparison of levosimendan and placebo using SAS (v9.4) 
for windows procedure PROC POWER. 
A total of 36 randomized subjects (at 1:1 levosimendan vs. placebo) will provide 80% power to detect the 
difference at two-sided 0.05 level, assuming a standard deviation (SD) of 5 mmHg in PCWP and a treatment 
difference of ≥4.9 mmHg. 
2.3 Study Endpoints 
2.3.1 Primary Efficacy Endpoint 
• 
Change from baseline PCWP during bicycle exercise (25 watts) at Week 6 
2.3.2 Secondary Efficacy Endpoints 
• 
Change in Cardiac Index at rest and with exercise at Week 6 
• 
Change in PVR effect at rest and with exercise at Week 6 
• 
Change in PCWP when supine and legs elevated at Week 6 
• 
Change in mean pulmonary artery pressure (mPAP) effect at rest and with exercise at Week 6 
• 
Change in right atrial pressure (RAP) effect at rest and with exercise at Week 6 
• 
Patient global assessment (based on a six-point Likert scale) at Week 6 
• 
6MWT at Week 6 (distance)  
• 
Physician’s Assessment of Functional Class 
• 
Clinical Events: Death and hospitalizations 
2.3.3 Exploratory Efficacy Endpoint 
• 
Change in echo measurements of RV size and tricuspid annular plane systolic excursion (TAPSE)  
2.3.4 Safety Endpoints 
• 
Adverse Event 
• 
Events of Special Interest 
• 
Clinical Laboratory Evaluations 
• 
Vital Signs 
• 
Electrocardiogram 


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• 
Cardiac monitoring data (baseline, Week 5) 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Study Day 
Study day will be calculated from the date of first dose of study drug (lead-in infusion).  The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There will be no 
Day 0. 
3.1.2 Definition of Baseline  
Baseline is defined as the value obtained prior to lead-in study drug infusion on Visit 1. Note: The protocol-
specified visit ‘Day 0’ will be referred to as ‘Visit 1’ for analysis purposes. 
3.1.3 Analysis Visit Windows 
Post-baseline assessments will be assigned a visit number based on the study day. Analysis visit windows 
will be defined as below: 
• 
Screening: ≤28 Days Prior to Visit 1, 
• 
Lead-In Visit: Visit 1/Week 1/Day 1, 
• 
Visit 2/Week 2/Day 8: Day 2 to Day 11, 
• 
Visit 3/Week 3/Day 15: Day 12 to Day 18, 
• 
Interim Office Visit: Between Visit 3/Week 3 and Visit 4/Week 4, 
• 
Visit 4/Week 4/Day 22: Day 19 to Day 25, 
• 
Visit 5/Week 5/Day 29: Day 26 to Day 32, and 
• 
Visit 6/Week 6/Day 36: Day 33 or later. 
3.1.4 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects.  The denominator 
used for the percentage calculation will be clearly defined.  Continuous data will generally be summarized 
with descriptive statistics including n (number of non-missing values), mean, median, standard deviation, 
minimum, and maximum. 
3.1.5 Handling of Dropouts and Missing Data 
In cases of missing or incomplete data (e.g. adverse event [AE] and concomitant medications), the missing 
component(s) will be assumed as the most conservative value possible. For example, AEs with missing 
start dates, but with stop dates either overlapping into the treatment period or missing, will be counted as 
treatment-emergent, taking the worst-case approach. When partial dates are present in the data, both a 
partial start date and/or a partial stop date will be evaluated to determine whether it can be conclusively 
established that the AE started prior to the start of study drug or ended prior to the start of study drug. If the 
above cannot be conclusively established based on the partial and/or present dates, then the AE will be 
considered as treatment-emergent. Actual data values as they appear in the original eCRF will be presented 
in the data listings. Missing values for other variables will not be imputed and only observed values will be 
used in data analyses and presentation. 


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3.2 Analysis Populations 
3.2.1 Screened Set 
The Screened Set is defined as subjects who signed informed consent.  
3.2.2 Enrolled Set 
The Enrolled Set is defined as subjects who signed informed consent and met open-label lead-in inclusion-
enrollment criteria. 
3.2.3  Randomized Set 
The Randomized Set is defined as enrolled subjects who met all the inclusion-randomization criteria as 
responders to levosimendan for whom a randomization number was assigned. 
3.2.4 Safety Analysis Set 
The Safety Analysis Set is defined as enrolled/randomized subjects who received open-label levosimendan 
and/or any blinded study drug. 
3.2.5 Full Analysis Set 
The Full Analysis Set is defined as randomized subjects who received any blinded study drug and completed 
the study with Week 6 office visit. 
3.2.6 Per-Protocol Set 
The Per-Protocol Set is defined as subjects in the Full Analysis Set who completed the final scheduled 
primary assessment for the study and did not have pre-defined major protocol deviation. 
Major protocol deviations may include but are not limited to: 
• 
Did not meet recruitment inclusion criteria 
• 
Did not complete the Week 6 office visit (or final office visit as rescheduled due to Coronavirus Disease 
2019 [COVID-19]) 
• 
Missed more than one study drug infusion 
• 
Did not have baseline and Week 6 (or final office visit as rescheduled due to COVID-19) data for 
primary endpoint 
3.2.7 Pharmacokinetic Set 
The Pharmacokinetic Set is defined as subjects in the Full Analysis Set for whom the primary 
pharmacokinetic data is considered sufficient and interpretable. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Subjects in each analysis population, as well as subjects who complete the study, and subjects who 
prematurely discontinue from the study will be summarized by treatment assignments in the double-blind 
phase using descriptive statistics. In addition, for subjects who prematurely discontinue from the study, the 
reasons for discontinuation will be summarized by treatment group.  
Subjects who discontinue the study prior to the Week 6 office visit will be replaced to ensure 18 randomized 
subjects in both arms (levosimendan, placebo) have completed the study for the primary analysis.  If a 
subject has been identified for replacement, the Interactive Response Technology (IRT) will select the 
lowest available randomization number (with the same treatment group as the subject being selected) in the 


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"Replacement Blocks" section of the randomization schedule for the treatment assignment of the 
replacement subject. Thus, the treatment assignment of both the subject being replaced and the replacement 
subject will remain blinded. 
3.3.2 Protocol Deviations 
CSR reportable protocol deviations as defined in the Medpace Protocol Deviation Plan will be summarized 
for the Safety Analysis Set by treatment assignments in the double-blind phase and in total. The number 
and percentage of subjects with deviations will be summarized by deviation and overall.  
A data listing of all CSR reportable protocol deviations will be provided by subject. 
3.3.3 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) and age categories (<65 years, ≥65 years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2)  
• 
Baseline hemodynamic parameters (PCWP, Cardiac Index, PVR, PAP (mean), RAP) 
• 
Baseline echo measurements 
• 
Baseline 6-Minute Walk Test (exercise distance) (m) 
Demographic and baseline characteristics will be summarized with descriptive statistics or counts and 
percentages of subjects as appropriate by treatment assignments in the double-blind phase and in total for 
the Safety Analysis Set and Full Analysis Set. 
3.3.4 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0.  Counts and percentages of subjects with medical history 
by system organ class and preferred term will be summarized by treatment assignments in the double-blind 
phase and in total based on Safety Analysis Set. 
3.3.5 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and preferred term 
using the World Health Organization Drug (WHODrug) Dictionary Mar 2018 Global B3 version.  For 
summary purposes, medications will be considered prior medications if they stopped prior to the first dose 
of study drug (lead-in infusion) and concomitant medications if they were taken at any time after the first 
dose of study drug (lead-in infusion) (i.e. started prior to the first dose of study drug and were ongoing or 
started after the first dose of study drug). 
Counts and percentages of subjects taking prior and concomitant medications by ATC class and preferred 
term will be summarized by treatment assignments in the double-blind phase and in total based on the 
Safety Analysis Set.   


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3.3.6 Study Duration and Drug Exposure 
Study duration will be calculated as the date of last visit – date of first dose (lead-in phase) + 1. Study 
duration will be summarized with descriptive statistics by treatment assignments in the double-blind 
phaseand in total. Additionally, study duration will be categorized according to the following categories: 
• 
1 to 15 days, 
• 
16 to 29 days, and 
• 
>29 days. 
A summary of subjects receiving the study drug will be provided by treatment assignments in the double-
blind phase and in total for each visit on the Safety Analysis Set and Full Analysis Set. 
The number of infusions for each subject will be summarized with counts and percentages by treatment 
assignments in the double-blind phase and in total on the Safety Analysis Set and Full Analysis Set. 
3.4 Efficacy Assessment 
All efficacy analyses will be based on the Full Analysis Set and all statistical tests will be 2-sided hypothesis 
tests performed at the 5% level of significance. Also, all confidence intervals will be 2-sided 95% 
confidence intervals, unless stated otherwise. All the efficacy analyses will be performed on the assigned 
treatments in the double-blind phase. 
3.4.1 Primary Efficacy Endpoints 
Primary Analysis 
The primary efficacy variable is defined as the change from baseline PCWP with bicycle exercise (25 watts) 
at 6 weeks. The baseline PCWP with bicycle exercise (25 watts) is defined as the value obtained prior to 
lead-in study drug infusion at Visit 1. 
The primary efficacy analysis will be conducted over the Full Analysis Set. The PCWP will be analyzed 
using an analysis of variance (ANOVA) model with change from baseline to Week 6 in PCWP as dependent 
variable, treatment group as a factor.  
An example of SAS code is provided below: 
*********************************************************************** 
** PCWP = Change in PCWP from Baseline                               ** 
** TREATMENT = Treatment group where 0 if Placebo, 1 if Levosimendan ** 
*********************************************************************** 
PROC GLM; 
  CLASS TREATMENT; 
  MODEL PCWP = TREATMENT; 
  LSMEANS TREATMENT / E PDIFF CL STDERR ALPHA=0.05; 
  ESTIMATE ‘LEVOSIMENDAN VS PLACEBO' TREATMENT 1 -1 / E; 
RUN; 
Sensitivity Analyses 
Sensitivity Analyses 1: A sensitivity analysis will include an adjustment for baseline. The PCWP will be 
analyzed using an analysis of covariance (ANCOVA) model with change from baseline to Week 6 in PCWP 
as dependent variable, treatment group as a factor and baseline as a covariate.  
Sensitivity Analyses 2: A sensitivity analysis by acetylation status. The PCWP with bicycle exercise (25 
watts) at 6 weeks will be analyzed using an ANOVA with change from baseline to Week 6 in PCWP as 
dependent variable, treatment group and the acetylation status (fast, intermediate, and slow) as factors.  
Supportive Analyses 


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An additional primary endpoint analysis will be repeated on the Per-Protocol Set. 
3.4.2 Secondary Efficacy Endpoints 
The secondary efficacy analyses will be performed on the Full Analysis Set. 
Analyses of hemodynamic endpoints will be performed using the same ANOVA model as the primary 
endpoint. Series Plots will be provided for PCWP by position and visit. 
Patient global assessment (based on a six-point Likert scale) at Week 6 will be performed by a Mann-
Whitney-Wilcoxon test for each of the six symptom’s grade. Total score will be calculated as the sum of 
all 6 scores for the subjects with all 6 scores available.  
6MWT exercise distance at Week 6 will be tested using the same ANOVA model as the primary endpoint. 
Physician’s assessment of New York Heart Association (NYHA) functional class (Class I to IV) will be 
summarized at each time point by treatment group as a shift table from baseline to post-baseline time point. 
Percentages will be based on the number of subjects with both a baseline and post-baseline (at the specific 
time point) assessment. The treatment difference of physician’s assessment of functional class at Week 6 
will be tested using the two-sided Pearson’s chi-squared test. 
The incidence of death and hospitalization will be summarized by treatment group. Two-sided 95% CIs for 
the observed difference in clinical events: death and hospitalizations between the treatment groups will be 
presented based on a continuity-correct Z-statistic. A by-subjects listing of subjects who died due to any 
cause will be provided. 
3.4.3 Exploratory Efficacy Endpoints  
Echo measurements of RV size and TAPSE will be summarized using descriptive statistics by visit for each 
treatment group. A listing of echo variables will be provided. 
In addition, individual subject responses in PCWP with exercise will be compared to the select 
hemodynamic variables and derived indices (at baseline) and echo measurements (at baseline) for 
correlations to individual subject responses in PCWP (at Week 6) if data permit. 
3.5 Pharmacokinetic Assessment 
The Pharmacokinetic (PK) analyses will be documented in a separate file and performed by another vendor 
and reported separately. 
3.6 Safety Assessment 
Safety data will be summarized by actual treatment received (and in total for selected analyses) in the 
double-blind phase based on the Safety Analysis Set. 
3.6.1 Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment. All AEs are collected 
from the time the informed consent is signed until the subject discontinues or until Week 6 (whichever 
is first). All AEs will be coded to system organ class and preferred term using MedDRA version 21.0.  
Treatment-emergent adverse events (TEAEs) are defined as AEs that start after the first dose of study drug 
(lead-in infusion).  
TEAEs with onset during the lead-in phase and double-blind phase will be summarized separately.  TEAEs 
that start on or after the lead-in infusion and prior to the first double-blind infusion will be attributed to the 
lead-in phase, while TEAEs that start on or after the first double-blind infusion will be attributed to the 
double-blind phase.  All AEs that start prior to the lead-in infusion will be listed. 


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Adverse events of special interest include the following preferred terms: hypotension, atrial fibrillation, 
clinically significant arrhythmia, aborted resuscitated death, and stroke. 
An overview of TEAEs will be provided including counts and percentages of subjects with the following: 
• 
Any TEAEs (overall and by maximum severity) 
• 
Any study drug related TEAEs (overall and by maximum severity) 
• 
Any TEAEs of special interest (overall and by maximum severity) 
• 
Any serious TEAEs (TESAEs) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to discontinuation of study 
• 
Any TEAEs leading to death 
Counts and percentages of subjects will also be presented by system organ class and preferred term for each 
of the categories in the overview. 
Listings will be presented specifically for SAEs and TEAEs leading to discontinuation of study drug. 
3.6.2 Clinical Laboratory Tests 
All laboratory data will be converted to standard units during the Data Management process.  
Summary statistics will be provided for laboratory values as well as their changes from baseline for all 
laboratory parameters by treatment group.  
Counts and percentages of subjects with any post-baseline observation that is below the lower limit of 
normal (<LLN) or above the upper limit of normal (>ULN) will be summarized for each laboratory 
parameter by treatment group and total. 
3.6.3 Vital Signs 
Vital signs parameters (weight, body mass index, blood pressure [systolic and diastolic blood pressure], 
heart rate, body temperature, and respiration rate) will be summarized using descriptive statistics for by 
visit for each treatment group. The changes from baseline will also be presented.  
A listing of all vital signs will be provided by subject.  
3.6.4 Electrocardiograms 
Electrocardiogram (ECG) parameters (PR, QRS, QT, and RR) will be summarized using descriptive 
statistics at baseline and Week 6/Early Termination for the treatment group. The overall interpretation will 
be summarized by counts and percentages by treatment group and total.  
All ECG measurements and the overall interpretation will be listed by subject. 
3.6.5 Cardiac Monitoring 
Selected cardiac monitoring parameters will be summarized using descriptive statistics at baseline and 
Week 5 for the treatment group. Shifts from baseline to Week 5 will be presented for the clinical alert 
findings by treatment group and total. 
All Cardiac monitoring data will be listed by subject. 
3.6.6 Other Safety Parameters 
The pregnancy test and Child-Pugh classification will be listed by subject and visit. 


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4 INTERIM ANALYSIS 
No interim analysis is planned for this study. 
5 CHANGES 
FROM 
PROTOCOL-SPECIFIED 
STATISTICAL 
ANALYSES 
The protocol states that the hemodynamic variables will be analyzed using an ANCOVA model with effects 
for treatment and investigative site. The model name is corrected to be ANOVA model in the SAP. 
The protocol states that one of the secondary endpoints is “Exercise duration 6-min walk test at Week 6”. 
To clarify the endpoint, this endpoint is updated to “6MWT at Week 6 (distance)” in the SAP. 
The change in mPAP and RAP (at rest and with exercise, baseline vs Week 6) are added to planned analyses 
of efficacy data.  Both measurements provide useful assessments of responses to study drug by the right 
heart.  Neither hemodynamic measurement was included in the protocol defined endpoints. 
The protocol states that the major protocol deviation “Did not receive all weekly infusions” is an exclusion 
criterion for Per-Protocol Set. This criterion is updated to “Missed more than one study drug infusion” due 
to the impact of the COVID-19 pandemic. Other major protocol deviations with minor changes are updated 
due to the same reason.  
6 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be presented in 
subject data listings which will be sorted by subject and visit date as applicable.  Detailed Programming 
Specifications will be provided in a separate document.