Open-Label Rollover Study of Levosimendan in Patients With Pulmonary Hypertension With Heart Failure and Preserved Left Ventricular Ejection Fraction (PH-HFpEF)
Phase: PHASE2
Conditions: Hypertension Pulmonary Secondary Heart Failure, Right Sided Heart Failure With Normal Ejection Fraction, Heart Failure With Normal Ejection Fraction
Sponsor: Tenax Therapeutics, Inc.

PROTOCOL: TNX-LVO-05 
 
TITLE: An Open-Label Rollover Study of Levosimendan in Patients with Pulmonary 
Hypertension with Heart Failure and Preserved Left Ventricular Ejection Fraction (PH-
HFpEF)  
 
NCT Number: NCT03624010 
 
Document Approval: 04 June 2021 
 
*Note:  There is an error on the title page of the protocol.  The NCT Number referenced 
(NCT03541603) is of the parent study.  The correct NCT Number is NCT03624010 as 
documented in this cover page. 

TNX-LVO-05; Version 4.1, 04JUNE2021 
PROTOCOL:  TNX-LVO-05 
 
TITLE: 
An Open-Label Rollover Study of Levosimendan in Patients with 
Pulmonary Hypertension with Heart Failure and Preserved Left 
Ventricular Ejection Fraction (PH-HFpEF) 
 
DRUG: 
Levosimendan  
 
IND: 
IND 47,025 
 
NCT NUMBER: 
NCT03541603 
 
SPONSOR*: 
Tenax Therapeutics, Inc. 
One Copley Parkway 
Suite 490 
Morrisville, NC 27560 
info@tenaxthera.com 
 
 
 
PROTOCOL 
VERSION AND 
DATE: 
 
Version 4.1, 04 June 2021 
 
 
 
*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. 

7 June 2021

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 3 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
Investigator’s Acknowledgement 
I have read this protocol no. TNX-LVO-05 (Version 4.1) 
Title:  An Open-Label Rollover Study of Levosimendan in Patients with Pulmonary 
Hypertension 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 Harmonisation 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 
 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 4 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
LIST OF STUDY CONTACTS 
Study Sponsor: 
Tenax Therapeutics, Inc. 
One Copley Parkway 
Morrisville, NC 27560 
Kevin M. Crawford, MS, CCRA 
Director, 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 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 5 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................. 2 
LIST OF STUDY CONTACTS ....................................................................................... 4 
ABBREVIATIONS ........................................................................................................ 10 
STUDY SYNOPSIS ....................................................................................................... 12 
SCHEDULE (IV TO ORAL TRANSITION) ................................................................ 15 
1. 
BACKGROUND INFORMATION ................................................................... 17 
1.1 
Transition from Weekly IV Levosimendan to Daily Oral Levosimendan 
Regimen .............................................................................................................. 17 
1.2 
Condition Background and Current Treatment .................................................. 17 
1.3 
Product Background ........................................................................................... 18 
 
Preclinical Information ................................................................................ 18 
 
Clinical Pharmacology ................................................................................. 19 
 
Chronic Intermittent Studies of IV Levosimendan in Heart Failure and 
Pulmonary Hypertension Patients ................................................................ 20 
 
Chronic oral levosimendan treatment in severe heart failure (PERSIST) ... 21 
 
Weekly Intravenous Levosimendan Treatment in Pulmonary Hypertension 
with Heart Failure and Preserved Ejection Fraction (PH-HFpEF) .............. 22 
 
Levosimendan Clinical Safety ..................................................................... 23 
 
Rationale for Chronic Oral Levosimendan .................................................. 25 
 
Target Plasma Concentrations of OR-1896 in chronic treatment of PH-
HFpEF Patients ............................................................................................ 27 
1.3.8.1 
IV Levosimendan .............................................................................. 29 
1.3.8.2 
Oral Levosimendan ........................................................................... 29 
1.3.8.3 
Individualized Oral Dose Regimen ................................................... 30 
2. 
STUDY OBJECTIVES AND PURPOSE .......................................................... 30 
2.1 
Rationale for the Study ....................................................................................... 30 
2.2 
Study Objectives ................................................................................................. 30 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 6 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
Primary Objectives ...................................................................................... 30 
 
Secondary Objectives .................................................................................. 30 
2.3 
Study Design ...................................................................................................... 31 
 
Regimen Transition: Weekly Intravenous to Daily Oral Levosimendan .... 31 
2.4 
Number and Type of Subjects ............................................................................ 32 
2.5 
Investigational Product ....................................................................................... 32 
2.6 
Sites and Regions ............................................................................................... 32 
3. 
STUDY POPULATION ..................................................................................... 33 
3.1 
Inclusion Criteria ................................................................................................ 33 
3.2 
Exclusion Criteria ............................................................................................... 33 
3.3 
Restrictions ......................................................................................................... 34 
3.4 
Withdrawal of Subjects ...................................................................................... 34 
 
Reasons for Discontinuation ........................................................................ 35 
 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ........................ 35 
4. 
PRIOR AND CONCOMITANT TREATMENT ............................................... 35 
4.1 
Prior Treatment ................................................................................................... 35 
4.2 
Concomitant Treatment ...................................................................................... 36 
4.3 
Allocation of Subjects to Treatment ................................................................... 36 
5. 
INVESTIGATIONAL PRODUCT .................................................................... 36 
5.1 
Levosimendan .................................................................................................... 36 
5.2 
Packaging ........................................................................................................... 36 
5.3 
Labeling .............................................................................................................. 37 
5.4 
IV Levosimendan (Weekly Infusions) ............................................................... 37 
 
Dosage and Administration ......................................................................... 37 
 
Dose Adjustment ......................................................................................... 38 
 
Storage ......................................................................................................... 38 
5.5 
Oral Levosimendan ............................................................................................ 38 
 
Dosage and Administration ......................................................................... 38 
 
Dose Adjustment ......................................................................................... 40 
 
Dose-limiting Events ................................................................................... 40 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 7 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
Storage ......................................................................................................... 40 
5.6 
Investigational Product Quality Complaints ...................................................... 40 
5.7 
Drug Accountability ........................................................................................... 40 
5.8 
Subject Compliance ............................................................................................ 41 
6. 
STUDY PROCEDURES (IV LEVOSIMENDAN) ........................................... 41 
6.1 
Ongoing Weekly Infusions ................................................................................. 41 
6.2 
Weeks 48, yearly, and Follow-Up Visit (at termination) (Office Visits) ........... 41 
6.3 
Study Evaluations and Procedures ..................................................................... 42 
6.4 
42 
7. 
STUDY PROCEDURES (IV TO ORAL TRANSITION) ................................. 42 
7.1 
Treatment Transition: Weekly Intravenous to Daily Oral Levosimendan ......... 43 
 
IV-Oral Transition Week 0 .......................................................................... 44 
 
IV-Oral Transition Week 2 .......................................................................... 44 
 
IV-Oral Transition Week 4 .......................................................................... 44 
 
IV-Oral Transition Week 6 – Final Visit ..................................................... 44 
 
IV-Oral Transition Week 8 .......................................................................... 45 
7.2 
Weeks 3, 6, 12. 24, 48, and yearly through the Follow-up and/or Termination 
visit (Office Visits) ............................................................................................. 45 
7.3 
Pharmacokinetic Collection and Analyses ......................................................... 46 
7.4 
Non-successful transition to oral levosimendan ................................................. 47 
8. 
STUDY EVALUATIONS AND PROCEDURES ............................................. 47 
 
Efficacy Measures ....................................................................................... 47 
 
Safety Assessments ...................................................................................... 48 
8.1.2.1 
Medical and Medication History ....................................................... 48 
8.1.2.2 
Physical Examination (Including Height and Weight) ...................... 48 
8.1.2.3 
Adverse Event Collection .................................................................. 48 
8.1.2.4 
Vital Signs ......................................................................................... 49 
8.1.2.5 
Clinical Laboratory Evaluations ........................................................ 49 
 
Electrocardiogram ........................................................................................ 50 
8.1.3.1 
Quality of Life Assessments .............................................................. 50 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 8 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
9. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ................ 50 
9.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ................................................................................................................. 50 
 
Severity Categorization ............................................................................... 51 
 
Relationship Categorization ......................................................................... 51 
 
Outcome Categorization .............................................................................. 52 
 
Symptoms of the Disease Under Study ....................................................... 52 
 
Study-specific Events of Interest ................................................................. 53 
 
Clinical Laboratory Evaluations .................................................................. 54 
 
Pregnancy .................................................................................................... 54 
 
Abuse, Misuse, Overdose, and Medication Error ........................................ 55 
9.2 
Serious Adverse Event Procedures ..................................................................... 56 
 
Reference Safety Information ...................................................................... 56 
 
Reporting Procedures ................................................................................... 56 
 
Serious Adverse Event Definition ............................................................... 57 
 
Serious Adverse Event Collection Timeframe ............................................ 57 
 
Serious Adverse Event Onset and Resolution Dates ................................... 58 
 
Fatal Outcome .............................................................................................. 58 
 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting .................................................................... 58 
10. 
DATA MANAGEMENT AND STATISTICAL METHODS ........................... 59 
10.1 
Data Collection ................................................................................................... 59 
10.2 
Clinical Data Management ................................................................................. 59 
10.3 
Statistical Analysis Process ................................................................................ 59 
10.4 
Subject Disposition ............................................................................................. 59 
10.5 
Demographic and Baseline Characteristics ........................................................ 60 
10.6 
Investigational Product Exposure ....................................................................... 60 
10.7 
Prior and Concomitant Medication .................................................................... 60 
10.8 
Safety Analyses .................................................................................................. 60 
10.9 
Efficacy Analysis ............................................................................................... 61 
11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ....................... 61 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 9 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
11.1 
Sponsor’s Responsibilities ................................................................................. 61 
  Good Clinical Practice Compliance ............................................................. 61 
  Public Posting of Study Information ........................................................... 61 
  Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Independent Ethics Committees ............ 61 
  Study Suspension, Termination, and Completion ....................................... 62 
11.2 
Investigator’s Responsibilities ........................................................................... 62 
  Good Clinical Practice Compliance ............................................................. 62 
  Protocol Adherence and Investigator Agreement ........................................ 62 
  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 ......................................................................................... 63 
11.2.3.3  Audit/Inspection ................................................................................ 64 
11.2.3.4  Financial Disclosure .......................................................................... 64 
11.3 
Ethical Considerations ........................................................................................ 64 
  Informed Consent ........................................................................................ 64 
  Institutional Review Board .......................................................................... 65 
11.4 
Privacy and Confidentiality ................................................................................ 65 
11.5 
Publication Policy ............................................................................................... 66 
12. 
REFERENCES ................................................................................................... 66 
13. 
APPENDICES .................................................................................................... 72 
13.1 
APPENDIX 1: Summary of Changes for Previous Protocol Amendments ....... 72 
14. 
ATTACHMENTS .............................................................................................. 82 
14.1 
ATTACHMENT 1: Child Pugh Classification .................................................. 83 
14.2 
ATTACHMENT 2: Kansas City Cardiomyopathy Questionnaire ..................... 84 
14.3 
ATTACHMENT 3: Cardiac Event Recommendations and Management ......... 88 
14.4 
ATTACHMENT 4: Study Drug Dose and Dosing Table .................................. 89 
14.5 
ATTACHMENT 5: Patient Diary of Daily Heart Rate and Blood Pressure 
Readings ............................................................................................................. 91 
  

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 10 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
ABBREVIATIONS 
6MWT/D 
AE 
6-minute walk test/distance 
adverse event 
ANCOVA 
analysis of covariance 
BA 
bioavailability 
BE 
BID 
Bioequivalence 
Twice daily 
BMI 
BUN 
CABG 
body mass index 
blood urea nitrogen 
coronary artery bypass graft 
CDER 
Center for Drug Evaluation and Research 
CFR 
CK 
Code of Federal Regulations 
Creatine kinase 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CRA 
Clinical Research Associate 
eCRF 
Case Report Form 
CRO 
eCRF 
eGRF 
Contract Research Organization 
electronic case report form 
estimated glomerular filtration rate 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HFpEF 
heart failure with preserved ejection fraction 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IV 
intravenous 
IWRS 
Interactive Web Response System 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 11 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
LNH 
Low, Normal, High 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency (UK) 
NDA 
New Drug Application 
PD 
PH 
Pharmacodynamic 
Pulmonary hypertension 
PK 
pharmacokinetic 
PP 
per-protocol 
QD 
QID 
once daily  
Four times daily 
QoL 
quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
SBP 
SmPC 
TAPSE 
TID 
Statistical Analysis Plan 
Systolic blood pressure 
Summary of Product Characteristics 
Tricuspid annular plane systolic excursion 
Three times daily 
t½   
apparent terminal-phase disposition half-life 
tmax 
time to maximum plasma concentration 
TMF 
Trial Master File 
WBC 
white blood cell 
z 
apparent terminal-phase disposition rate constant 
 
 
 
 
 
 
 
 
 
 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 12 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
STUDY SYNOPSIS  
Sponsor/Company 
Tenax Therapeutics, Inc. 
 
 
Finished product: 
Oral levosimendan 
Active ingredient:  
(-)-(R)-[[4-(1,4,5,6-tetrahydro-
4-methyl-6-oxo-3-
pyridazinyl)phenyl]hydrazono] 
propanedinitrile 
Study code: TNX-LVO-05 
Date: Version 4.1 04 June 2021 
Study title:  An Open-Label Rollover Study of Levosimendan in Patients with Pulmonary 
Hypertension with Heart Failure and Preserved Left Ventricular Ejection Fraction (PH-HFpEF) 
Investigators and study centers: Centers previously performing study with levosimendan 
Objectives:  
To continue treatment levosimendan in patients who were participating in a Tenax sponsored study 
after completion of the parent study. 
Protocol Version 4.1 provides for the transition of patients receiving weekly IV levosimendan to 
daily oral levosimendan, providing the potential for convenience, more stable dosing, and less risk 
of infection. 
Methodology: This open-label rollover study is designed to allow patients to continue 
levosimendan treatment if the patient has tolerated treatment in a clinical study sponsored by Tenax 
Therapeutics Inc. (the parent study) and if, in the opinion of the Investigator, the patient may 
benefit from continued levosimendan treatment. Patient safety will be evaluated in accordance with 
institutional standards of care. 
Sample size: All patients completing the parent study and in the opinion of the Investigator, may 
benefit from continued treatment.  
Diagnosis and main criteria for inclusion and exclusion:  
Patients must meet the following criteria to be enrolled in the study: 
Inclusion Criteria: 
1. Provide a personally signed and dated informed consent document prior to initiation of any 
study-related procedures that are not considered standard of care. 
2. Completed double-blind therapy in a PH-HFpEF clinical study sponsored by Tenax 
Therapeutics, Inc 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 13 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
3. May, in the opinion of the Investigator, benefit from continued levosimendan treatment. 
4. Female patients of childbearing potential must agree to use a highly effective method of 
contraception. 
5. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
Exclusion Criteria: 
1. Discontinued treatment in the parent study for any reason other than study completion or 
Sponsor termination of the study. 
2. Pregnant or breastfeeding women. 
3. Local access to commercially available levosimendan 
4. Inability to comply with planned study procedures 
5. Patients with scheduled lung or heart transplant or cardiac surgery 
6. Dialysis developed since enrollment in parent study (either hemodialysis, peritoneal 
dialysis, continuous venovenous hemofiltration, or ultrafiltration) 
7. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
8. Liver dysfunction with Child Pugh Class B or C (see Attachment 1) 
9. Evidence of systemic bacterial, systemic fungal, or viral infection refractory to treatment 
10. Weight > 150kg 
11. Systolic blood pressure (SBP) cannot be managed to ensure SBP > 100 mmHg at initiation 
of study drug 
12. Heart rate >100 bpm with study drug, persistent for at least 10 minutes at screening. 
13. Hemoglobin < 80 g/L 
14. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline that is unresponsive to 
management. 
Investigational product, dose, and mode of administration:  
Patients will receive levosimendan at the same dose and schedule they were administered at the 
conclusion of the parent study. Ongoing patients will be transitioned from weekly IV levosimendan 
administration to daily oral levosimendan administration up to 4 mg, as tolerated, for the remainder 
of the study. 
Duration of treatment: Patients will continue receiving levosimendan in this Open-Label 
Extension Study, TNX-LVO-05, and continue in the study for 3 years following transition to oral 
levosimendan or termination of the trial by the patient or physician decision. 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 14 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
Criteria for Evaluation:  
Primary Endpoint:     
 
Incidence and severity of adverse events (AEs), clinical laboratory tests (hematology, 
chemistry), physical examination, vital signs (blood pressure [BP] and pulse rate [PR]) and 
12-lead electrocardiogram (ECG) values. 
Secondary Endpoints: 
Assessed at Weeks 3, 6, 12, 24, 48, and yearly through Follow-up/termination visit: 
 
6-minute walk test (6MWT) 
 
Patient global assessment (Kansas City Cardiomyopathy Questionnaire (KCCQ) 
instrument)  
 
Physician’s Assessment of Functional Class 
 
Clinical Events:  Death and hospitalizations  
Evaluation and statistical methods:  
Safety and efficacy data will be summarized using descriptive statistics. Formal statistical 
comparisons will not be performed. 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 15 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
TIME AND EVENTS SCHEDULE 
Procedure or 
Assessment 
Ongoing 
Protocol 
Levosimendan IV to Oral Transition10  
Ongoing Protocol11 
Final 
Visit in 
Parent 
Study 
Week 
01 
Week 
21,5 
Week 
41,5 
Final 
Visit, 
Week 
61,4 
 
Patients 
titrated at 
Week 6 should 
return on 
Week 8 
Office Visits5 (Weeks 
3, 6, 12, 24, 48 and 
yearly) since 
enrolling in study 
Follow-up 
Visit 
(termination 
visit) 
Informed Consent 
X 
X 
 
 
 
 
 
 
Confirm Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
X6 
X 
 
X 
Body Weight 
X 
X 
 
 
 
 
X 
X 
Serum Chemistry 
and Hematology 
(Local Lab)7 
X 
X 
 
 
X6 
X 
X 
X 
Child Pugh Class7 
X 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic 
Sample 
 
X2 
 
X 
X2 
X2 
 
 
Electrocardiogram 
(ECG) 
X 
X 
 
 
X6 
X 
 
X 
Levosimendan 
Administration 
(oral) / Dose 
Titration3 
 
X 
X 
X 
X4 
 
 
 
NYHA Functional 
Class 
X 
X 
 
 
X6 
X 
X 
X 
6 - Minute Walk 
Test 
X 
X 
 
 
X6 
X 
X 
X 
Adverse 
Events/SAEs8 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
procedures and 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 KCCQ 
Assessment9 
X 
X 
 
 
X6 
X 
X 
X 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 16 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
Footnotes for Time and Events Schedule 
 
1. 
Visits will be scheduled 7-9 days following completion of the levosimendan IV dose and every 14 days through the 
oral levosimendan transition (+/- 48 hrs); at the Investigator’s discretion, Week 2 and 4 visits may be performed 
remotely. 
2. 
Blood sample to be taken prior to the patient’s daily dose of oral levosimendan. 
3. 
The first dose of oral levosimendan to be taken 7-9 days after the patient’s final weekly IV levosimendan dose. 
Once oral levosimendan begins, subjects must completely discontinue weekly levosimendan infusions.  
Patients will begin a daily dose regimen of 1mg daily and titrated at 1mg increments every 2 weeks, as tolerated. 
4. 
At the investigator’s discretion, patients that have not demonstrated an adequate response to drug therapy and a 
tolerance to the 1mg levosimendan TID may be titrated to 1mg QID.  Patients that have not tolerated 1 mg 
levosimendan TID should be down titrated to 1mg BID.   All patients that are titrated at Week 6 should return for a 
Week 8 visit. 
5. 
Due to the COVID-19 pandemic, the investigator may have a phone conversation with the patient rather than 
having the patient come in for an office visit.   The phone conversation should include the following, as reported by 
the patient; adverse events, concomitant medications (new or changed), concomitant procedures, and blood 
pressure & heart rate (use provided home blood pressure cuff).   
6. 
If a patient is up or down titrated and therefore scheduled for a Week 8 visit, these procedures do not need to be 
performed at Week 6. 
7. 
Local labs will be drawn (including NT-proBNP). Child-Pugh Class is only required for patients with documented 
liver disease. 
8. 
During routine visits and throughout a participation in the study, patients should be queried for any new or changes 
to AEs, concomitant medications, concomitant procedures, hospitalizations, and/or emergency room visits  
9. 
The KCCQ should be reviewed as soon as possible after the patient completes the questionnaire to ensure all 
questions have been answered. The patient should be given the appropriate time to complete the questionnaire and 
to ask any questions they may have.  
10. These visits only pertain to patients who have consented to the transition from IV to oral levosimendan. 
11. All patients will continue to follow the Ongoing Protocol Assessments. For patients who are on IV levosimendan, 
these visits will resume for two years based on the date the patient originally entered the TNX-LVO-05 study (e.g., 
the final visit in the parent study, TNX-LVO-04) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 17 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
 
1. 
BACKGROUND INFORMATION 
1.1 
Transition from Weekly IV Levosimendan to Daily Oral Levosimendan 
Regimen 
Tenax has recently licensed oral levosimendan from the Orion Corporation.  The availability of 
an oral levosimendan capsule provides a convenient alternative to the weekly 24hr IV 
levosimendan in this study.  Importantly, the safety concerns of local and systemic infections 
associated with IV administration through a PICC line or port-a-cath administration can be 
avoided.  This protocol amendment identifies the procedures that will be used in transitioning 
consenting patients to a daily oral levosimendan dose regimen. 
Patients that do not consent to this amendment will continue in the study on IV levosimendan. 
These patients will continue treatment until two years from the date of entry into the TNX-
LVO-05 study (i.e., the final visit in the parent study, TNX-LVO-04), at which time they will 
be discontinued.  
Numerous completed studies of oral levosimendan using immediate-release capsules provide 
a rich database of PK data (levosimendan and metabolites OR-1855 and OR-1896) in healthy 
volunteers and heart failure patients. These studies are listed in the updated Investigator’s 
Brochure.  Notably, Orion performed the PERSIST study in ~300 CHF patients receiving oral 
levosimendan at 1mg QD, 1mg BID, or placebo for 6 months.   
1.2 
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 

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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 treatment of PH-HFpEF subjects acknowledge that the accepted treatment target 
is 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)   
1.3 
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).  Over 1.8 million subjects have been treated with levosimendan worldwide 
by the end of December 2019.   
A more 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).  
 
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 

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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) 
 
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.  
 
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 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) 
 

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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.   
 
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 
(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 8 weeks. Similar responses were 
observed in the mPAP of subjects 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). 

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Chronic oral levosimendan treatment in severe heart failure (PERSIST) 
PERSIST was a randomised, double-blind, multi-centre, phase II study, where 2 doses of oral 
levosimendan were compared with placebo in 307 patients with severe CHF (NYHA functional 
class IIIb-IV). The patients received either 1 mg of levosimendan once daily (102 patients), 1 
mg of levosimendan twice daily (103 patients), or placebo (102 patients) as add-on therapy for 
at least 180 days (53, 54). 
The primary endpoint of the study was an exploratory composite (called ‘Patient Journey’), 
consisting of repeated patient’s symptom assessments, worsening heart failure events and all- 
cause mortality during the first 60 days. Additionally, Minnesota Living with Heart Failure QoL 
score (MLHFQoL) and plasma NT-pro-BNP concentration were assessed repeatedly. 
Patients assigned to the lower dose of levosimendan had more severe CHF at baseline, as 
suggested by a higher median NT-pro-BNP concentration, more hospitalizations within the 
previous 12 months, and the highest furosemide (or equivalent) dose at baseline. The steady- 
state concentration of the active metabolite OR-1896 was 2.7 and 4.3 ng/ml in the lower and 
higher levosimendan group, respectively. 
There were no differences in symptoms, worsening heart failure events, and death between the 
pooled levosimendan and placebo groups, resulting in a similar Patient Journey score during 
the 60 days after randomization (p = 0.567). However, the number of worsening heart failure 
events decreased with levosimendan, but the difference compared to placebo was not 
statistically significant. 
There was a decrease (= improvement) in the MLHFQoL score during the study in all groups. 
When the levosimendan groups were pooled, a net benefit of 3-4 points over placebo was seen 
with levosimendan (p < 0.001). A substantial and persistent reduction of 30-40% was seen in 
NT-pro-BNP in both levosimendan groups, while no change was observed with placebo (p < 
0.001). 
No differences were observed in time to death or worsening heart failure, all-cause and 
cardiovascular mortality, and number of days alive and out of hospital between the pooled 
levosimendan groups and placebo. Mortality was numerically higher in levosimendan treated 
patients: 15, 8, and 6 patients died in the levosimendan 1 mg, levosimendan 2 mg, and placebo 
groups, respectively. There was no clear pattern to the excess mortality and in particular no 
evidence of an increase in arrhythmias. The low overall mortality and the fact that the highest 
number of deaths was seen with the lower levosimendan dose, which also had the most severe 
heart failure at baseline, suggest that chance may have played an important role in distribution 
of deaths. The QTc interval (Fridericia) was virtually unchanged and similar in all treatment 
groups. HR increased by 7-8 bpm in both levosimendan groups, while it was unchanged with 
placebo (p < 0.0001). The changes in BP were modest; mean decrease in systolic BP was 
maximally 2.5 mmHg in the placebo group and 1.8 mmHg and 0.6 mmHg in the lower and 
higher levosimendan dose groups, respectively. 

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The most common AE was cardiac failure, which was reported numerically more often in the 
placebo group. Ventricular tachycardia or fibrillation was reported in 1, 2 and 6 patients in the 
levosimendan 1 mg, levosimendan 2 mg, and placebo groups, respectively.    
Renal function seemed to improve in levosimendan-treated patients, as suggested by a greater 
increase in creatinine clearance in the pooled levosimendan group compared with placebo (p < 
0.001). 
In conclusion, this study failed to show a beneficial effect of levosimendan on a novel and 
unvalidated composite primary endpoint (the Patient Journey), but improvements were 
observed in QoL score, renal function, and reductions in NT-pro-BNP.  Interpretation of the 
results may have been confounded by baseline imbalances in the severity of heart failure. 
 
Weekly Intravenous Levosimendan Treatment in Pulmonary Hypertension 
with Heart Failure and Preserved Ejection Fraction (PH-HFpEF) 
Levosimendan was studied in a Phase 2 double-blind clinical study of PH-HFpEF patients 
(HELP Study, TNX-LVO-04) that tested the effects of once-weekly intravenous levosimendan 
on patient’s hemodynamics and 6-minute walk distance.  Patients were required to have 
evidence of moderate-to-severe pulmonary hypertension defined hemodynamically by a 
pulmonary artery pressure (mPAP ≥35 mmHg), a pulmonary capillary wedge pressure (PCWP 
>20 mmHg), LVEF ≥40% and NYHA II-III).   
The study was conducted in two phases.  The Lead-in Phase (open-label) consisted of a right 
heart catheter at baseline including invasive hemodynamic measurements at rest, legs up, and 
supine bicycle exercise (25 watts).  All patients then received a 24-hour (±30 min) infusion of 
levosimendan (0.10 µg/kg/min) followed by a repeat right heart catheter and hemodynamic 
measurements.  To proceed to the Chronic Phase, patients were required to be considered a 
levosimendan “responder”, defined as exhibiting a ≥4 mmHg reduction of PCWP at during 
exercise at 25 Watts with no more than a 10% decrease of cardiac index.  Responders were 
randomized to receive once weekly outpatient infusions of levosimendan or placebo. Patients 
underwent a final right heart catheter with invasive hemodynamic assessments at the final visit 
(Week 6). All hemodynamic data were read by an independent reviewer, blinded to study 
treatment.  These data were used in the final analysis of the study.  Of 44 subjects enrolled, 37 
(84%) qualified as responders and were randomized to levosimendan (n=18) or placebo (n=19).   
Patients (69±9 years old, 61% women) displayed severe combined pre- and post-capillary PH 
at baseline (resting mPAP 41±9, exercise PCWP 37±11 mmHg).  
Levosimendan was shown to be safe and effective which represents the first evidence of drug-
related improvements in both hemodynamic and clinical endpoints in patients with PH-HFpEF. 
At Week 6, levosimendan-treated patients had significant reductions in PCWP versus baseline 
at rest and with legs up (-5.10 mmHg, p=0.0006 and -6.00 mmHg, p=0.0007, respectively). The 
effect on PCWP with 25 watts exercise versus baseline compared to placebo, the primary 
endpoint, was not significant (-1.40 mmHg, 95% CI, -7.7 to 4.8, p=0.65). However, in a mixed-

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effect repeated measure regression analysis incorporating all test conditions (rest, legs up, and 
exercise), levosimendan reduced PCWP by 3.9±2.0 mmHg as compared to placebo (p=0.047). 
Importantly, levosimendan-treatment resulted in significant reductions in resting mPAP and 
RAP, two hemodynamic measures that have been shown to be highly correlated with mortality 
in PH patients.   The change from baseline to Week 6 in mPAP and RAP measured at rest was 
-5.43 mmHg, p=0.0003 and -4.50 mmHg, p=0.0004, respectively.  These hemodynamic effects 
appear the result of K-ATP activation and independent of the drug’s inotropic activity, as the 
CI f levosimendan-treated patients was unchanged.  A detailed analysis of the mechanism of 
action looking at noninvasive pressure/volume relationships did not demonstrate any inotropic 
effects following the initial 24-hour infusion of levosimendan. Rather, the data support that 
effects on the estimated stress blood volume may be important. 
Patients receiving levosimendan also had a statistically significant, and clinically significant, 
improvement in exercise capacity over placebo as measured by their 6MWD (29.3 meters (2.5, 
56.1 95%CI) p=0.0329.  6MWD did not differ at baseline but decreased by an average of -12.7 
meters in the placebo group and increased by an average of 16.6 in the levosimendan. 
 
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. 

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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 
levosimendan. This is in contrast to the laboratory safety variable analyses; in IV studies 
decreases in hemoglobin and serum potassium have been consistently reported (29, 47). 
There have been 8 studies of oral levosimendan in HF patients, including 368 levosimendan 
treated patients.  The most frequently reported AEs in cardiac patients in all oral 
levosimendan studies versus placebo were headache (13.3% vs. 2.3%) and cardiac failure 
(12.0% vs. 15.9%) followed by increased HR (7.6% vs. 1.7%), tachycardia (6.5% vs. 6.8%), 
palpitations (6.5% vs. 0.6%), dizziness (6.3% vs. 4.5%) and hypotension (6.0% vs. 3.4%). 
 
In legacy 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 the Phase 2 HELP Study in PH-HFpEF patients levosimendan was well-tolerated with 
adverse events limited to generally mild events known to be associated with the drug (e.g. 
headache, tachycardia) and events related to the disease (e.g. dyspnea, cardiac failure).   Serious 
adverse events were few, including infusion-related infection and events expected in the 
population (cardiac failure).  
No patients were discontinued due to increased heart rate or hypotension.  One patient 
discontinued with moderate palpitations on Day 4 following their open label levosimendan IV 
administration.  The patient had atrial fibrillation, non-sustained supraventricular tachycardia 
accelerated junctional tachycardia at baseline. 
The low dose and modest rate of levosimendan infusion regimen (0.075-0.1µg/kg/minute for 
24 hours weekly without initial bolus) was safe with no concerns of hypotension after the initial 
dose. Cardiac monitoring at baseline and Week 5 demonstrated the cardiac safety of a weekly 
IV infusion of levosimendan at doses up to 0.10 µg/kg/minute for 24 hours.  The weekly low 

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levosimendan dose over an extended 24-hour infusion produced no signal of arrhythmias; 
increased atrial fibrillation, sustained atrial tachycardias, symptomatic atrial arrythmias of any 
kind, sustained monomorphic ventricular tachycardias, Symptomatic ventricular arrhythmias 
of any kind, of ventricular fibrillation. 
In marketed use, over 1.8 million subjects worldwide have been treated with Simdax® 
(levosimendan) injection. The most commonly reported adverse reactions in the adverse drug 
reaction reports received from health care 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).  
 
Rationale for Chronic Oral Levosimendan  
The use of chronic oral levosimendan in treatment of PH-HFpEF subjects is based on the 
following. 
 Levosimendan is 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). 
 In the Phase 2 HELP Study in PH-HFpEF patients, levosimendan promoted 
vasodilation and peripheral perfusion, reduced pulmonary capillary wedge pressure 
(PCWP) pulmonary arterial pressure (PAP) and right atrial pressure (RAP), and 
enhanced exercise capacity.  
 In the Phase 2 HELP Study in PH-HFpEF patients, levosimendan promoted 
vasodilation and peripheral perfusion, reduced pulmonary capillary wedge pressure 
(PCWP) pulmonary arterial pressure (PAP) and right atrial pressure (RAP), and 
enhanced exercise capacity. These positive effects of levosimendan may be due to 
levosimendan’s ability to increase venous capacitance and reduce stressed blood 
volume (55). 
 Oral daily dosing of levosimendan will result in more stable blood levels of the active 
metabolite OR-1896 which is responsible for the chronic efficacy. 
 Similar improvements in cardiovascular hemodynamics have been seen in studies that 
evaluated oral dosing of levosimendan in HFrEF patients. 
 
 
 
 

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o A single dose study comparing levosimendan IV vs Oral Administration was 
conducted by Harjola et al. This study found that single oral doses of 
levosimendan (1mg, 2mg, and 4 mg) generally produced similar hemodynamic 
effects seen with comparable IV bolus doses (56) 
 
 
 
 
 
o  A sub-study of the PERSIST trial was conducted (Jalanko et al) evaluated 
hemodynamic changes seen following chronic daily doses of 1mg and 2mg 
levosimendan. Favorable changes in PCWP and BNP were observed following 
90and 180 days of daily oral administration (57) 
 

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Target Plasma Concentrations of OR-1896 in chronic treatment of PH-
HFpEF Patients 
Levosimendan represents an active prodrug to the active metabolite OR-1896 with extended 
pharmacodynamic 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 chronically active moiety of levosimendan administration is the metabolite OR-1896.  
Levosimendan is cleared within 5 hours of ending an infusion. 
The wide range of OR-1896 concentrations observed in daily oral levosimendan dosing 
(PERSIST study, see Section 1.3.4) and weekly IV administration (HELP Study, Section 1.3.5) 
precludes the identification of a specific oral dose to be used in the IV to oral transition.  
Importantly, the range of OR-1896 plasma concentrations observed in the PERSIST study of 
class IIIb-IV CHF patients overlap those observed in the HELP Study of PH-HFpEF patients 
(Figure 3).   
 
 
 
 
 

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Figure 3.  Comparison of OR-1896 Plasma Concentrations in PERSIST Study of Daily Oral 
Levosimendan (1mg QD, 1 mg BID) versus the HELP Study of Weekly IV Levosimendan (0.1 
ug/kg/min for 24 hrs). 

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However, only one third of the HELP Study patients were sampled at peak OR-1896 levels, 2-
3 days following their previous levosimendan IV dose.  The remaining patients were sampled 
beyond the period of peak OR-1896 concentrations observed in a weekly IV levosimendan 
regimen.  An opportunity to titrate patients to 4 mg total daily dose (1mg QID), as tolerated 
based on blood pressure and heart rate, will ensure all transitioning patients will achieve 
adequate steady state levels of OR-1896. 
1.3.8.1 IV Levosimendan 
OR-1896 concentrations were modeled for the intravenous levosimendan dose regimen of 
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 were expected to be between 0.5 ng/mL and 
2.5 ng/mL in extended intermittent use.  
 
 
In the HELP Study, PK samples were collected at the final visit.   Generally, the samples were 
collected 2-8 days after completion of the final levosimendan infusion on Week 5.  There was 
a large range of OR-1896 levels (0.347 to 23.8 ng/mL).   Some of the variation is associated 
with the time since completion of the previous levosimendan dose.   Patients returning 2-3 
days after their dose tended to have higher plasma concentrations of the metabolites. There 
were several apparent anomalies in levosimendan, OR-1855 and OR-1896 plasma 
concentrations which have not been explained, despite an internal audit by the laboratory 
conducting the analyses.   There was no identifiable lower or upper limit of OR-1896 that 
predicts efficacy as measured by hemodynamic or 6MWD. 
 
1.3.8.2 Oral Levosimendan 
Orion performed the PERSIST study in 307 CHF patients receiving oral levosimendan at 1mg 
QD, 1mg BID, or placebo for 6 months.  Levosimendan patients demonstrated substantial 
reductions in NT-proBNP and dose-related improvement in the Minnesota Living with Heart 
Failure quality of life score (MLHFQOL).  The mean (SD) steady state OR-1896 
concentrations were 2.7 (SD 2.8) and 4.3 (SD 3.4) ng/mL at 1mg QD and 1mg BID, 
respectively on Day 30 and remained consistent through the treatment period.   
     
The plot of OR-1896 concentrations in patients receiving oral levosimendan at 1mg QD or 
1mg BID in the PERSIST study overlaps the range of OR-1896 concentrations observed in 
patients receiving weekly intravenous levosimendan at 0.1 µg/kg/min for 24 hours in the 
HELP Study of PH-HFpEF patients (Figure 3). OR-1896 concentrations in both studies were 
highly variable.   
 

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1.3.8.3 Individualized Oral Dose Regimen 
The broad range of observed OR-1896 concentrations in the HELP and PERSIST studies 
indicates a personalized daily dose may improve individual patient response to levosimendan 
and its active metabolite OR-1896.  The wide range in plasma levels of OR-1896 observed in 
the HELP and PERSIST studies indicate steady state concentrations from daily dosing will be 
somewhat independent of body weight or the severity of CHF. The transition from IV to oral 
levosimendan provides an opportunity for personalized dosing based on patient tolerability.    
 
The step wise increases from 1mg up to 4mg daily levosimendan doses will be based on 
tolerability of the therapy.  Heart rates and blood pressures will be monitored and recorded by 
the patient each day.  Guidance will be provided to ensure measurements are standardized at 
rest during the same approximate time each day. Investigators will review the heart rate and 
blood measure measurements to ensure the patient has tolerated their current levosimendan 
dose and guide the titration (up or down) according to Attachment 3 Cardiac Event 
Recommendations and Management and investigator judgment.  
2. 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
The study will evaluate the safety and efficacy of levosimendan 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. 
2.2 
Study Objectives 
 
Primary Objectives 
This study will evaluate the safety and tolerability of levosimendan in extended use after 
completion of the parent study. 
 
Secondary Objectives 
The study will evaluate whether the effectiveness of intermittent (weekly) levosimendan  and 
daily oral levosimendan (based on patient transition) is sustained in extended use.   

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2.3 
Study Design 
This extension study is designed to investigate the safety and efficacy of extended 
levosimendan in patients who previously received levosimendan in PH-HFpEF study sponsored 
by Tenax and may, in the investigator’s opinion, derive benefit from continued treatment. 
Patients will be screened for eligibility at the last visit in the treatment period of the parent 
study. Eligible patients will be enrolled into the study immediately upon confirmation of 
eligibility so that levosimendan is not interrupted. 
 
Efficacy assessments (6MWT, Patient global assessment (based on the KCCQ instrument), 
Physician’s Assessment of Functional Class, Clinical Events; Death and hospitalizations) will 
be performed at 3, 6, 12, 24, 48, and yearly through Follow-up/Termination visit. For patients 
that  transition from IV to oral (Week 0 and 6 or 8), the Time and Events Schedule for oral 
levosimendan should be followed Patients will undergo a Follow-Up Visit (at termination) as 
soon as possible after study drug discontinuation, but within 2 weeks. 
 
For patients that transition to oral levosimendan, the patient should be instructed to monitor 
their resting heart rate and blood pressure each day prior to the first dose. The patient should 
use the home monitoring device (provided at the initiation of the initial levosimendan study) to 
determine their resting heart rate and blood pressure after being seated at rest for at least 5 
minutes.  The heart rate and blood pressure readings should be recorded in the diary provided 
as well as the number of capsules the patient has taken each day.  The patient should have their 
diary ready to review with the investigative site in each communication with the site and at 
office visits.  
 
Patients whose BP falls below the specified range will be queried regarding any symptoms of 
hypotension which may result in the down titration of the levosimendan dose.  
 
Patients whose heart rate exceeds the specified range will be queried regarding symptoms of 
worsening heart failure.  An excessive heart rate in a patient with no evidence of worsening 
heart failure, suggests that the increased heart rate is a direct drug effect requiring adown 
titration of the levosimendan dose. 
 
 
Regimen Transition: Weekly Intravenous to Daily Oral Levosimendan  
With Version 4.1, current patients may transition from intravenous (IV) levosimendan to oral 
levosimendan.  
All patients that have signed consent will be transitioned from weekly IV levosimendan to daily 
oral levosimendan over a 6-week period, with visits every 2 weeks. 
Unless otherwise noted, patients will continue to visit the investigational site at Weeks 3, 6, 12, 
24, 48 and yearly through Follow-Up Visit (at termination) up/Termination visit per the date 
the patient first started the TNX-LVO-05 study (e.g., completion of the parent study). 

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2.4 
Number and Type of Subjects 
Patients who completed all study visits through the end of the parent study were eligible to 
enroll into the Open-Label extension study. 
2.5 
Investigational Product 
Upon entry into the study, levosimendan was administered in open-label, intravenously at 0.075 
µg/kg/min for 24 hours ±30 min, or as per directed by the treating physician. A physician was 
to assess the patient’s safety at Week 3 and up-titrate to 0.1 µg/kg/min for 24 hours. The 
decision to increase the dose was to be based on the absence of disease or drug related adverse 
events and the investigator’s discretion. 
If a subject was down-titrated to 0.05 µg/kg/min in the TNX-LVO-04 study for either the Lead-
In dose or during the double-blind portion of the study, the subject was to start at this dose, with 
the first opportunity to up-titrate following at Week 3. 
All subjects will be transitioned to an oral dose of levosimendan once an informed consent form 
has been signed.  Those currently receiving levosimendan IV weekly will return to the 
investigational site and receive 1mg levosimendan capsule daily for two weeks.   
Subjects may then be titrated up every 2 weeks at 1mg levosimendan increments up to 
maximum of 4 mg daily (1mg QID), based on assessments of safety and patient’s clinical 
response (see Attachment 3 Cardiac Event Recommendations and Management ).   Patients that 
tolerate 3 mg (1mg TID) oral levosimendan TID that have not demonstrated a 6MWD 
equivalent or better than the recorded 6MWD at initiation of their IV to oral levosimendan may 
be titrated to 4 mg (1mg QID).  Patient’s that experience identified safety concerns in 
Attachment 3 should be downtitrated at 1 mg/day increments or discontinued at the physician’s 
discretion.  
Once a patient completes the transition to oral levosimendan, all IV drug and ancillary supplies 
related to the administration of IV levosimendan will be returned to the central pharmacy for 
destruction.  
At the initial visit of the IV to oral levosimendan transition, each patient will receive a supply 
of 1mg oral levosimendan capsules.  Subsequent supplies may be shipped to the patient’s home. 
2.6 
Sites and Regions 
This study will be conducted at any site that participated in the parent study and has ongoing 
patients. 

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3. 
STUDY POPULATION 
3.1 
Inclusion Criteria 
Diagnosis and main criteria for inclusion and exclusion:  
Patients must meet the following criteria to be continued in the study: 
     Enrollment Criteria: 
1. Provide a personally signed and dated informed consent document prior to 
initiation of any study-related procedures that are not considered standard of 
care. 
2. Completed double-blind therapy in a PH-HFpEF clinical study sponsored 
by Tenax Therapeutics, Inc. 
3. May, in the opinion of the Investigator, benefit from continued 
levosimendan treatment. 
4. Female patients of childbearing potential must agree to use a highly 
effective method of contraception. 
5. Willingness and ability to comply with scheduled visits, treatment plan, 
laboratory tests and other study procedures. 
3.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met.  
1. Discontinued treatment in the parent study for any reason other than study completion 
or Sponsor termination of the study. 
2. Pregnant or breastfeeding women. 
3. Local access to commercially available levosimendan. 
4. Inability to comply with planned study procedures 
5. Patients with scheduled lung or heart transplant or cardiac surgery  
6. Dialysis developed since enrollment in parent study (either hemodialysis, peritoneal 
dialysis, continuous venovenous hemofiltration, or ultrafiltration) 

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7. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
8. Liver dysfunction with Child Pugh Class B or C (see Attachment 1) 
9. Evidence of systemic bacterial, systemic fungal, or viral infection refractory to 
treatment 
10. Weight > 150kg 
11. Systolic blood pressure (SBP) cannot be managed to ensure SBP > 100 mmHg at 
initiation of study drug 
12. Heart rate  100 bpm with study drug, persistent for at least 10 minutes at screening. 
13. Hemoglobin < 80 g/L 
14. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline that is unresponsive to 
management 
3.3 
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 
3.4 
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 Follow-Up Visit (at termination) evaluations.  Comments 
(spontaneous or elicited) or complaints 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 Case Report Form (eCRF) and 
source documents. 

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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. 
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  
 
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. 
4. 
PRIOR AND CONCOMITANT TREATMENT 
4.1 
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. 

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4.2 
Concomitant Treatment  
All subjects must be optimally managed on diuretics and oxygen therapy as indicated by the 
standard of care.  
 
Medication or treatment for heart failure or respiratory disease must be maintained during the 
trial, unless contraindicated.  
4.3 
Allocation of Subjects to Treatment 
This is an Open-Label extension of the parent study. All patients who enroll into this study 
received an open-label levosimendan.  With the availability of oral levosimendan capsules, all 
consenting patients in TNX-LVO-05 will be transitioned to daily doses of oral levosimendan 
and continue in the study for 3 years following transition to oral levosimendan or termination 
of the trial by the patient or physician decision.   
5. 
INVESTIGATIONAL PRODUCT 
5.1 Levosimendan  
IV Levosimendan 
Levosimendan will be provided to the subjects 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. 
Oral Levosimendan 
Oral levosimendan will be provided as a single-unit, immediate release, size 3, yellow and grey 
capsule.  Each capsule contains 1mg levosimendan, intended to be released rapidly for 
absorption from the gastrointestinal tract. In addition to active ingredient, the capsules contain 
the following excipients, all of which comply with the monographs of the European 
Pharmacopoeia.  
Levosimendan is supplied by the Orion Corporation, Espoo, Finland. 
5.2 
Packaging 
IV Levosimendan 
Levosimendan 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.  
Oral Levosimendan 

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Levosimendan will be provided in high-density polyethylene (HDPE)-container closed with 
HDPE/poly propylene (PP) screw closure.   
5.3 
Labeling 
Study drug labels will contain information to meet the applicable regulatory requirements. 
Each container will have appropriate directions for use and other required information. 
Drug accountability forms will be used for tracking study drug administration. Information 
from the container will be included on the subject’s drug accountability form to document 
capsule usage. 
 
5.4 
IV Levosimendan (Weekly Infusions) 
 
Dosage and Administration 
During the routine weekly infusion, patients will be administered a continuous intravenous (IV) 
infusion of a standard infusion dose of 0.075 - 0.1 µg/kg/min for 24 hours (±30 min); 
(levosimendan). The dose may be adjusted by the treating physician as needed (see section 
6.4.2). No bolus of study drug will be administered.  
Study drug concentrated solution (2.5 mg/mL), levosimendan, will be mixed with diluent and 
administered as weekly infusions at 0.075 µg/kg/min for 24 hrs.   Patients may have a dose 
escalation at Weeks 3 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 4) or other prohibitive rationale. 
If a subject was down-titrated to 0.05 µg/kg/min in the TNX-LVO-04 study for either the Lead-
In or during the double-blind portion of the study, the subject should start at this dose, with the 
first opportunity to up-titrate at Week 3 of the Open-Label Extension Study, TNX-LVO-05. 
Note:  A patient will be discontinued from the study, if the patient develops a complication or 
infection associated with the PICC line or port-a-cath that prevents its further use.  
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 4 of this protocol 
before administration of study drug to calculate the appropriate infusion rate based on the 
subject’s body weight. 
The diluted infusion is administered intravenously by a peripheral or central route. No other 
treatments should be administered via the same line. 

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The concentration of the diluted infusion 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.  
 
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.  
 
Storage 
Study drug (levosimendan infusion 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. 
5.5 
Oral Levosimendan 
 
Dosage and Administration 
Dosing Regimen: Subjects will start with a 1 mg levosimendan dose (in the morning) for 2 
weeks. If tolerated, the dose will be increased after 2 weeks to 1 mg BID, after 4 weeks to 1mg 
TID, and after 6 weeks (if applicable) 1 to 1mg QID.  The titration sequence is as follows: 
 
Previous IV 
Infusion  
Week 0 (Office)  
  
Week 2 
(Home)  
  
Week 4 
(Home)  
Final Visit 
Week 6  
(Office)   
Week 8  
(Office)  
  

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0.10 µg/kg/min  
1mg QD 
(1mg total daily 
dose) 
 
Morning 
1mg BID 
(2mg total daily 
dose) 
 
Every 12 hrs. 
1mg TID 
(3mg total 
daily dose) 
 
Every 8 hrs. 
Patient 
evaluated for 
further 
titration  
(up or down)1 
Only patients titrated (up or 
down) at Week 6  
 
 
No further dose titration above 
4mg QID 
 
1 At the investigator’s discretion, patients that have not demonstrated an adequate response to drug therapy and a 
tolerance to the 1mg levosimendan TID may be titrated to 1mg QID.  Patients that have not tolerated 1 mg 
levosimendan TID should be down titrated to 1mg BID.   All patients that are titrated at Week 6 should return for 
a Week 8 visit. 
 

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Dose Adjustment  
The oral levosimendan dose may be decreased in 1 mg increments 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 date of discontinuation or down titration. Patients should be 
monitored closely until clinically stable.  
Missed doses should be skipped and not taken as a double dose at the next dosing time. 
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.  
 
Dose-limiting Events 
Dose limiting cardiac events and instructions are detailed in Attachment 3 Cardiac Event 
Recommendations and Management. 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 levosimendan.  
 
Storage 
Study drug (levosimendan capsules) must be stored at room temperature.  
The Sponsor must be notified upon discovery of any excursion.  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/consumed by subjects until 
the impact is determined and product is deemed appropriate for use. 
5.6 
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.). 
5.7 
Drug Accountability 
Accurate records of all investigational product dispensed, used, returned, and/or destroyed must 
be maintained as detailed further in this section.  

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Investigational product will be administered only to subjects included in this study following 
the procedures set out in the study protocol.  All dispensing will be documented. 
No investigational product stock or returned inventory from a Tenax sponsored study may be 
removed 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. 
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. 
5.8 
Subject Compliance 
Compliance will be monitored throughout the transition period (IV to oral levosimendan) and 
ongoing throughout the remainder of the study. 
6. 
STUDY PROCEDURES (IV LEVOSIMENDAN) 
6.1 
Ongoing Weekly Infusions 
Weekly visits, occurring approximately every 7 days, should be performed within +48 hours of 
the scheduled visit. 
6.2 
Weeks 3, 6, 12. 24, 48, and yearly, and Follow-Up Visit (at termination) 
(Office Visits) 
Visits at Weeks 48, yearly, and Follow-Up Visit (at termination) should be performed within 
+72 hours of the scheduled weekly visit. These visits will be performed at the investigator’s 
office. The Follow-Up Visit (at termination) will be calculated as the earlier of two years from 
the subject’s date of entry into the TNX-LVO-05 Study or as soon as possible after study 
discontinuation, but within 1 week. 
During this visit, the following procedures will be performed: 
 
 Vital signs 
 Body Weight (Week 3 only) 

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 6MWT 
 Quality of Life (QOL) assessment 
 NYHA Functional Class 
 Physician Assessment 
 Assess adverse events 
 Concomitant medications and/or procedures 
For subjects who discontinue the study early, the same procedures as listed above should 
be performed.  
Adverse events experienced by the patient since the previous visit, should be assessed at 
any unscheduled visit at the investigator’s office. 
6.3 
Study Evaluations and Procedures 
Study procedures will occur according the Time and Events Schedule.  
Patients should be instructed to report adverse events associated with their in-home 
administration of the drug and any concerns that are identified between administration.   Each 
report should be evaluated with respect to the need for an office visit for further assessment of 
safety. 
Any adverse event identified by the patient during unscheduled visits should be recorded and 
followed, as appropriate, in accordance with Section 7. 
6.4 
 
7. 
STUDY PROCEDURES (IV TO ORAL TRANSITION) 
The Time and Events Schedule summarizes the frequency and timing of efficacy, safety, or 
other measurements.   
Section 6.1 describes the transition of patients from IV to oral levosimendan. Section 6.2 
outlines the routine visits that will occur according to the original date the patient entered the 
TNX-LVO-05 study from the parent study.  

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During both the transition period (6.1), ongoing visits (6.2), and throughout the duration of the 
trial, adverse events must be collected according to Good Clinical Practice (GCP). Sites should 
query the patients for any new adverse events, worsening of adverse events, and changes to or 
new concomitant medication and/or procedures. The ongoing documentation of blood pressure 
and heart rate should be maintained in the patient’s chart and in the case report form, as 
applicable. 
Attention should be paid to certain safety events and changes in concomitant medications. 
During ongoing and routine visits, the patient should be asked if they have experienced any of 
the following changes: 
 Palpitations associated with: 
o Shortness of breath 
o Significant lightheadedness 
o Passing out/syncope 
 Edema (swelling): 
o Frequency (never, occasionally, constantly) 
 Shortness of breath with activity: 
o Frequency (rarely, often, constantly) 
 Diuretic use: 
o Changes (increase, no change, decrease) 
 Hospitalization or Emergency Room visits 
7.1 
Treatment Transition: Weekly Intravenous to Daily Oral Levosimendan  
All ongoing patients will be transitioned from IV to oral levosimendan over 6 weeks.  
Any visit that occurs during the transition period that falls on the same day as a regularly 
scheduled visit (i.e. Week 3, 6, 12, 24, 48 or yearly) should include all the required procedures 
for both visits. 
The first patient visit will occur 7-9 days following the completion of their last levosimendan 
infusion. Prior to starting any procedures related to the transitions, patients must sign an updated 
informed consent form. 
Due to the ongoing pandemic (as of the date of this protocol) visits according to the Time and 
Events Schedule may be modified to accommodate patient scheduling. For example, a visit at 
transition Week 6 may be extended two additional weeks to accommodate either patient travel 
or hospital restrictions limiting patient visits.  
Following successful transition to oral levosimendan, the port-a-cath should be removed for 
purposes of this study. During the transition (Weeks 0 to 6 or 8), the port-a-cath should be 

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maintained by the patient (i.e., flushing) according to the investigational site’s institutional 
practices.  
 
 
 
IV-Oral Transition Week 0 
During this visit, the following procedures will be performed: 
 
 Vital signs and ECG 
 Physical Exam (including body weight)  
 6MWT 
 Hematology and chemistry blood samples 
 Pharmacokinetic sample 
o The sample should be taken before the patient consumes their first dose of oral 
levosimendan 
 NYHA Functional Class 
 Assess adverse events. 
 Concomitant medications and/or procedures 
 Kansas City Cardiomyopathy Questionnaire (KCCQ)  
 Oral levosimendan  
 
IV-Oral Transition Week 2 
During this visit, the following procedures will be performed (this visit may be performed 
virtually, at the investigator’s discretion): 
 
 Vital signs 
 Assess adverse events 
 
IV-Oral Transition Week 4 
During this visit, the following procedures will be performed (this visit may be performed 
virtually, at the investigator’s discretion): 
 
 Vital signs 
 Assess adverse events 
 Pharmacokinetic sample 
o Note: if this visit is performed remotely and a home health nurse is unavailable 
to draw the PK sample, this sample may be missed 
 
IV-Oral Transition Week 6 – Final Visit 
During this visit, the following procedures will be performed: 
 

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 Vital signs and ECG 
 Physical Exam 
 Hematology and chemistry blood samples 
 Assess adverse events 
 Pharmacokinetic sample 
 6MWT 
 NYHA Functional Class 
 Kansas City Cardiomyopathy Questionnaire (KCCQ)  
 
Once a patient transitions to oral levosimendan, all references in this protocol to the 
administration of IV levosimendan, will no longer apply for that patient. All study drug and 
ancillary supplies related to the administration of IV levosimendan will be returned to the 
central pharmacy for destruction. 
 
IV-Oral Transition Week 8  
This visit is only required for patients who titrated (up or down) at the Week 6 visit.  
 
During this visit, the following procedures will be performed: 
 
 Vital signs 
 Physical Exam 
 Hematology and chemistry blood samples 
 Assess adverse events 
 Pharmacokinetic sample 
 6MWT 
 NYHA Functional Class 
 Kansas City Cardiomyopathy Questionnaire (KCCQ)  
 
The Physical Exam, 6MWT, NYHA Functional Class, and KCCQ do not need to be performed 
for patients who are scheduled for a Week 8 visit, due to either up or down titration of study 
drug. 
Following the Final Evaluation (either Week 6 or Week 8), patients will continue to visit the 
investigational site at weeks 3, 6, 12, 24, 48, and yearly through the Follow-Up Visit (at 
termination) and/or Termination visit. These visit windows will be based on the date the patient 
originally enrolled in the TNX-LVO-05 study. Visits that overlap may be combined into one 
visit.  
Patients unable to return at the scheduled Week 6 or 8 visit, may have their final visit extended. 
7.2 
Weeks 3, 6, 12, 24, 48, and yearly through the Follow-up and/or Termination 

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visit (Office Visits) 
Visits at Weeks 3, 6, 12, 24, 48, and yearly through the Follow-up and/or Termination visit 
should be performed within +72 hours of the scheduled weekly visit. These visits may be 
performed at the investigator’s office. For any patients who remain on IV levosimendan, the 
Follow-Up Visit (at termination) will be calculated as the earlier of two years from the subject’s 
date of entry into the TNX-LVO-05 Study or as soon as possible after study discontinuation, 
but within 1 week. 
During this visit, the following procedures will be performed: 
 
 Vital signs 
 Physical Exam 
 Hematology and chemistry blood samples 
 Body Weight  
 6MWT  
 Kansas City Cardiomyopathy Questionnaire (KCCQ)  
 NYHA Functional Class 
 Physician Assessment 
 Assess adverse events 
 Concomitant medications and/or procedures 
 
If the Week 48 or yearly visit falls within two weeks of any of the IV to oral transition visits 
(i.e., Week 0, 2, 4, 6 or 8), these visits may be combined. 
For subjects who discontinue the study early, the same procedures as listed above should 
be performed.  
Adverse events experienced by the patient since the previous visit, should be assessed at 
any unscheduled visit at the investigator’s office. 
7.3 
Pharmacokinetic Collection and Analyses 
To better understand the plasma levels of levosimendan and its active metabolites, OR-1855 
and OR-1896, a pharmacokinetic (PK) blood sample will be drawn at IV to Oral Transition 
according to the Time and Events Schedule. 
Pharmacokinetic samples will be collected for ongoing patients, as of the date of 
implementation (e.g., IRB approval) of Version 4.1 at investigational sites.  Patients who 
discontinue the study prior to the ability to either consent or physically visit the investigational 
site will not be required to have a PK sample collected.  

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7.4 
Non-successful transition to oral levosimendan 
Patients who do not successfully transition to oral levosimendan may re-start IV 
levosimendan, within a minimum of 7 days from their last dose of oral levosimendan. Once a 
patient re-starts IV levosimendan, they will continue to receive study drug based on the 
original date of entry into the TNX-LVO-05 study (i.e., final visit in the parent study, TNX-
LVO-04) return to their weekly IV levosimendan dose regimen they were on prior to starting 
the oral transition. 
Patients that re-start IV levosimendan will not have the opportunity to be given oral 
levosimendan in the future.  
The starting dose of IV levosimendan should be at the same rate the patient was receiving prior 
to the transition to oral levosimendan. After re-starting IV levosimendan, the patient should be 
contacted by telephone after 2 weeks to assess for any safety events. 
8. 
STUDY EVALUATIONS AND PROCEDURES 
Study procedures will occur according the Time and Events Schedule.  
Patients should be instructed to report adverse events associated with their in-home 
administration of the drug and any concerns that are identified between administration.   Each 
report should be evaluated with respect to the need for an office visit for further assessment of 
safety. 
Any adverse event identified by the patient during unscheduled visits should be recorded and 
followed, as appropriate, in accordance with Section 7. 
 
Efficacy Measures 
6-Minute Walk Test (6MWT) 
The 6MWT should be performed at approximately the same time of day at each study visit 
and ideally, one of the first assessments to be performed.  
 
An online tutorial on how to perform the 6MW test properly will be required of all clinical 
coordinators who will be performing the test. Only those who successfully complete the 
tutorial will be allowed to administer the test. In addition, a patient information booklet 
describing the appropriate effort and performance of the 6MW test will be given to each 
patient. 
 
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, 

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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. 
 
• 
Patient global assessment (based on the KCCQ instrument)  
• 
Physician’s Assessment of Functional Class 
• 
Clinical Events:  Death and hospitalizations 
 
Safety Assessments 
All safety evaluations will be performed at the time points listed in the Time and Events 
Schedule.  
Any adverse events identified by the patient during unscheduled visits should be recorded and 
followed, as appropriate, in accordance with Section 7. 
Patients should be instructed to report adverse events throughout their participation in the study.   
Each report should be evaluated with respect to the need for an office visit for further 
assessment of safety. 
8.1.2.1 Medical and Medication History 
To be completed at the final office visit in the parent study to ensure subjects meet the inclusion 
criteria for the study. Any clinically significant history should be noted in the eCRF.  
8.1.2.2 Physical Examination (Including Height and Weight) 
Abnormalities identified at the final office visit in the parent study 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. 
8.1.2.3 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 the subject withdraws from the study, or the discontinuation of the 
study, whichever occurs first. Serious adverse events will be collected through in the same 
manner.  

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8.1.2.4 Vital Signs 
Blood pressure should be determined by cuff (using the same method, the same arm, and in the 
same position throughout the study, as appropriate).  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]. 
8.1.2.5 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.  
 
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).  
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 
 

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Serum Chemistry Panel 
Sodium 
Potassium 
Bicarbonate 
Blood urea nitrogen (BUN) 
Creatinine 
NT-proBNP 
 
Child-Pugh Class is only required for patients who have documented liver disease.  
 
Electrocardiogram 
Subjects have a 12-lead ECG performed as per the Time and Events Schedule. ECGs 
performed prior to administration of study drug in the parent study (where applicable). 
Abnormal ECGs may be repeated at the Investigator’s discretion. 
8.1.3.1 Quality of Life Assessments 
The 6-point Likert scale will be replaced with the KCCQ instrument (Attachment 2) and 
provided to subjects to completed as per the Time and Events Schedule. 
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 
and are to be recorded on the appropriate AE pages in the eCRF and in source documents. 
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 

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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. 
 
Severity Categorization 
The severity of AEs must be recorded during the course of 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. 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
 
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 

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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. 
 
 
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 
 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as 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. 
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). 

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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 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 
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. 
Ongoing Adverse Event Collection 
During ongoing study and routine standard of care visits, the patient should be asked if they 
have experienced any of the following changes: 
 Palpitations associated with: 
o Shortness of breath 
o Significant lightheadedness 
o Passing out/syncope 
 Edema (swelling): 

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o Frequency (never, occasionally, constantly) 
 Shortness of breath with activity: 
o Frequency (rarely, often, constantly) 
 Diuretic use: 
o Changes (increase, no change, decrease) 
 Hospitalization or Emergency Room visits 
 
All changes to a patient’s health status, including AEs, concomitant medication/procedures, and 
hospitalizations (including ER visits) must be documented in the case report form.  
 
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. 
 
Pregnancy 
All pregnancies are to be reported from the time first exposure to study drug 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 

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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 
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. 
 
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 1 category. 
 Abuse – Persistent or sporadic intentional intake of 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 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.  Medication errors are reportable to the Sponsor as defined 
below. 
 
Cases of subjects missing doses of product are not considered reportable as medication errors.  

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Medication errors should be collected/reported. 
The administration and/or use of an expired product should be considered as a reportable 
medication error.  
9.2 
Serious Adverse Event Procedures 
 
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. 
 
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 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” 

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Facsimile: +1-866-336-5320 or +1-1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 
 
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.  
 
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 1 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, an admission for a previously scheduled ventral hernia repair 
would not be classified as an SAE.  
However, complication(s) resulting from a hospitalization for an elective or previously 
scheduled surgery that meets serious criteria must be reported as SAE(s). 
 
Serious Adverse Event Collection Timeframe 
SAEs must be recorded from the time of signature of Patient Informed Consent through 30 days 
after completion of the last dose.  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 

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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. 
 
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. 
 
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). 
 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, 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. 

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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.  
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 in the 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. 
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 9.1 
or higher of SAS (SAS Institute, Cary, NC 27513).  
10.4 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.   

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10.5 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. 
10.6 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. 
10.7 Prior and Concomitant Medication 
Sites must maintain adequate records of concomitant medications and procedures throughout 
the study. 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.  
10.8 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. 

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10.9 Efficacy Analysis 
All efficacy endpoints are considered secondary endpoints. Descriptive statistics for efficacy 
endpoints will be reported at 3, 6, 12, 24, 48 and Follow-Up Visit (at termination) as well as 
Week 0 and Week 6 (or 8) for IV to oral transition patients. 
 
11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, and local 
ethical and legal requirements.   
11.1 
Sponsor’s Responsibilities 
 
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. 
 
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.  
 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Independent Ethics Committees 
The Sponsor will provide a summary of the Clinical Study Report within 1 year of the end of 
the study completion date to the competent authority of the Member State(s) concerned as 

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required by regulatory requirement(s) and to comply with the Community guideline on GCP (if 
applicable).   
 
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 
 
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 commitment 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. 
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).  
 
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 

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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. 
 
Documentation and Retention of Records 
11.2.3.1 Case Report Forms 
The electronic Case Report Form (eCRF) is supplied by MedPace CRO and should be handled 
in accordance with instructions from the Sponsor. Please see the Data Management Plan for 
further information. 
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.  
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 

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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 
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 
 
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 

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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. 
 
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. 
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. 

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After subjects have consented to take part in the study, the Sponsor and/or its representatives 
reviews 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 
within 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. 
12. 
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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. 

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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. 
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 randomised 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 
Pharmacol. 2009;49:109–15. 
52. Hoeper M, Badesch DB, et. al. Definitions and Diagnosis of Pulmonary Hypertension. J Am Coll 
Cardiol 2013;62: D42–50. 
53. Nieminen, Markku S., et al. "Oral levosimendan in patients with severe chronic heart failure—the 
PERSIST study." European journal of heart failure 10.12 (2008): 1246-1254. 
54. Pöder P, Nieminen MS, Airaksinen J, Anttonen O, Harjola V-P, Lilleberg J, et al. Effects of peroral 
levosimendan in the prevention of further hospitalisations in patients with chronic heart failure. A 
randomised, double-blind, placebo-controlled, multi-centre, parallel-group study (PERSIST). 
Clinical study report: Orion Pharma 2006. Report No.: 3001081. 

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55. Burkhoff, Daniel, et al. "24-hour Levosimendan Infusion Decreases Biventricular Filling Pressures 
and Increases Cardiac Output at Rest and Exercise in PH-HFpEF." Circulation 142.Suppl_3 (2020): 
A15294-A15294. 
56. Harjola, Veli-Pekka, et al. "Oral levosimendan improves cardiac function and hemodynamics in 
patients with severe congestive heart failure." The American journal of cardiology 83.12 (1999): 4-
8. 
57. Jalanko, Mikko, et al. "Oral levosimendan improves filling pressure and systolic function during 
long-term treatment." Scandinavian Cardiovascular Journal 45.2 (2011): 91-97. 
 
 

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13. 
APPENDICES 
13.1 
APPENDIX 1: Summary of Changes for Previous Protocol Amendments 

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Revisions included in Amendment 2 to the protocol, Version 4.1, dated 02 February 2021. 
 
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: 3.0, 19 June 2019, 4.1, 25 
January 2021 
 
Global Change 
Revised Stuart Rich, MD’s title to Chief Medical Officer, Tenax Therapeutics, 
Inc. 
Global Change 
Ongoing patients will be transitioned from weekly IV levosimendan 
administration to daily oral levosimendan administration up to 3 mg, as 
tolerated, for the remainder of the study. 
Patients will continue receiving levosimendan in this Open-Label Extension 
Study, TNX-LVO-05, for up to 2 years. and continue for 3 years following   
transition to oral levosimendan or termination of the trial by the patient or 
physician decision. 
Global Change 
Study visits that occur after Week 48 will occur yearly. 
Global Change 
Replaced the Likert Scale with the KCCQ instrument for patient QOL 
assessment. 
Time and Events Schedule 
Updated to reflect the addition of the 6-week transition period for patients 
transitioning from IV to oral levosimendan.  
Footnotes have been updated commensurate to changes.  
18 
BACKGROUND 
INFORMATION 
 
Section 1.1 explains the rationale for transitioning patients from IV to Oral 
levosimendan.  
 
20 
BACKGROUND 
INFORMATION 
Section 1.3 provides details of oral levosimendan use from the PERSIST study 

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20 
BACKGROUND 
INFORMATION 
 
Section 1.3.4 includes information from the PERSIST study, of patients who 
were randomised to either oral levosimenan or placebo in patients with severe 
CHF. 
22 
BACKGROUND 
INFORMATION 
 
Section 1.3.5 includes data from the completed TNX-LVO-04 (”HELP”) 
study.  
23 
BACKGROUND 
INFORMATION 
 
Section 1.3.6: Additional safety information included for the 8 studies of oral 
levosimendan in HF patients, as well as safety data from the HELP study. 
24 
BACKGROUND 
INFORMATION 
 
Section 1.3.7:  Rationale for Chronic Intermittent (weekly) Oral 
Levosimendan for PH-HFpEF Patients 
Updated the third and fourth bullet in this section to remove reference to IV 
and change to oral levosimendan  
26 
BACKGROUND 
INFORMATION 
 
Section 1.3.8: Target Plasma Concentrations of OR-1896 in intermittent 
chronic treatment of PH-HFpEF Patients 
Included figure for comparison of plasma concentrations between the HELP 
and PERSIST studies. 
31 
STUDY 
OBJECTIVES 
AND 
PURPOSE 
Section 2.3.1: (new section) Regimen Transition: Weekly Intravenous to 
Daily Oral Levosimendan 
31 
STUDY 
OBJECTIVES 
AND 
PURPOSE 
Section 2.5: Updated to include details of procedural steps to be taken as 
patients transition from IV to oral levosimendan 
35 
PRIOR 
AND 
CONCOMITANT 
TREATEMENT 
Section 4.3: redefined the allocation of treatement of subjects from IV to oral 
levosimendan  
36 
INVESTIGATIONAL 
PRODUCT 
Section 5: Included background information for oral levosimendan, inclucing 
Packaging, Labeling, and dosing 
38 
STUDY 
PROCEDURES 
Section 6: Included instructions on procedures that are to be followed for 
transition of patients from IV to oral levosimendan. Section 6.2 added.  
Included language pertaining to ongoing collection of adverse events. 
42 
STUDY 
PROCEDURES 
Section 6.4: Added the requirement for PK blood draws at Week 0, 4, and 6 
(or 8) for patients transitioning to oral levosimendan. 

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49 
Study-Specific 
Events of Interest 
Section 8.1.5:  Included ”Ongoing Adverse Event Collection” 
80 
ATTACHMENT 2 
Kansas City Cardiomyopathy Questionnaire (KCCQ) added 
85 
ATTACHMENT 4 
Added a patient diary to record daily BP, HR, and study drug consumption 

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Revisions included in Amendment 2 to the protocol, Version 3.0, dated 19 June 2019. 
 
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, 31 October 
2018Version 3.0, 19 June 2019 
 
Global Change 
Clarified that the Follow-Up Visit and the Termination Visit should be the 
same visit. The last office visit and study assessments in TNX-LVO-05,  will 
be the  ”Follow-up Visit (at termination)” at the completion of the 2 year 
study, within 1 week of the last dose. 
 
12 
SYNOPSIS: 
Diagnosis and main 
criteria for inclusion 
and exclusion: 
Inclusion Criteria: 
(modified to be consistent with the specific inclusion criterion in body of the 
protocol, Section 3.1) 
 
2. 
Received levosimendan as treatment for Completed double-blind 
therapy in a PH-HFpEF in a clinical study sponsored by Tenax Therapeutics, 
Inc. 
 
 
 
(inclusion criterion corrected to be consistent with the specific inclusion 
criterion in body of the protocol, Section 3.1.  This change maintains the 
criterion for female contraception as identified in the parent study, TNX-
LVO-04, and corrects the reference to ”male” contraception.  Reproductive 
toxicology studies have not identified a need for male contraception in the use 
of levosimendan.) 
 
4. 
Male patients and fFemale patients of childbearing potential must 
agree to use a highly effective method of contraception. 
 

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12 
SYNOPSIS: 
Diagnosis and main 
criteria for inclusion 
and exclusion: 
Exclusion Criteria: 
(added to be consistent with the exclusion criteria in body of the protocol, 
Section 3.2; these exclusions were inadvertently not included in the list of 
criteria within the Synopsis.).  
 
4. Inability to comply with planned study procedures 
5. Patients with scheduled lung or heart transplant or cardiac surgery  
6. Dialysis developed since enrollment in parent study (either 
hemodialysis, 
peritoneal 
dialysis, 
continuous 
venovenous 
hemofiltration, or ultrafiltration) 
7. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
8. Liver dysfunction with Child Pugh Class B or C (see Attachment 2) 
9. Evidence of systemic bacterial, systemic fungal, or viral infection 
refractory to treatment 
10. Weight > 150kg 
11. Systolic blood pressure (SBP) cannot be managed to ensure 
SBP >100 mmHg at initiation of study drug 
12. Heart rate >100 bpm with study drug, persistent for at least 10 
minutes at screening. 
13. Hemoglobin < 80 g/L 
14. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L that is unresponsive 
to correction 
13 
SYNOPSIS 
Duration of treatment: 
(corrected typographical error) 
 
Patients will continue receiving levosimendan in this Open-Label Extension 
Study, TNX-LVO-045, for up to 2 years. 
15  
TIME AND EVENTS 
SCHEDULE 
(added row for PICC line to Port-a-Cath conversion specified in Section 5.4.1) 
 
16 
Footnotes for Time 
and Events Schedule 
(added footnote regarding PICC line to Port-a-Cath conversion) 
 
7.  If at the Week 3 visit the open-label levosimendan has been well-tolerated 
by the patient, the investigator should review with the subject the opportunity 
to convert the PICC line to a port-a-cath in the coming weeks (Section 5.4.1). 
   

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24 
2.3  Study Design 
(paragraph removed for clarity; tudy length and office visits are identified in 
the following paragraph;the home health care nurse assessments at Week 1 
and 2 provide information to the site regarding patient health status.) 
Clinic visits for safety assessments and study drug dispensing will be 
performed at Week 3, week 6, and then every 12 weeks (± 14 days) through 
48 weeks study , or until treatment discontinuation criteria are met. Patients 
will be contacted at Weeks 1 and 2 after beginning the trial to assess health 
status.  
25 
3. 
 
STUDY 
POPULATION 
3.1  Inclusion Criteria 
Enrollment Criteria: 
(added to be consistent with the inclusion criterion in the Synopsis section of 
the protocol) 
 
3. May, in the opinion of the Investigator, benefit from continued 
levosimendan treatment. 
 
25 
3.2 
 
Exclusion 
Criteria 
(revised to be consistent with the text for this exclusion in the Synopsis section 
of the protocol) 
 
15. Discontinued treatment of blinded drug in the parent study for any 
reason other than study completion or Sponsor termination of the 
study. 
 
26 
3. 
STUDY 
POPULATION 
3.2 Exclusion Criteria 
 
(revised to exclude subjects only if a transplant or cardiac surgery is 
scheduled) 
 
5. Patients with scheduled planning lung or heart transplant or cardiac 
surgery in the next 4 months 
 
 
(revised to exclude only those subjects refractory to treatment of infections) 
 
9.  Evidence of systemic bacterial, systemic fungal, or viral infection in 
last 2 weeks refractory to treatment 
 
 
(revised to be consistent with the latest version in the parent study, TNX-
LVO-04, Version 4.0, dated 15 May 2019, which expanded the weight range 
to include those patients between 135 and 150 kg that can be effectively 
managed on the cath lab table) 
 
10. Weight > 135 150kg 
 
 
(revised to specify exclusion only of those subjects that are unresponsive to 
management of serum potassium) 
 

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14. Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline that is 
unresponsive to management 
28 
5. 
INVESTIGATIONA
L PRODUCT 
5.1  Levosimendan 
(corrected recipient of levosimendan supplies in this open-label extension 
study) 
 
Levosimendan will be provided to investigators the subjects by the sponsor as 
a sterile clear, yellow to orange solution in clear glass vials. 
30 
5.4.1 
Dosage and 
Administration 
(corrected reference to time of dose escalation) 
 
Patients may have a dose escalation at Weeks 3 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 4) or other prohibitive rationale. 
 
 
(clarified instructions regarding transition from PICC line to port-a-cath in 
patients choosing to continue PICC lines after Week 3) 
 
A subject that chooses to continue with a PICC line after Week 3 will be 
transitioned to a port-a-cath once the PICC line fails or will be discontinued 
from the study. 
 
 
(corrected incorrect reference to preoperative subjects) 
 
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. 
31 
5.4.2 
 
Self-
Administration 
of 
Levosimendan 
(clarified statement; removed extraneous phrase) 
 
The subject will be instructed on the preparation, administration, and 
disposal/return of levosimendan (including ancillary supplies) will be 
provided to each subject by the home healthcare nurse. 
33 
5.8  Drug  
Accoutability 
(clarified to remove reference to site, as drug is shipped to subject’s home) 
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.  
 
 
(clarified to remove reference to sudy blind, as this is an open-label study.) 
 
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. 
 
 
(clarified to remove reference to site, as drug is shipped to subject’s home) 
 
Based on entries in the site drug accountability forms, it must be possible to 
reconcile investigational products delivered with those used and returned.   

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33 
5.9 
 
Subject 
Compliance 
(clarified that the eCRF will document details of each administration that is 
supported by the home health care nurse; removed reference to study drug 
dipensed at the site) 
 
The details of each administration supported by a home health care nurse will 
be recorded in the eCRF.  The investigator or designated study personnel will 
maintain a log of all study drug dispensed and returned. 
36 
6.4  Weeks 3, 6, 12, 
24, Follow-Up Visit 
(at 
termination) 
(Office Visits) 
(added NYHA Functional Asssessment to the list of patient assessments at 
each office visit in keeping with the Time and Events Schedule in the 
Synopsis) 
 
•    NYHA Functional Class 
37 
6.5.2  Safety 
Assessments 
(modified leading section of safety assessments to emphasize the subject’s 
role in identifying and communicating safety information to the clinical site; 
site role in evaluation and subject follow-up) 
 
Any adverse events identified by the patient during unscheduled visits should 
be recorded and followed, as appropriate, in accordance with Section 7. 
 
Patients should be instructed to report adverse events associated with their in-
home administration of the drug and adverse events of concern that are 
identified between administration.   Each report should be evaluated with 
respect to the need for an office visit for further assessment of safety. 
45 
7.2.4 
Serious 
Adverse 
Event 
Collection Timeframe 
(sentence added to identify full time window for recording of SAEs) 
 
SAEs must be recorded from the time of signature of Patient Informed 
Consent through 30 days after completion of the last infusion.   
47 
8.2   Clinical Data 
Management 
(clarified sentence; corrected typographical omission) 
 
Data collected in the 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. 
60 
Appendix 1 
Summary of Changes 
for Previous Protocol 
Amendments 
(added this table of revisions included in TNX-LVO-05, Version 3.0) 

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Revisions included in Amendment 1 to the protocol, dated 31 October 2018 (Version 2.0) 
1. 
Removed right heart catheter and hemodynamic measurements at Week 48 
2. 
Removed echocardiography at Week 48 
3. 
The study will end at 2 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14. 
ATTACHMENTS 
 
 

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14.1 
ATTACHMENT 1: 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 into 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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14.2 
ATTACHMENT 2: Kansas City Cardiomyopathy Questionnaire 
The Kansas City Cardiomyopathy Questionnaire 
The following questions refer to your heart failure and how it may affect your life. 
Please read and complete the following questions. There are no right or wrong 
answers. Please mark the answer that best applies to you. 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel 
fatigue. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your 
ability to do the following activities over the past 2 weeks. 
Place an X in one box on each line 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited 
for 
other 
reasons 
or did 
not do 
the 
activity 
Dressing 
yourself 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Showering/Bat
hing 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Walking 1 
block on level 
ground 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Doing 
yardwork, 
housework or 
carrying 
groceries 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Climbing a 
flight of stairs 
without 
stopping 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Hurrying or 
jogging (as if to 
catch a bus) 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue or ankle swelling) 
changed? My symptoms of heart failure have become … 
 
Much worse 
Slightly 
worse 
Not changed 
Slightly better 
Much better 
I’ve had 
no 
sympto
ms over 

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1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel 
fatigue. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your 
ability to do the following activities over the past 2 weeks. 
the last 
2 weeks 
 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke up in the 
morning? 
 
Every morning 
3 or more 
times a 
week, but 
not every 
day 
1–2 times a week 
Less than once a 
week 
Never over 
the past 2 
weeks 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? It has been … 
 
Extremely bothers
ome 
Quite a 
bit botherso
me 
Moderately bother
some 
Slightly bothers
ome 
Not at 
all bothersom
e 
I’ve 
had no 
swellin
g 
 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want? 
All of the time 
Several times per 
day 
At least 
once a day 
3 or more times per 
week but not every 
day 
1–2 times per 
week 
Less than 
once a week 
Never 
over the 
past 2 
weeks 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
6. Over the past 2 weeks, how much has your fatigue bothered you? It has been … 
 
Extremely bothers
ome 
Quite a 
bit botherso
me 
Moderately bother
some 
Slightly bothers
ome 
Not at 
all bothersom
e 
I’ve 
had no 
fatigue 
 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what you 
wanted? 
All of the time 
Several times per 
day 
At least 
once a day 
3 or more times per 
week but not every 
day 
1–2 times per 
week 
Less than 
once a week 
Never 
over the 
past 2 
weeks 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
8. Over the past 2 weeks, how much has your shortness of breath bothered you? It has been … 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 86 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel 
fatigue. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your 
ability to do the following activities over the past 2 weeks. 
 
Extremely bothers
ome 
Quite a 
bit botherso
me 
Moderately bother
some 
Slightly bothers
ome 
Not at 
all bothersom
e 
I’ve 
had no 
shortne
ss of 
breath 
 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at 
least 3 pillows to prop you up because of shortness of breath? 
 
Every night 
3 or more 
times a 
week, but 
not every 
day 
1–2 times a week 
Less than once a 
week 
Never over 
the past 2 
weeks 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
10. Heart failure symptoms can worsen for a number of reasons. How sure are you that you know what to do, or 
whom to call, if your heart failure gets worse? 
 
Not at all sure 
Not 
very sure 
Somewhat sure 
Mostly sure 
Completely s
ure 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
11. How well do you understand what things you are able to do to keep your heart failure symptoms from getting 
worse? (for example, weighing yourself, eating a low salt diet, etc.) 
 
Do not understand 
at all 
Do not 
understand 
very well 
Somewhat 
understand 
Mostly 
understand 
Completely 
understand 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
12. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It 
has extremely limi
ted my enjoyment 
of life 
It has 
limited my 
enjoyment 
of life quite 
a bit 
It 
has moderately lim
ited my enjoyment 
of life 
It 
has slightly limi
ted my 
enjoyment of 
life 
It has not 
limited my 
enjoyment of 
life at all 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
13. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about 
this? 
 
Not at all satisfied 
Mostly 
dissatisfied 
Somewhat satisfied Mostly satisfied 
Completely 
satisfied 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 87 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel 
fatigue. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your 
ability to do the following activities over the past 2 weeks. 
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your heart failure? 
 
I felt that way all 
of the time 
I felt that 
way most 
of the time 
I occasionally felt 
that way 
I rarely felt that 
way 
I never felt 
that way 
 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
15. How much does your heart failure affect your lifestyle? Please indicate how your heart failure may have 
limited your participation in the following activities over the past 2 weeks. 
Please place an X in one box on each line 
Activity 
Severely limited 
Limited qui
te a bit 
Moderately limited Slightly limited Did not limit 
at all 
Does 
not 
apply or 
did not 
do for 
other 
reasons 
Hobbies, 
recreational 
activities 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Working or 
doing 
household 
chores 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Visiting family 
or friends out 
of your home 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
Intimate 
relationships 
with loved ones 
❑ 
❑ 
❑ 
❑ 
❑ 
❑ 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 88 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
14.3 
ATTACHMENT 3: Cardiac Event Recommendations and Management 
Changes in BP or HR that could represent a significant safety concern should be reported to the treating 
physician. 
If the subject meets any of the dose-limiting event criteria, the following actions on study drug should be 
undertaken: 
1. Blood pressure (systolic) management  
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 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 dose 
3. Symptomatic low BP management 
a. Follow recommendations of asymptomatic scenario (above), and 
i. BP <100 mild symptoms = levosimendan dose reduction 
ii. BP <100 severe symptoms = IV phenylephrine and levosimendan dose reduction 
iii. BP <90 on lowest dose = discontinue study 
4. Sinus tachycardia at rest  
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 dose reduction 
d. HR >120 (validated) without symptoms = obtain ECG do determine if sinus tachycardia 
or atrial-fibrillation. (If HR>120, the treating physician should be contacted.) 
i. If sinus tachycardia = levosimendan dose reduction or withdraw 
ii. If atrial fibrillation = heart rate drug management 
e. Persistent HR>120 despite any/all above measures = discontinue study 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 89 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
14.4 
ATTACHMENT 4: Study Drug Dose and Dosing Table 
Preparation of the infusion 
Levosimendan 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 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 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 0.1 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 0.1 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. 
 
 
 
 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 90 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
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 infusion.  
Patient’s 
weight (kg) 
Infusion rate (mL/h) 
 
0.1 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. 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 91 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
14.5 
ATTACHMENT 5: Patient Diary of Daily Heart Rate and Blood Pressure Readings 
Week 0 through Week 2: (#) ____ capsules per day (#, as directed by physician) 
Each morning, please monitor your blood pressure and heart rate. You should be sitting down and at rest for at least five minutes before 
taking your blood pressure and heart rate. The numbers you write down should be the same as those that appear on the monitor screen 
(do not round the numbers up or down). In the comments section, please write down anything that could have affected your reading, 
such as feeling unwell or changes in your medication. 
NOTE: If your heart rate above 110 or your Systolic Blood Pressure is below 100, please call your doctor.  
Date 
Time 
Heart 
Rate 
Systolic BP 
(top number) 
Diastolic BP 
(bottom number) 
Study Drug 
# of capsules 
taken daily 
 
PLEASE CHECK IF YOU ARE 
EXPERIENCING ANY OF THE 
FOLLOWING: 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 92 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
Week 2 through Week 4: (#) ____ capsules per day (#, as directed by physician) 
Each morning, please monitor your blood pressure and heart rate. You should be sitting down and at rest for at least five minutes before 
taking your blood pressure and heart rate. The numbers you write down should be the same as those that appear on the monitor screen 
(do not round the numbers up or down). In the comments section, please write down anything that could have affected your reading, 
such as feeling unwell or changes in your medication. 
NOTE: If your heart rate above 110 or your Systolic Blood Pressure is below 100, please call your doctor.  
Date 
Time 
Heart 
Rate 
Systolic BP 
(top number) 
Diastolic BP 
(bottom number) 
Study Drug 
# of capsules 
taken daily 
 
PLEASE CHECK IF YOU ARE 
EXPERIENCING ANY OF THE 
FOLLOWING: 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 93 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
 
Week 4 through Week 6: (#) ____ capsules per day (#, as directed by physician) 
Each morning, please monitor your blood pressure and heart rate. You should be sitting down and at rest for at least five minutes 
before taking your blood pressure and heart rate. The numbers you write down should be the same as those that appear on the monitor 
screen (do not round the numbers up or down). In the comments section, please write down anything that could have affected your 
reading, such as feeling unwell or changes in your medication. 
NOTE: If your heart rate above 110 or your Systolic Blood Pressure is below 100, please call your doctor.  
Date 
Time 
Heart 
Rate 
Systolic BP 
(top number) 
Diastolic BP 
(bottom number) 
Study Drug 
# of capsules 
taken daily 
 
PLEASE CHECK IF YOU ARE 
EXPERIENCING ANY OF THE 
FOLLOWING: 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 

Tenax Therapeutics, Inc. 
CONFIDENTIAL 
     04 June 2021 
Protocol TNX-LVO-05 
Version: 4.1 
Page 94 of 94 
TNX-LVO-05; Version 4.1, 04JUNE2021 
Week 6 through Week 8: (#) ____ capsules per day (#, as directed by physician) 
Each morning, please monitor your blood pressure and heart rate. You should be sitting down and at rest for at least five minutes before 
taking your blood pressure and heart rate. The numbers you write down should be the same as those that appear on the monitor screen 
(do not round the numbers up or down). In the comments section, please write down anything that could have affected your reading, 
such as feeling unwell or changes in your medication. 
NOTE: If your heart rate above 110 or your Systolic Blood Pressure is below 100, please call your doctor.  
Date 
Time 
Heart 
Rate 
Systolic BP 
(top number) 
Diastolic BP 
(bottom number) 
Study Drug 
# of capsules 
taken daily 
 
PLEASE CHECK IF YOU ARE 
EXPERIENCING ANY OF THE 
FOLLOWING: 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________ 
 
 
 
 
 
 
 
 
Palpitations 
Light headedness 
Chest pain 
Worsening shortness of breath 
Worsening edema (swelling) 
Other___________________