A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of Concept and Dose-Finding Phase II Clinical Trial to Investigate the Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients With Septic Shock and Elevated Adrenomedullin
Phase: PHASE2
Conditions: Septic Shock
Sponsor: Adrenomed AG

 
 
TRIAL PROTOCOL 
 
 
Title:  
A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of 
Concept and Dose-Finding Phase II Clinical Trial to Investigate the 
Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients with 
Septic Shock and Elevated Adrenomedullin 
 
Short Title:  
Treatment of patients with septic shock and bio-ADM concentration > 70 
pg/mL with ADRECIZUMAB 
 
Protocol Version / Date:    Final 4.2 / 28-Aug-2019 
Protocol No.:   
       ADR-02 
EudraCT-No:   
       2016-003883-38 
NCT:   
 
       NCT03085758 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
Trial Protocol - Version 4.2, 28-August 2019 
 
Page 1 of 79 
 
TRIAL PROTOCOL 
 
 
Title: 
A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of 
Concept and Dose-Finding Phase II Clinical Trial to Investigate the 
Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients with 
Septic Shock and Elevated Adrenomedullin  
 
Short Title: 
Treatment of patients with septic shock and bio-ADM concentration  
> 70 pg/mL with ADRECIZUMAB 
 
Protocol Code: 
AdrenOSS-2 
 
Protocol No.: 
ADR-02 
 
EudraCT No.: 
2016-003883-38 
 
Protocol Version / Date: 
Final 4.2 / 28-Aug-19 
 
Sponsor: 
 
 
ADRENOMED AG 
 
 
 
 
Neuendorfstr. 15a 
 
 
 
 
16761 Hennigsdorf 
 
 
 
 
Germany 
 
Emergency Phone No.: 
++49 (0) 17623781763 
 
____________________________________________________________________________ 
 
 
 
This clinical trial will be conducted in accordance with the International Council for  
Harmonization Good Clinical Practices Guideline 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under 
control of ADRENOMED AG, and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable or Independent Ethics 
Committee. The information is only to be used by you in connection with authorized clinical trials of 
the investigational drug described in the protocol. You will not disclose any of the information to others 
without written authorization from ADRENOMED AG, except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. 
 
 
 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 2 of 79 
1. 
TABLE OF CONTENTS 
 
1.1 
List of Abbreviations ............................................................................................................... 5 
2. 
PROTOCOL SYNOPSIS ........................................................................................................ 7 
2.1 
Protocol Summary ................................................................................................................... 7 
Figure 1 Study Flow Chart for Randomized Patients........................................................................... 13 
Figure 2 PK Sampling – Substudy ....................................................................................................... 15 
Figure 3 Study Flow Chart for Screen Failure Patients........................................................................ 16 
3. 
INTRODUCTION AND RATIONALE ................................................................................ 17 
3.1 
Background Information ........................................................................................................ 17 
3.1.1 
Septic Shock  ........................................................................................................................ 17 
3.1.2 
Investigational Medicinal Product ..................................................................................... 18 
3.1.2.1 
Clinical Experience .............................................................................................................. 19 
3.2 
Rationale for the Clinical Trial ........................................................................................... 20 
3.2.1 
Study Design  ........................................................................................................................ 21 
3.2.2 
Dose Selection ....................................................................................................................... 22 
3.3 
Assessment of Potential Risks and Benefits and Risk Management ............................... 23 
4. 
TRIAL OBJECTIVES AND ENDPOINTS .......................................................................... 25 
4.1 
Primary Objective .................................................................................................................. 25 
4.2 
Secondary Objectives ............................................................................................................ 25 
4.3 
Endpoints for Primary Objective (Safety and Tolerability) ............................................ 25 
4.4 
Endpoints for Secondary Objective (Efficacy) .................................................................. 25 
4.5 
Endpoints for Pharmacokinetics ........................................................................................ 26 
5. 
INVESTIGATIONAL PLAN ................................................................................................ 27 
5.1 
Study Design  ........................................................................................................................ 27 
5.2 
Study Population .................................................................................................................... 27 
5.2.1 
Selection of Study Population ............................................................................................. 27 
5.2.2 
Inclusion Criteria ................................................................................................................... 28 
5.2.3 
Exclusion Criteria .................................................................................................................. 28 
5.3 
Patient Numbering ................................................................................................................. 29 
5.4 
Screen Failure Patients........................................................................................................... 29 
5.5 
Discontinuation of Individual Subjects .............................................................................. 29 
5.6 
Stopping of Clinical Trial .................................................................................................... 30 
5.7 
Concomitant Treatment ...................................................................................................... 31 
5.8 
Cornerstone Medication -  Permitted Concomitant Medication ............................................ 31 
5.9 
Vasopressor Therapy ............................................................................................................. 31 
5.10 
Lost to Follow-up .................................................................................................................. 31 
6. 
INVESTIGATONAL TREATMENTS .............................................................................. 32 
6.1 
Investigational Medicinal Product (IMP) .......................................................................... 32 
6.2 
Packaging, Labeling and Shipment .................................................................................... 33 
6.3 
Handling, Storage and Preparation ................................................................................... 34 
6.4 
Accountability ...................................................................................................................... 35 
6.5 
Treatment Assignment ........................................................................................................ 35 
6.5.1 
Randomization Procedures ................................................................................................. 35 
6.5.2 
Maintenance of the Randomization Code ......................................................................... 35 
6.5.3 
Emergency Unblinding ........................................................................................................ 36 
6.5.4 
Routine Unblinding ............................................................................................................. 36 
7. 
STUDY CONDUCT .............................................................................................................. 37 
7.1 
Standards of Study Conduct ............................................................................................... 37 
7.2 
Informed Consent .................................................................................................................. 37 
7.2.1 
Patients Able to Provide Consent Personally......................................................................... 37 
7.2.2 
Patients Unable to Provide Consent Personally ..................................................................... 37 

 
 
 
Protocol No. 
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EudraCT-No: 
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7.2.3 
Screen Failure Patients........................................................................................................... 38 
7.3 
Protocol Amendments............................................................................................................ 38 
7.4 
Study Visits and Procedures .................................................................................................. 39 
7.4.1 
Pre-Treatment: Screening ...................................................................................................... 39 
7.4.2 
Eligibility Confirmation:........................................................................................................ 40 
7.4.3 
Day 1: Start of Treatment ...................................................................................................... 40 
7.4.4 
Follow-up Period ................................................................................................................... 41 
7.4.5 
Screen Failure Patients........................................................................................................... 42 
7.5 
Premature Discontinuation .................................................................................................... 42 
7.6 
Visit Window  ........................................................................................................................ 42 
8. 
STUDY PROCEDURES ..................................................................................................... 43 
8.1 
Demography  ........................................................................................................................ 43 
8.2 
Medical History .................................................................................................................... 43 
8.3 
Physical Examination ............................................................................................................ 43 
8.4 
Vital Signs and Body Temperature ........................................................................................ 44 
8.5 
Glasgow Coma Scale ............................................................................................................. 44 
8.6 
Fluid Balance  ........................................................................................................................ 44 
8.7 
12-lead ECG  ........................................................................................................................ 44 
8.8 
Local Laboratory Assessments .............................................................................................. 45 
8.8.1 
Day 2 through day 7 or discharge (whatever comes first) ..................................................... 45 
8.8.2 
Day 8 through Day 27 or discharge (whatever comes first): ................................................. 45 
8.8.3 
Follow-up Day 28: ................................................................................................................. 46 
8.8.4 
Pregnancy test ........................................................................................................................ 46 
8.9 
Blood Sampling for bio-ADM and Biomarker ...................................................................... 46 
8.9.1 
Blood Sampling for measurement of bio-ADM ( screening) ................................................ 46 
8.9.2 
Blood Sampling for Biomarker for central laboratory ........................................................... 46 
8.10 
Organ Dysfunction Characterized by SOFA Score ............................................................... 47 
8.11 
Pharmacokinetic Analysis - Substudy ................................................................................... 47 
8.12 
Contraception, Pregnancy, Breastfeeding .............................................................................. 48 
8.12.1 
Contraception  ........................................................................................................................ 48 
8.12.2 
Pregnancy 
 ........................................................................................................................ 48 
8.12.3 
Breatfeeding Women ............................................................................................................. 48 
8.13 
Patient Reported Outcomes ................................................................................................... 49 
8.14 
Echocardiography (optional) ................................................................................................. 49 
9. 
PHARMACOVIGILANCE ................................................................................................... 50 
9.1 
Definitions 
 ........................................................................................................................ 50 
9.1.1 
Adverse Event (AE) ............................................................................................................... 50 
9.1.2 
Serious Adverse Event (SAE)................................................................................................ 50 
9.1.3 
Recommendations to Treat Overdosing and Intoxication with the Study Medication .......... 52 
9.1.4 
Investigational Product Complaints ....................................................................................... 52 
9.2 
Period of Observation ............................................................................................................ 52 
9.3 
Documentation and Reporting of Adverse Events ................................................................. 52 
9.3.1 
Documentation and Reporting of Adverse Events by Investigator........................................ 52 
9.3.2 
Assessment of Severity .......................................................................................................... 53 
9.3.3 
Assessment of Causality ........................................................................................................ 54 
9.3.4 
Follow-up of Missing Information ........................................................................................ 55 
9.3.5 
Determination of Expectedness, Reference Safety Information ............................................ 56 
9.3.6 
Expedited Reporting of Adverse Events / SUSAR Reporting ............................................... 56 
9.4 
Follow-up of Adverse Events ................................................................................................ 56 
10. 
STATISTICAL CONSIDERATIONS .................................................................................. 58 
10.1 
Demographic and Other Baseline Characteristics ................................................................. 58 
10.2 
Statistical Methods for Safety Parameters ............................................................................. 58 

 
 
 
Protocol No. 
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EudraCT-No: 
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10.3 
Handling of Withdrawals, Protocol Deviations and Missing Values .................................... 58 
10.4 
Safety Analysis ...................................................................................................................... 58 
10.5 
Efficacy Analysis ................................................................................................................... 59 
10.5.1 
Sepsis Support Index (SSI) and Penalized Sepsis Support Index (pSSI) .............................. 59 
10.5.2 
All-cause Mortality at Follow-up Day 28 and Day 90 .......................................................... 60 
10.5.3 
SOFA Score  ........................................................................................................................ 60 
10.6 
Sample Size Determination / Power Analysis for Primary Efficacy Endpoint (SSI 
within14 days  ........................................................................................................................ 60 
10.7 
Statistical Methods for Pharmacokinetic Parameters ............................................................ 61 
10.8 
Analysis of Observational Data and Exploratory Analysis ................................................... 61 
11. 
DATA MANAGEMENT and DATA HANDLING .............................................................. 62 
11.1 
Data Management .................................................................................................................. 62 
11.2 
Data Handling and Recording of Data ................................................................................... 62 
11.3 
Source Data  ........................................................................................................................ 63 
12. 
ETHICAL CONSIDERATIONS ........................................................................................... 64 
12.1 
Good Clinical Practice ......................................................................................................... 64 
12.2 
Independent Ethic Committees (IEC) and Competent Authorities (CAs) ............................. 64 
12.3 
Subject Insurance ................................................................................................................... 64 
12.4 
Steering Committee ............................................................................................................... 64 
12.5 
Data and Safety Monitoring Board ........................................................................................ 65 
13. 
ADMINISTRATIVE STRUCTURE AND RESPONSIBILITIES ....................................... 66 
13.1 
Study Monitoring ................................................................................................................... 66 
13.2 
Investigator Study File ........................................................................................................... 66 
13.3 
Changes in Study Conduct ..................................................................................................... 66 
13.4 
Protocol Compliance ............................................................................................................. 67 
13.5 
Protocol Deviations ............................................................................................................... 67 
13.6 
Drug Accountability .............................................................................................................. 67 
13.7 
Audits and Inspections ........................................................................................................... 67 
13.8 
Confidentiality ....................................................................................................................... 67 
13.9 
Patient Data and Data Protection ........................................................................................... 68 
13.10 
Reports 
 ........................................................................................................................ 68 
13.11 
Publication of Study Results .................................................................................................. 68 
13.12 
Study Documents and Record Retention ........................................................................... 69 
13.13 
Data Archiving ..................................................................................................................... 70 
14. 
REFERENCES .................................................................................................................... 71 
APPENDICES 
 ........................................................................................................................ 73 
Appendix 1: Declaration of Sponsor and Investigator .......................................................................... 74 
Appendix 2: APACHE II Score ............................................................................................................ 75 
APACHE II Severity of Disease Classification System ....................................................................... 76 
Appendix 3: SOFA Score ...................................................................................................................... 77 
Appendix 4: IMP Body weight Adjustment .......................................................................................... 78 
Appendix 5: Protocol History ............................................................................................................... 79 
 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
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CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 5 of 79 
1.1 
List of Abbreviations 
 
 
 
ADM 
Adrenomedullin 
AE 
Adverse Event 
AESIs 
Adverse Event of Special Interest 
 
 
 
 
 
 
Bio ADM 
Biologically active Adrenomedullin, measured by Sphingotec bio-
ADM assay 
BGA 
Blood Gas Analysis 
cAMP 
cyclic Adenosine Monophosphate 
CA 
Competent Authority 
CCC 
Clinical Coordinating Center 
CHF 
Chronic Heart Failure 
 
 
COPD 
Chronic Obstructive Pulmonary Disease 
 
 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
 
 
EU 
European Union 
GCS 
Glasgow Coma Scale 
GCP 
Good Clinical Practice 
hCRLR 
human Calcitonin Receptor-Like Receptor 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization  
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IL6 
Interleukin 6 
ILMA 
Immuno LuminoMetric Assay 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
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CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 6 of 79 
LPS 
Lipopolysaccharide 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
MR-proADM 
Mid-Regional pro-Adrenomedullin 
NOAEL 
Non Observed Adverse Event Level 
PaO2/FiO2 
Horowitz Index 
 
 
PCT 
Procalcitonine 
penKid 
Sphingotec penKid – a novel biomarker for kidney dysfunction 
PK 
Pharmacokinetic 
pSSI 
penalized Sepsis Support Index 
RAMP3 
Receptor Activity Modifying Protein 3 
SAE 
SC 
Serious Adverse Event 
Steering Committee 
SEM 
Stand Error Mean 
SOFA Score 
Sequential Organ Failure Assessment Score 
SSI 
Sepsis Support Index 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 7 of 79 
2. 
PROTOCOL SYNOPSIS 
 
 
2.1 
Protocol Summary 
 
Full Title: 
A Double Blind, Placebo-Controlled, Randomized, Multicenter 
Proof of Concept and Dose-Finding Phase II Clinical Trial to 
Investigate 
the 
Safety, 
Tolerability 
and 
Efficacy 
of 
ADRECIZUMAB in Patients with Septic Shock and Elevated 
Adrenomedullin 
 
Short Title: 
Treatment of patients with septic shock and bio-ADM 
concentration > 70 pg/mL with ADRECIZUMAB 
 
Protocol Code: 
 
AdrenOSS-2 
 
Protocol Number: 
ADR-02 
 
Phase: 
Clinical Trial Phase II – Proof of Concept 
 
Study Centers: 
Multicenter study conducted in the European Union 
 
Indication: 
Patients with early septic shock and an elevated bio-
adrenomedullin (concentration > 70 pg/ml) 
 
Study Objectives: 
Primary Objective: 
To investigate the safety and tolerability of ADRECIZUMAB in 
patients with early septic shock and elevated bio-ADM 
(concentration of > 70 pg/ml) in treatment arm A (2 mg/kg) and 
in treatment arm B (4 mg/kg) over the 90 days study period. 
 
Secondary Objective(s): 
• To obtain first data on efficacy of ADRECIZUMAB in 
patients with early septic shock and a bio-ADM 
concentration of > 70 pg/mL in the treatment arms compared 
with placebo.  
• To study the PK of free-ADRECIZUMAB with a focus on 
plasma accumulation and elimination  
 
Sample Size: 
300 randomized patients 
 
Randomization 1:1:2 to the following treatment arms and 
placebo (control group): 
• Treatment arm A: 2 mg/kg (75 evaluable patients) 
• Treatment arm B: 4 mg/kg (75 evaluable patients) 
• Control group: Placebo (150 evaluable patients) 
 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 8 of 79 
Duration of Treatment / 
Dosing: 
Intravenous infusion over approximately 1 hour 
Single i.v. dose of 2 mg/kg (treatment arm A) 
Single i.v. dose of 4 mg/kg (treatment arm B) 
Single i.v. dose of placebo (control group) 
Subject Enrollment 
Period: 
24 months 
Study Duration per 
Patient: 
The total study duration for primary efficacy endpoint is 14 
days, for safety up to 90 days: 
• Treatment period: single dose as i.v. infusion over 
approximately 1 hour 
• Follow-up period: Until 90 days after end of infusion.  
Inclusion Criteria: 
 
1. Written informed consent by patient or legally designated 
representative (according to country – specific regulations) 
2. Male and female patient, age ≥ 18 years  
3. Body weight 50 kg – 120 kg 
4. Bio-ADM concentration > 70 pg/ml 
5. Patient with early septic shock (start of vasopressor therapy 
 < 12 hours) 
6. Women of childbearing potential must have a negative serum 
or urine pregnancy test before randomization  
7.  Highly effective method of contraception must be 
maintained for 6 months after study start by women of 
childbearing potential and sexually active men. 
8. No care limitation 
Exclusion Criteria: 
1. Moribund  
2. Pre-existing unstable condition (e.g. a recent cerebral 
hemorrhage or infarct, a recent acute unstable myocardial 
infarction (all < 3 months), congestive heart failure – NYHA 
Class IV) 
3. Patients that required cardiopulmonary resuscitation in the 
last 4 weeks prior to evaluation for enrollment 
4. Severe COPD with chronic oxygen need at home  
(GOLD IV) 
5. Any organ or bone marrow transplant within the past  
24 weeks 
6. Uncontrolled serious hemorrhage (≥ 2 units of blood / 
platelets in the previous 24 hrs.). Patients may be considered 
for enrollment if bleeding has stopped and patient is 
otherwise qualified 
7. Uncontrolled hematological / oncological malignancies 
8.  Absolute neutropenia < 500 per µL)  
9. Severe chronic liver disease (Child-Pugh C) 
10. Systemic fungal infection or active tuberculosis 
11. Neuromuscular disorders that impact breathing / 
spontaneous ventilation 
12. Burns > 30% of body surface 
13. Plasmapheresis 
14. Breastfeeding women 
15. Participation in a clinical trial involving another 
investigational drug within 4 weeks prior to inclusion 
16. Unwilling or unable to be fully evaluated for all follow-up 
visits 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 9 of 79 
Trial Design: 
This is a double-blind, placebo-controlled, randomized, 
multicenter proof of concept and dose-finding phase II study 
using two doses of ADRECIZUMAB in patients with early septic 
shock and a bio-ADM plasma concentration at admission of > 70 
pg/ml. 
 
“Early” septic shock is defined as  
a life-threatening organ dysfunction due to dysregulated host 
response to a proven or suspected infection which leads to a 
decline of MAP < 65 mmHg, which is refractory to fluid 
resuscitation and requires vasopressors. Early is defined as a 
maximum of less than 12 hours between onset of the 
cardiovascular 
organ-dysfunction 
and 
administration 
of 
ADRECIZUMAB. Refractoriness to fluid resuscitation is 
defined as a lack of response to the administration of 30 mL of 
fluid per kilogram of body weight or is determined according to 
a clinician’s assessment of inadequate hemodynamic results.  
 
It is intended to enroll 300 patients from surgical, medical and 
mixed ICU at multiple centers in Europe. 
 
All patients will be treated according to “International Guidelines 
for Management of Severe Sepsis and Septic Shock”. 
 
Eligible patients (confirmed by central verification) will be 
randomized (1:1:2) to ADRECIZUMAB treatment arm A  
(2 mg/kg) or to ADRECIZUMAB treatment arm B (4 mg/kg) or 
to placebo as control group. Patients assigned to the treatment 
arm A or B will be administered a single dose of 
ADRECIZUMAB as intravenous infusion over approximately 1 
hour; patients assigned to the control group will be administered 
placebo as intravenous infusion over approximately 1 hour.  
 
As long as the patients are on the ICU, measurements of clinical 
signs and laboratory data will be collected for safety reasons and 
for determination of SOFA score. Additional blood samples for 
central laboratory analyses will be taken prior to start of IMP 
infusion (day 1) and  24 hours, 48 hours, 96 hours and 144 hours 
after end of infusion (+/- 10 hours) or between scheduled 
assessments, if discharged earlier from the ICU ((whatever 
comes first) for measurement of biomarkers. 
 
The SOFA score and its components will be determined daily for 
all patients over the entire stay on the ICU (28 days or until 
discharge whatever comes first) as long as an arterial line is in 
place. 
Safety monitoring for each patient will begin at the time of 
signing the Informed Consent Form and continue for 90 days 
after end of short-term infusion of study medication. 
 
At selected study centers a PK substudy will be performed to 
determine the profile of ADRECIZUMAB in 80 randomized 
patients. 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
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CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 10 of 79 
An interim analysis for efficacy is planned after 50% of patients 
have completed the study day 28 (n=150). 
 
 
Investigational 
Medicinal Product 
(IMP): 
Test Substance: ADRECIZUMAB 
ADRECIZUMAB (HAM8101) is a humanized IgG1 mono-
clonal antibody (mAb). 
 
Dosage form:Solution for injection in 200 mg vials 
Strength: 
10,4 mL HAM8101 protein for an extractable 
volume of 10 mL 
Dose: 
2 mg/kg single dose or 4 mg/kg single dose 
Route: 
i.v. infusion over approximately 1 hour 
Stored: 
2 – 8 °C, protected from light (refrigerator) 
 
Reference Substance: Placebo 
Histidine-HCl and Glycine solution in water for injection. 
Route of administration corresponding to ADRECIZUMAB. 
 
Any study medication has to be diluted from the Drug Product 
Stock solution with sterile NaCl solution 0.9%. 
 
 
Study Endpoints 
Endpoints for primary objective (safety and tolerability): 
• 
Mortality 
• 
Interruption of infusion 
• 
Severity and frequency of treatment-emergent adverse 
events 
 
Endpoints for secondary objectives (efficacy and PK): 
• Primary efficacy endpoint: 
Sepsis Support Index (SSI) defined as: days with organ 
support or dead within 14 days follow up. 
 
More precisely: In the time frame of 14 day follow-up, each 
day on support with vasopressor, and/or mechanical 
ventilation (defined as any ventilation received on this day, 
independent from the duration of mechanical ventilation), 
and/or renal dysfunction (defined as renal SOFA = 4), or 
not alive, is counted as 1. The sum over the follow-up 
period is defined as SSI. 
 
 
• Secondary efficacy endpoints: 
Sepsis Support Index (SSI) at day 28 follow-up 
- 
Penalized Sepsis Support Index (pSSI) at 14 and 28 day 
follow-up, defined similar to the SSI with the exception 
that patients that die get penalized by assigning the 
maximum value, i.e. the pSSI is set to 14 or 28 day 
respectively. 
- 
Persistent organ dysfunction or death at 14 and 28 day 
follow-up  
- 
Day 28 and day 90 mortality rate 
- 
SSI and pSSI excluding the renal component 

 
 
 
Protocol No. 
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EudraCT-No: 
2016-003883-38 
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Trial Protocol –Version 4.2, 28-August 2019 
 
Page 11 of 79 
- 
Individual SSI components (hemodynamic, respiratory 
and renal failure) with and without mortality 
- 
Sequential Organ Failure Assessment (SOFA) Score 
o Mean/maximum/total daily SOFA score during stay at 
ICU 
o Change in SOFA score within 48 hours 
o Delta SOFA score, defined as maximum versus 
minimum SOFA during ICU stay 
o SOFA-3 (score limited to cardiovascular, respiratory 
and renal function) 
- 
Improvement in renal function as change in penKid and 
creatinine  (day 3 – day 1, day 7 – day 1) 
- 
Duration of stay at ICU/ hospital 
- 
Changes of functional and other parameters during stay 
at ICU (MAP, creatinine, PaO2/FiO2, blood lactate, fluid 
balance, MR-proADM, inflammatory markers PCT, IL-
6) 
- 
Vasopressor use (drug, highest/lowest dose, duration) 
- 
Quality of Life by Euro-QoL-5 (day 28 and day 90) 
- 
Vital signs (heart rate, blood pressure) 
 
• Endpoints for pharmacokinetics sub-study: determine key PK 
parameters, including  
- 
peak plasma concentrations (Cmax) 
- 
systemic exposure (AUC) 
- 
volume of distribution (V) 
- 
systemic clearance (CL) 
- 
elimination half-life (t½) 
 
Data and Safety 
Monitoring Board 
(DSMB): 
The independent Data and Safety Monitoring Board will consist 
of two clinical experts in the field of sepsis, one statistician and 
one Pharmacovigilance representative. 
 
The DSMB will review and evaluate the safety data monthly 
during the course of the study and will recommend to the sponsor 
whether to continue, modify or terminate the study based on the 
mortality rate. 
 
 
Steering Committee: 
The SC will provide oversight of the conduct of the study to 
ensure that the study is conducted to the rigorous standards set 
out in Good Clinical Practice.  
 
Statistical Methods: 
 
 
 
 
 
 
 
 
A total sample size of 300 patients is needed for the study and 
assuming that delta SSI is >10%, the power is > 80% to 
demonstrate an improvement of SSI of > 0 with at least 80% 
probability. The lower bound of the confidence interval will be 
determined based on the non-parametric Wilcoxon test. 
 
Power simulations are based on using real patient data on the 
combined endpoint from the ALBIOS study [2]. Simulations 
were extended to and results confirmed by data from the 
AdrenOSS observational study. 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
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CONFIDENTIAL 
Trial Protocol –Version 4.2, 28-August 2019 
 
Page 12 of 79 
 
An interim analysis with futility stop will be performed when 150 
patients (n=150) have completed the study day 28. The study will 
be stopped if the probability of a positive outcome is below 40% 
once 50% of patients (n=150) completed study day 28. Power 
remains > 80% if futility stop is included in the simulation. 
 
 
 
 
 

 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
______________________________________________________________________________________________________________________________________________________________________________________ 
 
CONFIDENTIAL 
Trial Protocol - Version 4.2, 28-August 2019 
 
Page 13 of 79 
Figure 1 Study Flow Chart for Randomized Patients 
 
 
Hospitalization and ICU 
Follow-up 
Visit 
Pre-Treatment 
Start of  
Treatment 
Day 1 
2 
3 
4 
5 
6 
7 
8 - 27 or 
Discharge* 
28 
28 
** 
90 
Phone 
Contact 
Screening  
Eligibility 
Confirmation 
 
 
 
 
 
 
 
 
 
 
 
 
+/- 3 days 
Written Informed Consent 
X1) 
 
 
 
 
 
 
 
 
 
 
 
 
Retrospective Written Informed Consent 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
(X2)) 
 
Diagnosis of early septic shock 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Information on Hospital and ICU 
Admission 
X3) 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X4) 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
(includes body weight and height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X5) 
 
X6) 
X6) 
X6) 
X6) 
X6) 
X6) 
X6) 
X6) 
X6) 
X5) 
 
Echocardiography (optional) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma bio-ADM concentration 
X7) 
 
 
 
 
 
 
 
 
 
 
 
 
Local Laboratory Assessment 
X8) 
 
 
X9) 
X9) 
X9) 
X9) 
X9) 
X9) 
X10) 
X9) 
X9) 
 
Arterial Blood Gas Analysis 
 
 
X11) 
X12) 
X12) 
X12) 
X12) 
X12) 
X12) 
X12) 
X12) 
 
 
Pregnancy test (urine or serum) 
X 
 
 
 
 
 
 
 
 
 
X13) 
X13) 
 
APACHE II 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Central Verification of Inclusion and 
Exclusion Criteria 
 
X14) 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
X15) 
 
 
 
 
 
 
 
 
 
 
Therapy of special interest (vasopressor) 
X16) 
 
X17) 
X17) 
X17) 
X17) 
X17) 
X17) 
X17) 
X17) 
X17) 
 
 
Cornerstone Medication and  
Concomitant Medication 
X18) 
 
X18) 
X18) 
X18) 
X18) 
X18) 
X18) 
X18) 
X18) 
X18) 
X18) 
 
Fluid Balance 
 
 
 
X19) 
X19) 
X19) 
X19) 
X19) 
X19) 
X19) 
X19) 
 
 
Evaluation of Organ Dysfunction 
(SOFA) 
 
 
X20) 
X21) 
X21) 
X21) 
X21) 
X21) 
X21) 
X21) 
X21) 
 
 
Blood Sampling for biomarkers 
 
 
X22) 
X 
X 
(X23)) 
X 
(X23)) 
X 
 
 
 
 
PK Substudy 
 
 
X24) 
X 
X 
(X25)) 
X 
(X25)) 
X 
 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life by Euro-QoL-5 
 
 
 
X26) 
X26) 
X26) 
X26) 
X26) 
X26) 
X26) 
X26) 
X 
X27) 
 
* 
(whatever comes first) 
** 
For all patients discharged prior to day 28 

 
 
 
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(1) Written informed consent must be obtained prior to any study specific procedures. In case the patient is 
not able to give informed consent due to the emergency nature of the patient’s condition, legally 
designated representatives according to local law or local regulation should sign informed consent form. 
(2) Retrospective consent from the study patient is required to be obtained for continuation with study 
procedures and should be obtained as soon as the patient is able to provide the written informed consent. 
(3) Date, time, location before admission, type of admission, origin of sepsis to be recorded at hospital and 
ICU admission, start of vasopressor administration if prior to admission. 
(4) Document all ongoing conditions and relevant medical history and co-morbidities present or treated 
within the last year (cardiovascular and non-cardiovascular) and concomitant illnesses present at 
inclusion. 
(5) Vital signs (blood pressure, heart rate, MAP, respiratory rate and oral or tympanic temperature) will be 
collected as single value. 
(6) Vital signs (blood pressure, heart rate, MAP, respiratory rate and oral or tympanic temperature) will be 
collected as minimal as well as maximal value of the study day. 
(7) Plasma bio-ADM concentration of > 70 pg/mL required for enrollment. Measurement is allowed to 
be repeated in case concentration is < 70 pg/mL and as long as definition of septic shock is still 
applicable at the time of repeated measurement. 
(8) 
For screening lab values can be used which hav already been analyzed for clinical routine (e.g. routine 
blood test at ICU) and not for study purposes specifically. However, only documentation from lab 
analyses should be considered, which is closest to the time point of IMP administration: BUN or urea, 
sodium, potassium (at screening only). creatinine, total bilirubin, platelet counts, hemoglobin, 
hematocrit, blood lactate concentration, white blood count, differential blood count (at screening only). 
 
(9) Day 2 to day 7 and day 28 (taken at the morning routine) or discharge from ICU (whatever comes first) 
and follow-up day 28: BUN or urea, sodium, creatinine, total bilirubin, platelet count, hemoglobin, 
hematocrit, blood lactate concentration, white blood count. 
(10) Day 8 to day 27 or discharge from ICU (whatever comes first): Daily measurement of creatinine . 
Total bilirubin, platelet count and blood lactate concentration will be measured every other day.  
(11) Day 1: PaO2/FiO2 (if arterial line in place) and arterial pH (APACHE II score), prior to IMP 
administration. 
(12) Day 2 to day 28 or discharge from ICU (whatever comes first): PaO2/FiO2 (if arterial line in place) and 
arterial pH minimal and maximal values. 
(13) Pregnancy test will be performed on day 28 (for patients still on ICU) or on follow-up day 28 (for 
patients discharged from ICU). 
(14) Eligibility Confirmation: Inclusion and Exclusion criteria to be sent to Clinical Coordinating Center for 
central evaluation. Only after receipt of results of central verification, randomization of patient to one 
of the treatment arms or to the placebo control group possible. 
(15) Day 1: Start of treatment within 12 hours after start of vasopressor administration due to septic shock. 
(16) Screening: Record start and stop date/time, drug, dose, unit, of the first vasopressor administration due 
to septic shock. 
(17) Day 1 to day 28 or discharge from ICU (whatever comes first): Record start and stop date/time, drug, 
dose (highest/lowest) and unit. 
(18) Concomitant medication  and cornerstone medication: Should be recorded from screening to day 28 or 
discharge from ICU (whatever comes first) as well as on follow-up day 28 if patient was discharged 
from ICU before day 28. 
(19) Fluid balance: Difference between fluid administered (intravenous fluid, blood products, enteral fluids) 
and fluid lost (ultrafiltrate from renal replacement therapy, urine output for 24 hours, enteral losses, 
drain losses) in the last 24-h period. 
(20) Day 1: Evaluation of Organ dysfunction (SOFA score): Cardiovascular system, respiratory system, 
kidneys, coagulation, liver, nervous system (Appendix 3) to be performed shortly before IMP 
administration.  
(21) Day 2 to day 28 during stay in ICU: Data for SOFA score to be recorded are always the worst values 
within 24 hours. 
(22) Day 1: Central laboratory assessment to be performed for biomarkers prior to start of IMP infusion. 
(23) Day 2 to day 27 in the morning of the sampling day): Central laboratory assessment at 24 hours, 48 
hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, 
if discharged earlier from the ICU (whatever comes first). 

 
 
 
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(24) At pre-selected sites only. On day 1 plasma concentration of free ADRECIZUMAB to be determined 
prior to IMP infusion. 
(25) Day 2 to day 7 and day 28 (either during day in ICU or on follow-up day 28, if discharged from ICU 
prior to day 28): Determination of PK after 30 minutes, 24 hours, 48 hours, 96 hours, 144 hours and 
648 hours after end of infusion). (+/- 10 hours) or between scheduled assessments, if discharged earlier 
from the ICU (whatever comes first). 
(26) Only on discharge from ICU. 
(27) Completion of paper questionnaire by telephone. 
 
Others: 
In the time frame of 14 day follow-up, each day on support with vasopressor, and/or mechanical ventilation 
(defined as any ventilation received on this day, independent from the duration of mechanical ventilation), 
and/or renal dysfuncion (defined as renal SOFA = 4), or not alive, is counted as 1. The sum over the follow 
up period is defined as SSI. 
 
 
 
Figure 2 PK Sampling – Substudy 
 
 
Day 
 
 
 
1 
2 
3 
5 
7 
28* 
Hours 
 
Pre-
dose 
0 
After 
end of 
infusion 
30 min 
24 
48 
96 
144 
648 
 
 
 
 
+/- 10 
min 
+/- 10 
hours 
+/- 10 
hours 
+/- 10 
hours  
+/- 10 
hours 
+/- 3 days 
IMP 
i.v. Infusion 
 
 
 
 
 
 
 
 
 
 
PK Sampling 
Adrecizumab 
Plasma  
Concentration 
 
 
 
 
 
 
 
 
 
 
 
* 
Day 28: Sample to be taken either during stay in ICU or on day 28  
follow-up, if patient is discharged from ICU prior to day 28 
 
 
Biomaker Determination (Central Lab) 
• 
After approval of eligibility of patient by CCC and prior to start of IMP infusion 
• 
After 24 hours +/- 10 hours after end of infusion 
• 
After 48 hours +/- 10 hours after end of infusion 
• 
After 96 hours +/- 10 hours after end of infusion 
• 
After 144 hours +/- 10 hours after end of infusion 
 
or between scheduled assessments, if discharged earlier from ICU (whatever comes first). 
 
 
 

 
 
 
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Figure 3 Study Flow Chart for Screen Failure Patients 
 
 
 
Hospitalization and ICU 
Follow-up 
Day 
1 (Screening) to 14 or 
Discharge 
28 
90 
 
 
 
 
Sepsis Support Index (SSI) 1) 
X 
 
 
Survival / Mortality 
 
X 
X 
 
 
 
 
 
(1) Investigator will be asked to contact the patient on day 14 for calculation of the SSI (screening 
to day 14) during stay at ICU as well as on follow-up day 28 and day 90 for recording and 
evaluation of survival / mortality. For assessment of the SSI and for recording and evaluation 
of survival / mortality data the investigator should seek to obtain the patient’s consent. 
 
 
 

 
 
 
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3. 
INTRODUCTION AND RATIONALE 
 
3.1 
Background Information 
 
3.1.1 
Septic Shock 
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response 
to infection. Organ dysfunction can be identified as an acute change in 2 total SOFA score points 
subsequent to the infection. Septic shock is a subset of sepsis in which underlying circulatory 
and cellular/metabolic abnormalities are profound enough to substantially increase mortality. 
Patients with septic shock can be identified with a clinical construct of sepsis with persisting 
hypotension requiring vasopressors to maintain MAP > 65 mm Hg and having a serum lactate 
level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. With these criteria, hospital 
mortality is in excess of 40% [4, 22]. 
 
One important factor in the pathogenesis of sepsis and septic shock seems to be Adrenomedullin 
(ADM), a circulating hormone and a local autocrine/ paracrine mediator. ADM is an autocrine 
and paracrine hormone where the local ADM concentration (i.e. in the immediate vicinity of 
endothelial and vascular muscle cells) is assumed to be substantially higher than the plasma 
concentrations; this applies for healthy conditions, but for sepsis as well. It is therefore assumed 
that the ADM plasma concentrations are an overspill of local concentrations. Therefore, the 
exact mechanism of action is difficult to explain based on the plasma concentrations.  
 
In several preclinical and clinical studies ADM was infused to healthy volunteers or CHF 
patients. The ADM infusion led to an arterial blood pressure decrease, increase of heart rate and 
cardiac index [7, 8, 9, 10, 11, 12, 18, 19, 24]. 
 
Ueda et al. reported that the plasma ADM concentrations in patients with septic shock were 
more than 10-fold over normal [25]. Hirata et al have also shown that an increase of plasma 
ADM concentrations over time in septic intensive care unit (ICU) patients is associated with 
fatal outcome, whereas in septic patients who recovered from sepsis ADM concentrations 
decreased over time [6]. Nishio et al. investigated in a prospective clinical trial plasma 
concentrations of adrenomedullin in patients with septic shock and the potential association of 
these concentrations with relaxation of vascular tone. The mean plasma concentration of 
adrenomedullin was markedly higher in patients than in controls (226.1 +/- 66.4 [SEM] vs. 5.05 
+/- 0.21 fmol/mL, p <.01). Moreover, these concentrations correlated significantly with cardiac 
index, stroke volume index, and heart rate values, and correlated significantly with decreases in 
diastolic blood pressure, systemic vascular resistance index, and pulmonary vascular resistance 
index. They concluded, that the enhanced production of Adrenomedullin in patients with septic 
shock may contribute to reduced vascular tone, hypotension, or both [13]. 
 
ADM has also an effect on endothelial permeability via the phosphatidyl-Inositol-3-Kinase/ Akt 
pathway. ADM reduces the endothelial permeabilty by reducing tyrosin-phosphorylation of VE-
cadherin (Tyr 731) and enhances the binding of ß-catenin to the cytoplasmic  tail of VE-cadherin 
which leads to enhanced vascular integrity. 
 
 
 

 
 
 
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3.1.2 
Investigational Medicinal Product 
HAM8101 is classified as a biotechnology-derived pharmaceutical falling into the scope of ICH 
S6(R1). Therefore, the non-clinical development program was based on the ICH S6(R1) 
guidance and in addition follows recommendations provided during a Scientific Advice Meeting 
with Paul Ehrlich Institute in November 2012. 
 
Mode of Action 
A possible mode of action for the anti-Adrenomedullin antibody Adrecizumab has been 
developed on the basis of published data, own experimental data and theoretical considerations. 
The model has been discussed with key opinion leaders in the field (Prof. Hippenstiel, Charité 
Berlin, Germany, and Prof. Ouafik, University Marseille, France). 
 
The model developed is described here: 
 
 
 
ADM is a relatively small peptide comprising 52 amino acids, which is synthesized mainly in 
endothelial and smooth muscle cells and is secreted from these cells. Several functions of ADM 
have been described, including vasodilatory activity and stabilization of endothelial 
permeability. ADM acts in an autocrine/paracrine way but also as a hormone. Due to its small 
size, ADM is supposed to be able to freely diffuse between the blood circulation and the 
interstitium. The inner wall of blood vessels is composed of endothelial cells. Smooth muscle 
cells, on the contrary, have no direct contact to the blood circulation, as they are located distal 
at the basal site of the endothelial cell layer of arteries. Thus, it can be assumed that ADM 
located in the blood circulation can act on endothelial cells to stabilize endothelial permeability, 
but from this compartment cannot directly exert its vasodilatory activity on smooth muscle cells. 
Rather, smooth muscle cells are accesible for ADM, when it is located in the interstitium. 
 
When the anti-Adrenomedullin antibody Adrecizumab is administered in the blood circulation 
at high concentrations by far exceeding those of plasma ADM, the compartmental distribution 
of ADM is altered. Adrecizumab, an IgG with a molecular weight of more than 150 kDa, is too 
large to freely diffuse from the blood circulation to the interstitium. 
 
With its fast association kinetics Adrecizumab quickly binds to ADM in the blood circulation 
and „pulls“ ADM, which has been initially located in the interstitium, from this compartment to 

 
 
 
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the blood circulation. The more Adrecizumab is applied, the stronger is the „pulling“ effect and 
the higher the resulting concentrations of Adrecizumab-bound ADM in the blood circulation. 
The increase of Adrecizumab-bound ADM in the blood circulation occurs within 5-15 minutes 
after administration of Adrecizumab, and no parallel increase of MR-proADM, another peptide 
derived from the same precursor as ADM, has been observed. Thus, it can be excluded that 
Adrecizumab leads to an immediate transcriptional activation of the ADM gene or release of a 
pool of ADM-precursor derived peptides from secretory vesicles, but that it rather induces a 
translocation of preformed ADM. As a consequence of this redistribution, the ADM 
concentration in the interstitium decreases, and less ADM is able to act on smooth muscle cells 
to exert its vasodilatoryactivity. In the progression to septic shock, when it comes to excessive 
vasodilation and hypotension, administration of Adrecizumab thus can reduce vasodilation by 
substracting excessive levels of interstitially located ADM. 
 
At the same time levels of Adrecizumab-bound ADM increase in the blood circulation, and it is 
assumed that this can be functionally relevant: Due to its epitope specificity for the N-terminal 
moiety of ADM, Adrecizumab is a special anti-Adrenomedullin antibody. While it is a high-
affinity antibody, its binding to ADM does not completely block the function of ADM, but 
rather only partially reduces its capacity to elicit a second messenger response. The net effect of 
an increase of Adrecizumab-bound ADM in the blood circulation on the one hand, and an only 
partial functional inhibition of ADM brought about by the binding of Adrecizumab on the other 
hand, is that more ADM activity is present in the blood circulation after administration of 
Adrecizumab than without administration of Adrecizumab. The increased net activity in the 
blood circulation could promote stabilization of endothelial permeability. 
 
An additional effect of binding of Adrecizumab to ADM in the blood circulation could be an – 
at least partial and/or temporal – protection from otherwise occurring proteolytic decay of ADM. 
Proteolytic degradation of ADM occurs at its N-terminus. It is exactly this site, where 
Adrecizumab binds to ADM. 
 
 
3.1.2.1 
Clinical Experience 
Prior to investigating ADRECIZUMAB in septic patients, the safety, tolerability and 
pharmacokinetics/-dynamics of single administrations of ADRECIZUMAB was evaluated in a 
Phase I study in healthy volunteers, consisting of two parts (Phase Ia and Phase Ib). 
 
In the Phase Ia part healthy male subjects were randomized in a double-blind, placebo-controlled 
study with single escalating doses of ADRECIZUMAB administered as intravenous (i.v.) 
infusion in 3 sequential groups of 8 subjects each, 1st group 0,5 mg/kg, 2nd group 2 mg/kg, 3rd 
group 8 mg/kg (n=6 active, n = 2 placebo for each group). 
 
The main inclusion criteria were written informed consent, age 18 – 35 years, agreement to use 
a reliable way of contraception and a BMI between 18 and 30 kg/m². Subjects received a single 
i.v. dose of ADRECIZUMAB (0,5 mg/kg; 2 mg/kg; 8 mg/kg) or placebo by slow infusion over 
a 1-hour period in a research unit. 
 
 
 

 
 
 
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As the minimal effect concentration in healthy animals based on studies Safety-01 and Safety-
06 is between 0.1 and 0.5 mg/kg, which showed an increase in total plasma ADM concentrations 
starting at a HAM8101 concentration of 0.5 mg/kg rising upon further increase in dose of 
applied drug, the starting dose was chosen at 0.5 mg/kg. 
 
The apparent terminal elimination half-life is approximately 14 – 15 days. Due to the slow 
elimination the mean residence time was also long: ~ 17 days. The small volume of distribution 
also indicates the weak distribution properties of ADRECIZUMAB. Thus, the administered 
dose is localized predominantly in the circulation and distributed and eliminated slowly. 
 
This phase 1a study in healthy volunteers has been completed with the result that no SAEs or 
SUSARs were observed, no clinically significant electrocardiographic abnormalities were 
observed, normal local tolerability and no obvious abnormalities, vital signs or clinical 
laboratory values. 
 
A Phase 1b study was conducted to investigate the safety and tolerability of ADRECIZUMAB 
under inflammatory conditions in healthy volunteers. The experimental human endotoxemia 
model, in which healthy male volunteers receive a low dose of LPS derived from Escherichia 
coli, is widely used to study the effects of systemic inflammation in humans in vivo and is 
considered a safe and highly reproducible method to activate the innate immune system. After 
induction of the systemic inflammation the study design (ADRECIZUMAB doses and 
administration and study assessments) were the same as for the Phase Ia study. No clinical 
relevant AEs/SAEs were observed after administration of ADRECIZUMAB. 
 
After these phase I studies it is intended to start a phase II study in 300 patients with early septic 
shock. 
 
 
3.2 
Rationale for the Clinical Trial 
The importance and the potential clinical relevance of Adrenomedullin in sepsis has also been 
confirmed in several observational clinical studies with patients with sepsis, severe sepsis and 
septic shock. It could be demonstrated in a pilot study that in patients who had a bio-ADM 
concentration < 70 pg/mL there was a significant lower mortality than those with a bio-ADM 
concentration > 70 pg/mL. Keep in mind that Adrenomedullin has to be amidated when 
biologically active (please refer to more information to the investigator’s brochure). Interesting 
is the observation that those patients who had a higher bio-ADM concentration > 70 pg/mL and 
remained high over the next four days had a mortality of around 65%, but  of those who had a 
significant decline of bio-ADM concentration over the next four days 100 % survived [14]. This 
observation was also confirmed by data from Marx et al. in septic patients on a surgical ICU. 
Patients with a bio-ADM concentration of 97.5 pg/mL had a significantly higher mortality rate 
than those with a bio-ADM concentration of 42.6 pg/mL. Patients who had a median bio-ADM 
concentration of around 40 pg/mL did not need any vasopressor support over the entire stay at 
ICU [21]. 
 
In a further observational study, similar observations were made in the FROG-ICU study: ICU 
patients with severe sepsis on admission (n=61) had a bio-ADM concentration of around 
70 pg/mL compared to around 120 pg/mL in septic shock patients who received 
vasopressor/inotropics on the day of admission [16, 17]. 
 

 
 
 
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These data indicate that ADM plays an important role in the pathogenesis of sepsis. 
ADRENOMED AG has developed an epitope–specific antibody for therapeutic use in patients 
with septic shock. 
 
Aim of a targeted therapy should be to maintain the beneficial effect of ADM, while 
counteracting an excess of ADM.  
 
Therefore, several mouse monoclonal anti-ADM antibodies were developed which inhibit the 
ADM function differently depending on their epitopes. While the anti-ADM antibody directed 
against C-terminal moiety of ADM led to a 100% inhibition of ADM activity, the anti-ADM 
antibody activity against the N-terminal moiety of ADM led to a inhibition of ADM function of 
approx. 35% - 50 % [23]. Only the antibody leading to a partial inhibition (directed against the 
N-terminal moiety of ADM) has shown the most benefit in preclinical septic models: 
Administration of this antibody largely improved survival in CLP mice [23], and in a 
resuscitated mouse CLP model led to an improvements of hemodynamics (reduced 
catecholamine demand to maintain MAP > 65 mmHg), increase of creatinine clearance, less 
positive fluid balance and reduced systemic inflammation [26]. Also, the CLP induced 
deterioration in kidney barrier function, expressed by extravascular albumin accumulation, was 
significantly reduced [15]. Therefore the antibody has been further developed to a humanized 
variant (ADRECIZUMAB).  
 
The main preclinical results obtained with ADRECIZUMAB can be summarized as follows: 
It was shown that the administration of ADRECIZUMAB in a two-hit pig model of systemic 
bacteremia led to an improvement of renal function, an attenuated inflammatory response and a 
significant reduction of vasopressor use in acute shock [20]. Delayed treatment of CLP rats 
improved mean arterial pressure [1]. Overall, these results illustrate that the administration of 
ADRECIZUMAB exerts beneficial effects in sepsis models demonstrated by 
 
• reduced edema formation,  
• reduced fluid demand, 
• improved fluid balance 
• improved kidney function,  
• improved blood pressure and  
• reduced inflammation. 
 
ADRECIZUMAB was tested for safety extensively in mice, rats, dogs and in non-human 
primates. The NOAEL (none-observed adverse events level) in NHP was 100 mg/kg (max. 
tested) and the NOAEL in rats is 400 mg/kg (max. tested).  
 
 
3.2.1 
Study Design 
This is a double-blind, placebo-controlled, dose-finding, multicenter randomized proof of 
concept phase II study using two doses of ADRECIZUMAB in patients with early septic shock 
and a bio-ADM plasma concentration at admission of > 70 pg/ml. 
 
 
“Early” septic shock is defined as  
a life-threatening organ dysfunction due to dysregulated host response to a proven or suspected 
infection which leads to a decline of MAP < 65mm Hg which is refractory to fluid resuscitation 
and requires vasopressors. Early is defined as a maximum of < 12 hours between onset of the 
cardiovascular organ-dysfunction (start of vasopressor use) and administration of 

 
 
 
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ADRECIZUMAB. Refractoriness to fluid resuscitation is defined as a lack of response to the 
administration of 30 mL of fluid per kilogram of body weight or is determined according to a 
clinician’s assessment of inadequate hemodynamic results. 
 
In this phase II study 300 patients with early septic shock and a plasma concentration of bio-
ADM > 70 pg/mL from surgical, medical and mixed ICU at multiple centers in Europe will be 
randomized. This concept is based on the observation of the clinical observation study 
AdrenOSS-1, in which 201 out of 291 patients with septic shock and a bio-ADM concentration 
> 70 pg/mL had a 28-day mortality rate of approximately 35% compared with 84 out of 291 
patients with a bio-ADM concentration < 70 pg/mL who had a 28-day mortality rate of 23 %. 
 
All patients will be treated according to “International Guidelines for Management of Severe 
Sepsis and Septic Shock” [3]. 
 
300 patients with early septic shock will be randomized into two treatment arms and one control 
group. After informed consent has been signed by patient or legally designated representative 
and the result from plasma-ADM concentration (> 70 pg/ml) is available, inclusion and 
exclusion criteria will be checked via a centralized procedure. After fulfilling the inclusion and 
exclusion criteria patients will be assigned randomly (randomization 1:1:2; four – block 
randomization per center) to the treatment arms (2 mg/kg or 4 mg/kg) or to the placebo control 
group. 
 
Patients assigned to the treatment arms will be administered a single dose of ADRECIZUMAB 
as i.v. infusion over approximately 1 hour; patients assigned to the control group will be 
administered placebo  as i.v. infusion over approximately 1 hour. 
 
Patients will be evaluated for safety and tolerability of the therapy, but also for signs of clinical 
efficacy. As long as the patients are on the ICU, measurements of clinical signs and laboratory 
data will be collected for safety reasons and for determination of SOFA score as long as arterial 
line is in place for determination of PaO2/FiO2. 
 
Additional blood samples for determination of Adrenomedullin (prior to infusion) and the 
biomarker MR-proADM and inflammatory biomarkers PCT, IL-6 and penKid will be taken 
prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after 
end of IMP infusion (day 2). Further blood sampling for biomarker assessment will follow at 48 
hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled 
assessments, if discharged earlier from ICU (whatever comes first). 
 
Patient accrual is expected to be completed within 24 months. 
 
An interim analysis is planned after 50% of patients (n=150) have completed study after day 
28 . 
 
3.2.2 
Dose Selection 
The rationale for the chosen doses of 2 mg/kg or 4 mg/kg is based on model considerations: It 
was derived from in vitro studies (Adrenomedullin-induced cAMP response in CHO cells 
overexpressing hCRLR/RAMP3) that the local ADM concentration is assumed to be 
substantially higher than what is found under normal conditions in plasma. This is also true for 
sepsis and septic shock situations – the local concentration of ADM is likely much higher than 
what is found in the plasma. It is therefore assumed that the ADM plasma levels reflect an 
overspill of local concentrations. Since the aim is to provide with a single dose of 

 
 
 
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ADRECIZUMAB an excess in order to bind all endogenous ADM (systemic and local) for at 
least 7 days, a dose of 2 mg/kg or 4 mg/kg has been determined as the target doses for Phase II. 
These thoughts derived from model should be confirmed in this study. 
 
In a phase Ia/Ib study additional doses of ADRECIZUMAB (0.5 mg/kg and up to 8 mg/kg) are 
tested for safety. No relevant AEs were observed in any of the groups in the Phase Ia study. The 
Phase Ib study was conducted and completed before start of the Phase II study. Nonclinical 
safety studies in various animal species have been conducted in order to cover the safety of the 
target dose. In summary, in all species no adverse events, even at the highest tested dose (in 
rodents up to 800 mg/kg) were detected. 
 
3.3 
Assessment of Potential Risks and Benefits and Risk Management 
Primary aim of this phase II study is to demonstrate safety and tolerability as well as efficacy of 
ADRECIZUMAB in patients with septic shock. The current phase II study is underpowered to 
detect a relevant reduction of 28-day mortality by ADRECIZUMAB; on the other hand, there 
is evidence from our animal models that ADRECIZUMAB can improve organ function. The 
improvement in organ function is measurable using days with relevant organ support (cardiac, 
renal, respiratory) while on ICU. Therefore, a composite endpoint of days with organ support 
AND all-cause of mortality will be used: the “Sepsis Support Index” (SSI). Further, it is intended 
to determine pharmacodynamics and pharmacokinetics of ADRECIZUMAB. 
 
ADRECIZUMAB is a humanized monoclonal antibody. Therefore, there is a general potential 
risk of an allergic reaction or allergic shock when administered to patients. To minimize this 
risk strict compliance with the inclusion and exclusion criteria of the conducted clinical trials is 
necessary. Furthermore, Adrecizumab should be given as an infusion over 1 hour to be able to 
stop the infusion in case of an allergic reaction AND patients should only be treated under the 
controlled environment of an ICU. In case of an allergic reaction or allergic shock in a study 
patient, the local standard treatment should be followed. 
 
During the first administration of ADRECIZUMAB to 36 male, healthy volunteers in the Phase 
Ia and phase Ib studies ADRECIZUMAB was very well tolerated and no serious adverse events, 
in particular no allergic reactions/allergic shock, and no clinically relevant adverse events and 
no clinically relevant disturbances in the ECG were observed. Local tolerability was normal and 
there were no obvious deviations in the vital signs (blood pressure, pulse and respiratory rate) 
or in clinical laboratory values. 
 
The side effects of ADRECIZUMAB that occurred were equally distributed across all dosage 
groups, were only transient and required no medical treatment. The following adverse effects 
were observed: 
 
• 
Headache, 13 events; 
• 
Influenza-like symptoms/blocked nose, 27 events; 
• 
Back pain, 3 events; 
• 
Shoulder pain, 4 events; 
• 
Nosebleeds, 2 events; 
• 
Inflammatory skin change (eczema), 2 events. 
 
The following side effects only occurred once: Skin infection (on the toe), skin rash at the 
infusion site, abdominal pain, blood loss in the rectum (once), dull pain/sensation in the thumb, 

 
 
 
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sleep-disordered breathing (in the sleep laboratory), bone fracture in the wrist, swelling of the 
upper eyelid.  
 
ADRECIZUMAB has not been used before in septic patients. Therefore AEs could occur which 
are not predictable. The administration of ADRECIZUMAB in septic patients will occur after 
comprehensive preclinical studies have been conducted and after completion of the phase Ia and 
phase Ib study in healthy volunteers with and without LPS challenge without observation of any 
relevant side effects. Therefore, the striking effect of ADRECIZUMAB in preclinical testing 
and excellent safety data from phase Ia and phase Ib study let expect a positive benefit/risk ratio 
for the treatment in patients with septic shock. Therefore it is considered to launch this phase II 
proof of concept study. 
 
Additional information can be found in the IB. 
 
 

 
 
 
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4. 
TRIAL OBJECTIVES AND ENDPOINTS 
 
4.1 
Primary Objective 
The primary objective of this study is 
 
• To investigate the safety and tolerability of ADRECIZUMAB in patients with early septic 
shock and elevated bio-ADM (concentration of > 70 pg/ml) in treatment arm A (2 mg/kg) 
and in treatment arm B (4 mg/kg) over the 90 days study period. 
 
 
4.2 
Secondary Objectives 
The secondary objectives of this study are  
 
• To obtain first data on efficacy of ADRECIZUMAB in patients with early septic shock and 
a bio-ADM concentration of > 70 pg/mL in the treatment arms compared with placebo. 
• To study the PK of free-ADRECIZUMAB with a focus on plasma accumulation and 
elimination. 
 
 
4.3 
Endpoints for Primary Objective (Safety and Tolerability) 
The endpoints for the primary objective are to determine over the 90 days study period: 
 
• 
Mortality 
• 
Interruption of infusion 
• 
Severity and frequency of treatment-emergent adverse events 
 
 
4.4 
Endpoints for Secondary Objective (Efficacy) 
 
The primary efficacy endpoint of this study is the 
• Sepsis Support Index (SSI) defined as: days with organ support or dead within 14 day 
follow up 
More precisely: In the time frame of 14 day follow-up, each day on support with 
vasopressor, and/or mechanical ventilation (defined as ventilation received on this day, 
independent from the duration of mechanical ventilation), and/or renal dysfunction 
(defined as renal SOFA = 4), or not alive, is counted as 1. The sum over the follow up 
period is defined as SSI. 
 
Secondary efficacy endpoints include: 
• Sepsis Support Index (SSI) at 28 day follow-up 
• Penalized Sepsis Support Index (pSSI) at 14 and 28 day follow-up, defined similar to the SSI 
with the exception that patients who die get penalized by assigning the maximum value, i.e. 
the pSSI is set to 14 or 28, respectively 
• Persistent organ dysfunction or death at 14 and 28 day follow-up [5] 
• Day 28 and day 90 mortality rate 
• SSI and pSSI excluding the renal component 
• Individual Sepsis Support Index components (hemodynamic, respiratory and renal failure) 
with and without mortality 
 
 

 
 
 
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• Sequential Organ Failure Assessment (SOFA) Score 
- Mean/maximum/total daily SOFA score during stay at ICU 
- Delta SOFA score, defined as maximum versus minimum SOFA during ICU stay 
- Change in SOFA score within 48 hours 
- SOFA-3 (score limited to cardiovascular, respiratory and renal function) 
• Improvement in renal function as change in penKid and creatinine (day 3 – day 1, 
day 7 – day 1) 
• Duration of stay at ICU/ hospital 
• Changes of functional parameters and other parameters during stay at ICU (MAP, creatinine, 
PaO2/FiO2, blood lactate, fluid balance, MR-proADM, inflammatory markers PCT, IL6) 
• Vasopressor use (drug, highest/lowest dose, duration) 
• Quality of Life by Euro-QoL-5 (day 28 and day 90) 
• Vital signs (heart rate, blood pressure) 
 
 
4.5 
Endpoints for Pharmacokinetics 
 
In sub-study (with 80 patients only) to determine key PK parameters, including: 
• peak plasma concentrations (Cmax) 
• systemic exposure (AUC) 
• volume of distribution (V) 
• systemic clearance (CL) 
• elimination half-life (t½) 
 
 
 

 
 
 
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5. 
INVESTIGATIONAL PLAN 
 
5.1 
Study Design 
 
This study is designed to evaluate the potential of ADRECIZUMAB as targeted therapy in 
preselected patient using the biomarker ADM with regard to safety and tolerability, PK and 
efficacy. Therefore, it is intended to enroll patients with “early” septic shock (start of 
vasopressor therapy < 12 hours) and ADM level of > 70 pg/ml. 
 
For the purpose of this protocol a total of 300 patients from surgical, medical and mixed ICU 
will be randomized at multiple centers in the European Union. 
 
For appropriate randomization the central Clinical Coordination Center (CCC) in Brussels will 
be used to confirm eligible patients prior to randomization to treatment arm A with 
ADRECIZUMAB 2 mg/kg or to treatment arm B with ADRECIZUMAB 4 mg/kg or to the 
placebo control group in a 1:1:2 ratio for a single dose intravenous infusion over 1 hour. 
 
As long as the patients are on the ICU, measurements of clinical signs and laboratory data will 
be collected for safety reasons and for determination of SOFA score as long as arterial line is in 
place for determination of PaO2/FiO2.  
 
Additional blood samples for determination of ADRECIZUMAB, inflammatory biomarker and 
cardiac biomarkers will be taken prior to start of IMP infusion (day 1) and within the time frame 
of 24 hours (+/- 10 hours) after end of IMP infusion (day 2). Further timepoints for blood 
sampling will follow as specified in Figure 2 at 48 hours, 96 hours and 144 hours after end of 
infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU 
(whatever comes first). 
 
The SOFA score and its components will be determined daily for all patients over the entire stay 
on the ICU until day 28 or discharge (whatever comes first). Safety monitoring for each patient 
will begin at the time of signing the Informed Consent Form and continue for 90 days after end 
of short-term infusion of study medication. 
 
At selected study centers a PK substudy will be performed to determine the profile of 
ADRECIZUMAB in 80 randomized patients. 
 
Patient accrual is expected to be completed within 24 months. 
 
An interim analysis is planned after 50% of patients (n=150) have completed study day 28. 
 
 
5.2 
Study Population 
 
5.2.1 
Selection of Study Population 
In this phase II study up to 300 adult male and female patients with “early” septic shock and a 
bio-ADM concentration at inclusion of > 70 pg/mL will participate. 
 
To qualify for randomization and treatment with the study medication, patients must meet all 
inclusion criteria and none of the exclusion criteria at inclusion. Eligibility will be re-checked 

 
 
 
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and confirmed by a central Clinical Coordinating Center (CCC) in Brussels prior to 
randomization.  
 
No deviation to the following inclusion or exclusion criteria is allowed. 
 
 
5.2.2 
Inclusion Criteria 
To participate in the study, patient must meet all of the following inclusion criteria: 
 
1. 
Written informed consent by patient or legally designated representative (according to 
country – specific regulations) 
2. 
Male and female  patients, age ≥ 18 years  
3. 
Body weight 50 kg – 120 kg 
4. 
Bio-ADM concentration > 70 pg/ml 
5. 
Patient with early septic shock *(start of vasopressor therapy < 12 hours) 
* 
Early septic shock < 12 hours between onset of the cardiovascular organ-dysfunction and administration 
of ADRECIZUMAB  
 
Definition: 
Septic shock is defined as a life-threatening organ dysfunction due to dysregulated host response to 
a proven or suspected infection which leads to a decline of MAP < 65 mmHg, which is refractory** 
to fluid resuscitation and requires sustained vasopressors 
** 
Refractory: Defined as lack of response to the administration of 30 mL of normal saline/kg body weight 
or according to a clinician's assessment of inadequate hemodynamic results 
 
6. 
Women of childbearing potential must have a negative serum or urine pregnancy test 
before randomization. 
7. 
Highly effective method of contraception must be maintained for 6 months after study 
start by women of childbearing potential and sexually active men. 
8. 
No care limitation 
 
 
5.2.3 
Exclusion Criteria 
A patient who meets any of the following criteria must be excluded from the study: 
 
1. 
Moribund 
2. 
Pre-existing unstable condition (e.g. a recent cerebral hemorrhage or infarct, a recent acute 
unstable myocardial infarction (all < 3 months), congestive heart failure – NYHA Class 
IV) 
3. 
Patients that required cardiopulmonary resuscitation in the last 4 weeks prior to evaluation 
for enrollment 
4. 
Severe COPD with chronic oxygen need at home (GOLD IV) 
5. 
Any organ or bone marrow transplant within the past 24 weeks 
6. 
Uncontrolled serious hemorrhage (≥ 2 units of blood / platelets in the previous 24 hrs). 
Patients may be considered for enrollment if bleeding has stopped and patient is otherwise 
qualified 
7. 
Uncontrolled hematological / oncological malignancies 
8. 
Absolute neutropenia < 500 per µL 
9. 
Severe chronic liver disease (Child-Pugh C) 
10. Systemic fungal infection or active tuberculosis 
11. Neuromuscular disorders that impact breathing/ spontaneous ventilation 

 
 
 
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12. Burns > 30% of body surface 
13. Plasmapheresis 
14. Breastfeeding women 
15. Participation in a clinical trial involving another investigational drug within 4 weeks prior 
to inclusion 
16. Unwilling or unable to be fully evaluated for all follow-up visits 
 
 
5.3 
Patient Numbering 
Inclusion- and exclusion criteria from patients admitted to the ICU will be verified by the 
investigator to identify potential patients to be enrolled into the study. 
 
After availability of written informed consent by patient or legally designated representative (or 
other accepted procedure according to local requirements in case patient is unable to sign 
informed consent personally due to the emergency nature) patient will be assigned a unique 6-
digit patient identification number in ascending order at inclusion which will include country (1 
digit), site number (2 digits), patient number (3 digits). For example 1-01-001, 1-02-001, 2-01-
001, 2-02-001 etc. This patient identification number will be maintained throughout the study 
without any reassignment. 
 
The eligibility of each patient, based on assessment of all inclusion- and exclusion criteria 
including the bio-ADM concentration of > 70 pg/mL, must be confirmed by the central CCC 
prior to randomization to one of the two treatment arms or to the placebo control group. An 
overview of the randomization procedure is provided in section 6.5. 
 
5.4 
Screen Failure Patients 
Patients who sign the informed consent form but fail to meet one or more of the eligibility 
criteria, or who decline study participation before receiving IMP, will be defined as screen 
failures. For those patients the investigator will be asked to contact the patient on day 14 for 
calculation of the SSI during stay at ICU (screening to day 14) as well as on follow-up day 28 
and day 90 for recording and evaluation of survival / mortality. For assessment of the SSI 
(screening to day 14) and for recording and evaluation of survival / mortality data the 
investigator should seek to obtain the patient’s consent. 
 
5.5 
Discontinuation of Individual Subjects 
Participation in this clinical study is strictly voluntary and any subject may withdraw from the 
study at any time without providing an explanation. This will not affect his/her right for future 
medical care. 
 
In the event that a patient withdraws from the study, the investigator must be informed 
immediately. The date, circumstances and any reason provided will be documented on the 
withdrawal page of the eCRF. If the patient already received the investigational treatment prior 
to withdrawal of consent, he/she will be asked to perform the assessments for day 28 or day of 
discharge and to complete the quality of life questionnaire on day 28. For the completion of the 
paper telephone Euro-QoL-5 Quality of Life Short Form, the patient will be called from the 
investigator’s site on day 90 of the follow-up period. 
 
No data obtained after withdrawal of consent will be recorded on eCRFs - with the exception of 
any case of death until 90 days for safety reasons - and will not be evaluated as part of the 
clinical study. For recording and evaluation of survival / mortality data the investigator should 
seek to obtain the patient`s consent. 

 
 
 
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In both arms treatment may be withheld temporarily or stopped definitively at the investigator’s 
discretion at any time. Possible reasons include: 
 
• Serious adverse event (SAE) considered to be related to treatment with the study medication 
• Any situation in which, in the investigator's opinion, a continuation of the treatment with the 
study medication would be harmful to the patient's safety and well-being. 
 
Time, circumstances and reason/s for stopping treatment will be documented in the eCRF. The 
sponsor must be informed within 24 hours about any treatment discontinuation of a patient 
including the reason. Patients whose treatment is stopped stay in the study unless they withdraw 
consent. After the treatment is stopped, patients are followed according to the plan for the 
follow-up visits. 
 
Patients may be withdrawn from treatment or from the study by the investigator or the sponsor 
in case of a major protocol deviation considered being relevant by the investigator and/or the 
sponsor (e.g. deviation of selection criteria) or if new information arise making the continued 
study participation of a patient unadvisable. Patients withdrawn from the study will be informed 
about the reasons for withdrawal. 
 
 
5.6 
Stopping of Clinical Trial 
All safety signals including suspected unexpected serious adverse reaction (SUSAR) and SAEs 
will be reviewed on a continuous basis by the Data and Safety Monitoring Board (DSMB) (see 
section 12.5). The stopping rules defined below apply to any treatment-related AE and clinical 
laboratory assessments. However for clinical laboratory assessments, the rules apply only if 
deviations of laboratory parameters relate to the same organ system, indicating clinical 
significance. A single deviation of a laboratory value without any clinical symptoms will not be 
considered clinically significant. 
 
The stopping rules are stipulated as follows: 
 
• Following investigation of AEs the DSMB may recommend stopping the study if 
continuation may pose a substantial risk to subjects. 
• The DSMB may recommend stopping the study if previously unknown data become 
available and raise concern about the safety of the study drug, so that continuation would 
pose a potential risk to the patients. 
 
The sponsor may terminate the study for other important reasons at his discretion. Such reasons 
may be external information that impact the risk-benefit assessment for patients or technical or 
operational reasons such as unexpectedly slow recruitment that may put the scientific value of 
the study at risk.  
 
If the study is prematurely terminated or suspended, the investigator will promptly inform the 
patient and assure appropriate therapy and follow-up. 
 
Furthermore, the study can be terminated at any time if the authorization and approval to conduct 
the study is withdrawn by ethics committee, by regulatory authority decision, insufficient 
accrual, emergency, new data impacting the scientific value of the study on ethical grounds. 
 
 

 
 
 
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5.7 
Concomitant Treatment 
Standard medical treatment(s), including all therapies and medications, prescriptions and over-
the-counter, being taken by the patient upon entry in the study, maintained throughout the study 
including any medication to treat AEs or SAEs will be collected. Any changes in concomitant 
medication must be recorded from screening until day 28 or discharge from ICU, (whatever 
comes first) as well as on follow-up day 28 if patient was discharged from ICU before day 28. 
 
Recording of treatment for ongoing AEs or SAEs will be continued after day 28 until resolution 
or until end of study for new AEs or SAEs occurred during the follow-up period. 
 
 
5.8 
Cornerstone Medication -  Permitted Concomitant Medication 
The main therapy administered according to the international guidelines for treatment of patients 
with septic shock (Surviving Sepsis Campaign), e.g. enteral / parenteral nutrition, 
antimicrobiotic therapy (drug, dose, duration), insulin, blood transfusion should be documented 
on a daily basis from screening to day 28 or discharge from ICU (whatever comes first) as well 
as on follow-up day 28 if patient was discharged from ICU before day 28. 
 
 
5.9 
Vasopressor Therapy 
Vasopressors are provided for patients with septic shock who do not respond to fluid 
resuscitation. 
 
Use of vasopressors (dopamine, dobutamine, phenylephrine) in combination with 
catecholamine (adrenaline, noradrenaline*) will be recorded from admission to ICU at time 
point of diagnosis of septic shock and daily thereafter from day 1 through day 28 or discharge 
from ICU (whatever comes first) (drug name, highest / lowest dose, starting time and duration 
of use of vasopressor therapy). 
* used equivalent to epinephrine and norepinephrine 
 
5.10 
Lost to Follow-up 
For patients whose status is unclear because they fail to appear for the follow-up visit on day 28 
and fail to have the phone call on day 90 without stating an intention to withdraw, the 
investigator should show "due diligence" by contacting the subject, family or family physician 
as agreed in the informed consent and by documenting in the source documents steps taken to 
contact the patient, e.g. dates of telephone calls, registered letters, etc. A subject should not be 
considered lost to follow-up until his/her scheduled phone call on day 90 would have occurred. 
 
 
 

 
 
 
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6. 
INVESTIGATONAL TREATMENTS 
 
6.1 
Investigational Medicinal Product (IMP) 
ADRECIZUMAB (HAM8101) is a humanized IgG1 monoclonal antibody (mAb) directed 
against the N-terminus of adrenomedulling (ADM) and intended for the treatment of sever 
sepsis and septic shock. The antibody was generated by complementarity determining region 
(CDR) grafting a murine IgG2a mAB, which was obtained by immunizing female Balb/c mice 
with the ADM 1-10 peptide (H-YRQSMNQGSC-OH) using a peptide-BSA (bovine serum 
albumin) – conjugate. 
 
The epitope of ADRECIZUMAB on ADM comprises the first 5 amino acids in the N-terminal 
region of the peptide hormone, and binding requires the N-terminal tyrosine residue of ADM to 
be free. This epitope is identical among many mammalian species including mouse, rat, dog, 
pig and cynomolgus monkey. The binding of ADM to its receptor is achieved via the C-
terminus, which is identical across all species tested [27]. 
 
The quality control standards and requirements for each study medication are described in 
separate release protocols/certificates of analysis. 
 
ADRENOMED AG will supply ADRECIZUMAB 2 mg/kg and 4 mg/kg and placebo for 
intravenous infusion to the investigator as a sterile solution for infusion. Each vial will contain 
200 mg ADRECIZUMAB. Excipients contained in ADRECIZUMAB are listed below. The 
solution will be diluted with NaCl 0,9% up to 50 mL to reach an osmotic strength of 
< 300 mOsmol/L. The volume has to be adjusted to the infusion volume of 0,5 mL/kg plus the 
dead volume that will remain in the line for infusion. 
 
Table 1 
Composition of the ADRECIZUMAB Drug Product 
 
Name of 
Ingredient 
Function 
Quantity  
(per mL) 
Quantity for 10.4 mL 
filled vials 
ADRECIZUMAB 
protein 
Active 
18 - 22 mg 
187.2 – 228.8 mg 
Histidin-HCl 
monochlorid 
Buffer 
4.19 mg 
43.6 mg 
Glycine 
Stability 
22.5 mg 
234.0 mg 
Water 
Solvent 
qs to 1.0 mL 
qs to 10.4 mL 
 
 
Table 2 
Composition of the Placebo Product 
 
Name of 
Ingredient 
Function 
Quantity  
(per mL) 
Quantity for 10.4 mL 
filled vials 
Histidin-HCl 
monochlorid 
Buffer 
4.19 mg 
43.6 mg 
Glycine 
Stability 
22.5 mg 
234.0 mg 
Water 
Solvent 
qs to 1.0 mL 
qs to 10.4 mL 
 
 

 
 
 
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Stability: 
The shelf life will be established from the real-time results of the stability 
testing program, which will monitor stability over 36 months. Expiry date is 
indicatedon the IMP label. 
 
Storage: 
at 2 – 8 °C and protected from light 
 
Manufacturer: Celonic Deutschland GmbH & Co. KG 
Czernyring 22 
69115 Heidelberg, Germany 
 
Packaging and  CSM Clinical Supplies Management Europe GmbH 
Labeling: 
Am Kronberger Hang 3 
 
65824 Schwalbach a.Ts. 
 
Germany 
 
QP Release: 
Celonic Deutschland GmbH & Co. KG 
Czernyring 22 
69115 Heidelberg, Germany 
 
 
6.2 
Packaging, Labeling and Shipment 
ADRECIZUMAB 200 mg solution for infusion and ADRECIZUMAB placebo are in clear Type 
I glass vials, size 10R, sealed with fluoropolymer coated bromobutyl rubber stoppers and tear-
off plain aluminum cover seals. 
 
Clinical supplies are provided in boxes containing 8 vials respectively. Individual vials have a 
nominal volume of 10 mL (see section 6.3). 
 
The packaging and labeling of the investigational medicinal product (IMP) will be performed 
by CSM Clinical Supplies Management Europe GmbH, Am Kronberger Hang 3, 65824 
Schwalbach a.Ts., Germany according to requirements of ECGuide on GMP, Annex 13 (4). 
 
IMP kits will be supplied by sponsor including a certificate of compliance issued by the 
European Qualified Person. The IMP boxes will be shipped under controlled and monitored 
temperature conditions at 2 – 8°C. The receiving center has to confirm the receipt and the 
condition of the delivery via appropriate study forms. Should the temperature monitoring device 
indicate that the specific shipment conditions were not maintained during the transport, the IMP 
kits must be quarantined such they cannot be used unintentionally and the sponsor must be 
contacted immediately. 
 
All vials and secondary packaging will be labeled for purpose of the clinical study in accordance 
with applicable regulatory requirements. 
 
The IMP kits will be labelled in local language according to local requirements. The vial-label 
will contain a tear-off section which, after IMP administration, will be attached in the 
appropriate field of the Preparation and Dispensing Proecedure Log - IMP. 
 
 
 
 

 
 
 
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6.3 
Handling, Storage and Preparation 
The IMP kits must be stored at temperature between 2°C – 8 °C, protected from light under 
temperature controlled and restricted access conditions either in the local pharmacy or at the 
ICU. Any temperature deviation (temperature below +2°C and/or above +8°C) must be reported 
to the Sponsor for an evaluation if the IMP can be used or not. In case the IMP kit is stored in 
the local pharmacy one kit of IMP will be ordered according to the processes being in place at 
the hospital for transportation of the IMP to the ICU under ambient conditions once a patient 
has been approved for randomization. 
 
The vials will be warmed up to room temperature no longer than 1 hour prior to their use and 
product is diluted with sterile 0.9% sodium chloride for infusion. IMP administration has to be 
started within a maximum of 2 hours after its preparation. 
 
In case of interruption of IMP administration (e.g. technical issues), it is allowed to restart the 
IMP administration as long as the infusion can be completed within 6 hours after IMP 
preparation. Cave: This patient is not eligible any longer for the PK substudy. No further PK 
samples should be collected. 
 
Treatment will consist of a body weight adjusted dose of ADRECIZUMAB up to 100 kg body 
weight or an equivalent amount of placebo. Patients with a body weight of > 100 – 120 kg will 
get the highest dose of the assigned treatment arm. This is reasonable because the 
ADRECIZUMAB dose is administered in excess over Adrenomedullin plasma concentrations 
and sufficient to still elicit increased Adrenomedullin concentration (>25 pg/ml) until seven 
days after application. Therefore differences will not be expected between different weight 
groups. 
 
All patients will receive an intravenous infusion using an infusion pump over approximately 
1 hour by medically trained personnel who are part of the study team. ADRECIZUMAB 
2 mg/kg and 4 mg/kg and placebo will be administered under completely blinded conditions. 
 
Study medication will be provided in boxes according to the 4 –block-randomization list. 
 
Each box contains:  
• 1 vial ADREZICUMAB+ 1 vial placebo 
• 2 vials ADREZICUMAB  
• 2 vials placebo 
• 2 vials placebo 
 
If the patient is assigned to one of the two treatment arms or to the placebo group the body 
weight adjusted dose of study medication is calculated according to the following formula: 
 
Infusion volume =20 mL – ( (100 kg – actual BW) x 20) added up to 50 mL with 0.9% NaCl 
 
 
 
 
    100 
 
 
For dose calculation, please refer to Appendix 4. 
 
The solution for infusion must be visually inspected prior to use. Only clear, colorless solutions 
without particles must be used. Should IMP kit fail to meet these criteria the corresponding IMP 
kit has to be separated and the sponsor has to be contacted immediately. 
 

 
 
 
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Aseptic techniques must be strictly observed throughout preparation of IMP kits, since they 
contain no preservative. Standard laboratory care should be used during handling and 
preparation ofIMP kits, i.e. use of gloves and other protective clothing to prevent skin contact 
is recommended. 
 
 
6.4 
Accountability 
In agreement with the sponsor, the PI will designate a responsible person for receipt, storage 
and preparation of the study medication. 
 
Regular study drug reconciliation will be performed throughout the study to document drug 
assigned, drug administered, and drug remaining, or drug inadvertently damaged. This 
reconciliation will be documented on the IMP Inventory Log. All study medication supplies and 
associated documentation will be reviewed and verified by the monitor at regular intervals. Any 
discrepancies noted will be investigated, resolved and documented prior to return for destruction 
of unused study drug. 
 
Used IMP vials will be kept at the center for monitoring/ reconciliation before they are discarded 
according to local requirements. Upon instruction by the sponsor unused IMP kits will be 
returned to the sponsor or designee for destruction. 
 
6.5 
Treatment Assignment 
 
6.5.1 
Randomization Procedures 
In order to ensure the appropriate number of patients to be enrolled on identifying a potential 
study patient the investigator is required to complete a site authorization worksheet for 
confirming patient eligibility by the central Clinical Coordination Center (CCC). When 
appropriate investigator will receive confirmation for randomization of patient from the CCC 
by providing a authorization number.  
 
Patient will then be randomly allocated to treatment arm A, to treatment arm B or to the placebo 
control group in a 1:1:2 randomization ratio (ADRECIZUMAB 2 mg/kg, ADRECIZUMAB 4 
mg/kg and Placebo). Patient is not allowed to be enrolled until this confirmation has been 
received. 
 
The randomization code list will be generated within the Biometrics Department of the 
designated CRO by an independent statistician not involved in the study. 
 
 
6.5.2 
Maintenance of the Randomization Code 
This study will be performed in a double-blind fashion. The Investigator and site staff, patients, 
monitors, Sponsor and CRO staff will remain blinded to the treatment assignment until study 
closure. The investigational drug and its matching placebo are indistinguishable and all study 
drug kits will be packed in the same way. 
 
The randomization list is kept strictly confidential. It is accessible only to authorized persons 
who are not involved in the conduct and analysis of the study, until time of unblinding. 
 
Sets of sealed envelopes with the randomization codes will be prepared containing information 
about treatment and the dose the patient had received (dose of ADRECIZUMAB or placebo) 
for each patient: 

 
 
 
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• One set is kept at the clinical study site to be used in case of emergency (during the entire 
study period) 
• One set is kept with the secretary of the DSMB (pharmacovigilance expert) 
• One set is kept with the party responsible for reporting of a suspected unexpected serious 
adverse reaction (SUSAR) as required by the regulatory agencies. The evaluation and 
decision as to whether a Serious Adverse Event (SAE) qualifies as an SUSAR is the 
responsibility of the Sponsor or designee.  
 
 
6.5.3 
Emergency Unblinding 
Under normal circumstances, the blinding should not be broken. The blinding should be broken 
only if specific emergency treatment would be indicated by knowing the treatment status of the 
patient. Whenever a code is broken, the person breaking the code must record the time, date and 
reason as well as his/her initials in the source documents. Unblinding will result in 
discontinuation of the patient from the study. 
 
Unblinding will be performed via the emergency envelopes. 
 
In such cases the sponsor must be contacted prior to breaking the code unless an emergency 
dictates otherwise. In all cases, the investigator is required to notify the sponsor within 24 hours 
following the code break reporting the reason for the unblinding. 
 
Unblinding will be performed at spm² for reporting of SUSARs as required by CAs. 
 
All codes (whether broken or not) must be kept throughout the study period in the Investigator 
Site File. Accountability of all broken or unbroken codes will be performed at every monitoring 
visit until study closure and will be collected at the last monitoring visit by the monitor and 
forwarded to the sponsor if not otherwise instructed by sponsor. 
 
 
6.5.4 
Routine Unblinding 
After completion of the study, locking of the clinical database, and performance of a blinded 
data review, a routine unblinding will be authorized by the Sponsor. 
 
 

 
 
 
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7. 
STUDY CONDUCT  
 
7.1 
Standards of Study Conduct 
This study will be conducted in compliance with applicable regulatory requirements, in 
particular the EU Clinical Trials Directive and the Declaration of Helsinki. It will be conducted 
strictly following the study protocol and in compliance with the revised ICH guidance E6, the 
EU-GCP directive and all applicable national laws and regulations. 
 
This protocol and any amendment will be submitted to the Competent Authorities and to 
Independent Ethical Committees for formal approval to conduct the study. Informed consent 
will be obtained by all patients participating in this clinical study as discussed in protocol section 
7.2. 
 
 
7.2 
Informed Consent 
 
7.2.1 
Patients Able to Provide Consent Personally 
Prior to any study-related activity, any patient to be included in this study must give informed 
consent in accordance with the EU Clinical Trial Directive, the Declaration of Helsinki and with 
ICH-GCP requirements. The responsibility for obtaining informed consent remains with the 
investigator. Each investigator will maintain a list of all patients who signed the informed 
consent form. 
 
The written information addresses the rights of the patient to ask for updated information on 
what data are recorded, to require corrections of errors, to know who will be responsible for 
keeping the data and who will have access to them. 
 
The investigator will provide sufficient information about the study orally and with the patient 
information, to enable the patient to understand the study and any risks in details. Upon 
receiving this information, the patient will be given opportunity to ask any questions he/she 
might have and will be given appropriate time to decide on the participation in the study. The 
voluntary agreement to study participation by the patient will be documented by his personally 
dated signature on the informed consent form. The written informed consent must be co-signed 
and personally dated by the person who obtained the informed consent on the Informed Consent 
Form (ICF). The patient will be provided with copy or second original of the signed ICF. 
 
The patient will be informed in a timely manner of any changes to the conduct of the study or 
other relevant information that may alter the risk benefit ratio of study participation or that may 
be relevant to the patient’s willingness to continue participating in the study. 
 
It will be guaranteed that personal data are kept confidential and will be used only for study 
related purposes. 
 
 
7.2.2 
Patients Unable to Provide Consent Personally 
For patients unable to give consent due to the emergency nature of the patient’s condition the 
investigator will provide sufficient information about the study to the legally designated 
representative of the patient, designated according to the applicable national law, local 
regulations in the involved countries to enable the patient’s legally designated representative to 
understand the study and any risks in detail. 
 

 
 
 
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Upon receiving this information, the patient’s legally designated representative will be given 
opportunity to ask any questions he/she might have and will be given appropriate time to decide 
on the participation in the study on the patient’s behalf. 
 
The voluntary agreement to study participation by the patient’s legally designated representative 
will be documented by his personally dated signature on the informed consent form. The written 
informed consent must be co-signed and personally dated by the person who obtained the 
informed consent on the Informed Consent Form (ICF). The patient’s legally designated 
representative will be provided with copy or second original of the signed ICF. 
 
Once the patient has recovered and is able to understand the nature of this study a consent will 
be obtained retrospectively after the patient has been provided information about he study by 
the investigator in detail and after the patient has been given ample time to consider his/her 
further participation in the study to take a voluntary decision. After his/her decision in favor of 
further participation the patient will confirm his/her willingness to continue in this study by 
personally dated signature on the informed consent form, co-signed and dated by the informing 
investigator. The patient will be provided with copy or second original of the signed ICF. 
 
Patient and / or the patient’s legally designated representatives can withdraw their consent on 
study participation at any time without necessarily giving a reason and without any penalty or 
loss of benefits to which they are entitled. 
 
 
7.2.3 
Screen Failure Patients 
In case the patient was unable to provide consent personally and information about the study 
was provided to the the legally designated representative of the patient and informed consent 
was obtained from the legally designated representative of the patient afterwards, investigator 
should seek to get a retrospective ICF signed from the patient once the patient has recovered 
and is able to understand the nature of this study (see also 7.2.2). 
 
 
7.3 
Protocol Amendments 
Changes to the protocol during the study will be documented as amendments. The amended 
protocol will be signed by the relevant personnel at ADRENOMED AG und by the investigator. 
Depending on the content of the amendment and local legal requirements, the amendment will 
be submitted to the relevant Independent Ethics Committee (IEC) and, where necessary, to the 
relevant Competent Authorities. 
 
When a patient is currently undergoing study procedures and is affected by the amendment, then 
the patient must be asked to consent again using the new information sheet. The new information 
sheet must be used to obtain consent from new patients before enrollment. 
 
The investigator should not implement any deviation from, or changes to the protocol, without 
agreement by ADRENOMED AG and prior review and documented approval/favorable opinion 
of the appropriate IEC and, if legally required, competent authorities, except where necessary 
to eliminate an immediate hazard to the patients, or when the change(s) that were approved by 
ADRENOMED AG involve only logistical or administrative aspects of the study. 
 
 

 
 
 
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7.4 
Study Visits and Procedures 
Study procedures are scheduled for screening, administration of study medication and for 
assessment of the safety and tolerability of the investigational treatment, as well as until end of 
study as outlined in the flow-charts (Figure 1, Figure 2 and Figure 3). The procedures on 
particular study days are described in more detail in the following sections. 
 
 
7.4.1 
Pre-Treatment: Screening  
Before starting any screening procedure, patient or legally designated representative must 
provide written informed consent as described in protocol section 7.2.1 and 7.2.2. 
 
The investigator will keep a log of all screened and randomized patients. For patients who were 
not entered into the study the reason for no enrolment must be documented. 
 
After providing written informed consent, patient will undergo the following screening 
assessments including further required documentation: 
 
• 
Check availability of signed informed consent form 
• 
Assign patient identification number 
• 
Record information on hospital and ICU admission, including date, time and location 
before admission in ICU (surgical, medical or mixed ICU) 
• 
Record diagnosis of the admission (early septic shock) and origin of sepsis 
Definition: 
Septic shock is defined as a life-threatening organ dysfunction due to dysregulated host 
response to a proven or suspected infection which leads to a decline of MAP < 65 mmHg, 
which is refractory** to fluid resuscitation and requires sustained vasopressors 
** Refractory: Defined as lack of response to the administration of 30 mL of normal 
saline/kg body weight or according to a clinician's assessment of inadequate 
hemodynamic results 
• 
Record time from hospital admission to ICU admission 
• 
Record starting time of vasopressor administration due to septic shock  
• 
Document medical history including all ongoing conditions and relevant medical history 
and co-morbidities present or treated within the last year (cardiovascular and non-
cardiovascular) and concomitant illnesses present at inclusion (see section 8.2) 
• 
Record concomitant medication, age, gender and Ethnic origin (see section 5.6, 8.1) 
• 
Conduct physical examination, body weight and height (see section 8.1, 8.3) 
• 
Record vital signs (blood pressure, heart rate, MAP, respiratory rate and oral or tympanic 
temperature) (see section 8.4) 
• 
Record 12-lead ECG (supine or semi-supine position) (see section 8.7) 
• 
Record Echocardiography (optional) (see section 8.14) 
• 
Blood sampling for laboratory examinations (see section 8.8) of: 
• 
BUN or urea, sodium, potassium creatinine, total bilirubin, platelet counts, hemoglobin, 
hematocrit, blood lactate concentration, white blood count, differential blood count 
Perform pregnancy test (urine or serum) (see section 8.8) 
• 
Blood sampling for measurement of bio-ADM plasma concentration by using sphingotest® 
bio-ADMCDx  (see section 8.9.1 - Cave: In case bio-ADM is ≤ 70 pg/mL patient will not 
qualify for inclusion) 
• 
Calculation of APACHE II score (see Appendix 2) 
• 
Evaluation of organ dysfunction by calculation of SOFA score (see section 8.10) 

 
 
 
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• 
Check of inclusion / exclusion criteria 
• 
Recording of (S)AEs 
 
 
7.4.2 
Eligibility Confirmation: 
For patients who meet all inclusion criteria and do not meet any of the exclusion criteria a site 
authorization worksheet will be completed and forwarded to the central CCC in Brussels for 
confirmation of patients’ eligibility. 
 
 
7.4.3 
Day 1: Start of Treatment 
Permission for randomization for the central CCC granted by receipt of the authorization 
number. The patient will then be randomized to one of the two treatment arms (A or B) or to the 
control group (placebo) and the following activities and assessments will be performed: 
 
• 
Prior to IMP infusion:  
➢ Blood sampling for central laboratory assessment of MR-proADM and biomarkers 
(see section 8.9.2) and PK (at designated centers only) (see Figure 2, section 8.11) 
➢ arterial blood collection for measurement / calculation of PaO2/FiO2 and arterial 
pH (see section 8.8) 
➢ Evaluation of organ dysfunction by calculation of SOFA score (see section 8.10) 
• 
IMP administration of body weight adjusted dose (see section 6.3) as intravenous infusion 
using an infusion pump over approximately 1 hour within 12 hours after start of vasopressor 
administration due to septic shock 
• 
Recording of vasopressors therapy (drug, highest / lowest dose, duration) (see section 5.9) 
• 
Recording of cornerstone medication and concomitant medication (see section 5.8) 
• 
Start of calculation of daily fluid balance according to baseline body weight (see section 
8.6) 
• 
PK blood sampling (at designated centers only) 30 minutes after end of infusion (see Figure 
2, section 8.11) 
• 
Recording of vital signs (minimum / maximum valueat) 
• 
Recording of (S)AEs 
 
 
Day 2 – Day 28 (or discharge, whatever comes first)  
Day 2 and all consecutive days will start with the ICU day change (with the next morning routine 
which starts according to the individual hospital’s time schedule). Each hospital follows its own 
time schedule for the morning routine. 
 
The following activities and assessments will be performed during stay on ICU: 
 
• 
Daily recordings of vital signs (minimum / maximum values within 24 hours) 
• 
Daily arterial blood sampling for PAO2/FiO2 (if arterial line in place) and arterial pH until 
day 7 
• 
Daily blood sampling for laboratory examinations until day 7 and on day 28: 
BUN or urea, sodium, creatinine, total bilirubin, platelet count, hemoglobin, hematocrit, 
blood lactate concentration, white blood count 
• 
Daily blood sampling for laboratory examinations from day 8 to day 28 (during stay in 
ICU): 
- PAO2/FiO2 (if arterial line in place) and arterial pH, creatinine 

 
 
 
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- Blood sampling every other day: total bilirubin, platelet count, blood lactate 
concentration 
• 
Daily recording of vasopressors therapy (drug, highest / lowest dose, duration) 
• 
Daily recording of cornerstone medication and concomitant medication 
• 
Daily calculation of daily fluid balance according to baseline body weight for 24 hours 
• 
Daily evaluation of organ dysfunction by calculation of SOFA score 
• 
Blood sampling for central laboratory assessment for MR-proADM and biomarkers at 24 
hours, 48 hours, 96 hours and 144 hours or at discharge (whatever comes first) after end of 
IMP infusion 
• 
PK blood sampling (at designated centers only) at 24 hours, 48 hours, 96 hours, 144 hours 
and on  day 28 (after 648 hours, in case patient is not discharged from ICU) after end of 
IMP infusion 
• 
Recording of (S)AEs 
• 
Perform pregnancy test on day 28 (urine or serum for patients not discharged from ICU 
prior to day 28) 
• 
Completion of Quality of Life Questionnaire Euro-QoL-5 on day 28 (on discharge day 
whatever comes first) 
 
Patients may be discharged from ICU on day 28 or earlier depending on patients’ conditions. It 
is the investigator’s decision to keep patients under medical supervision as long as needed to 
protect their safety. 
 
 
7.4.4 
Follow-up Period  
 
Day 28 (+/- 3 days) 
The following activities and assessments will be performed for all patients already discharged 
from ICU prior to day 28:  
 
• 
Recording of vital signs 
• 
Blood sampling for laboratory examinations: 
BUN or urea, sodium, creatinine, total bilirubin,platelet count, hemoglobin, hematocrit, 
blood lactate concentration, white blood count 
• 
Record cornerstone medication and concomitant medication 
• 
Perform pregnancy test (urine or serum) 
• 
PK blood sampling on day 28 (648 hours) after end of IMP infusion  
• 
Recording of all (S)AEs since discharge from hospital 
• 
Completion of Quality of Life Questionnaire Euro-QoL-5 
 
Patients already discharged from hospital and not returned to perform the required assessments 
for day 28 in the follow-up period will be contacted by phone to ensure all deaths and 
hospitalizations and their causes are captured.  
 
Day 90 (+/-3 days) 
Follow-up contact by phone will be performed when the patient is not hospitalized anymore. If 
patient is anticipated to visit the hospital as part of routine follow-up then this can be combined. 
 
All patients will be contacted by phone 90 days after enrollment into the study to ensure all 
deaths and hospitalizations and their causes are captured. The paper telephone Quality of Life 
Questionnaire Euro-QoL-5 will be completed by the interviewer with the answers from the 

 
 
 
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patient on line. Further the patient will be asked if he has experienced any (S)AEs since the last 
contact including any treatments. In case of a pregnancy, course and outcome will be followed 
up. 
 
 
7.4.5 
Screen Failure Patients 
Patients who did not get permission to be randomized by the central CCC in Brussels after 
completion of the screening procedures (see 7.4.1) or who decline study participation before 
receiving IMP will be defined as screen failures. 
Additional informed consent from the patient or the legally designated representative of the 
patient has to be obtained for collection of the following data: 
 
Screening – day 14 (or discharge) 
Patients will be contacted by the Investigator for the calculation of the SSI during stay at ICU. 
 
Follow-up Period Day 28 and Day 90 
Patients will be contacted by phone for recording and evaluation of the patient’s survival or 
death. 
 
 
7.5 
Premature Discontinuation 
All patient have the right to withdraw formal consent without prejudice at any time during the 
study. If a patient withdraws formal consent, the investigator should make a reasonable effort 
to determine the cause for withdrawal of consent. For these patients, as well as all other patients 
who require premature discontinuation due to ADRECIZUMAB, the investigator should make 
a reasonable effort to complete all trial procedures listed above for day 28 or discharge. 
 
 
7.6 
Visit Window 
The study flow chart (see Figure 2.1) must be followed. However, under special conditions, e.g. 
holidays, weekends, etc. a window of +/- 3 days is allowable for the day 28 follow-up visit as 
well as for the follow-up phone call on day 90. These visit windows are not applicable for day 
1 through day 28 or discharge. 
 
 

 
 
 
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8. 
STUDY PROCEDURES 
 
8.1 
Demography 
Demographic data are to be collected at screening and will include age, gender, Ethnic origin as 
well as body weight and height. 
 
 
8.2 
Medical History 
In addition to the diagnosis of early septic shock all ongoing conditions and relevant medical 
history and co-morbidities present or treated within the last year (cardiovascular and non-
cardiovascular) and concomitant illnesses present at inclusion need to be documented. 
Whenever possible, diagnosis and not symptoms will be recorded. 
 
Cardiovascular co-morbidities: 
 
Non cardiovascular co-morbidities: 
Chronic Heart Failure 
COPD 
Hypertension 
Chronic Renal Disease 
Diabetes Mellitus 
Hemodialysis 
Blood Lipid Disorder (Dyslipidemia) 
Chronic Liver Disease 
Obesity 
Active / recent malignant tumors 
Coronary Artery Disease 
Depression 
Stroke or Transient Ischemic Attack (TIA) 
Anemia 
Peripheral Artery Disease 
HIV 
Congenital Heart Defect 
Dystyroidism 
Severs valval disease or previous valvar 
surgery 
Chronic Inflammatory Disease 
Pulmonary embolism 
Cognitive dysfunction 
Atrial fibrillation / flutter 
Alcohol (> 30g/day for male and  
> 20g/day for woman) 
Pulmonary Hypertension 
LVEF % (if available) 
Smoking (active or stopped within the last 
year) 
 
 
8.3 
Physical Examination 
Physical examination including general appearance will be assessed at inclusion into the study. 
 
Physical examination will include the following body systems: 
• 
Mouth, ear, nose, throat 
• 
Thyroid and neck 
• 
Lymph nodes and spleen 
• 
Respiratory system 
• 
Cardiovascular system including blood pressure measurements in sitting position  
• 
Abdomen 
• 
Musculoskeletal system 
• 
Central and peripheral nervous system 
• 
Skin 
 
 

 
 
 
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8.4 
Vital Signs and Body Temperature 
Vital signs (blood pressure, heart rate, MAP, respiratory rate and oral or tympanic temperature) 
will be collected at screening and daily from day 1 to day 28 or discharge as well as on the 
follow-up visit day 28. Vital signs must be assessed as min/max values within 24 hours except 
at screening and on the follow-up visit day 28. 
 
 
8.5 
Glasgow Coma Scale 
GCS will be used for daily assessment of impairment of conscious level in response to define 
stimuli after confirmation of eligibility on day 1 shortly before IMP administration. Lowest 
(worst) value of GCS will be recorded daily from day 2 to day 28 or discharge. Observations on 
patient’s current conditions regarding opening eyes, verbal communication and motoric 
reactions will be assessed.  
 
In the calculation of the score, the worst value for each paramenter in the 24 hours period will 
be used. When patient is stable, the estimation would be based on clinical experience. In sedated 
patients, the Glasgow Coma Score Scale at the time of the intubation will be used to evaluate 
the neurological status. When sedation is removed, the GCS is recorded to actual values. In the 
rare event that the patient experiences a stroke or bleeding after the initial intubation the GCS 
estimation of 3 – 4 will be used. 
 
 
8.6 
Fluid Balance 
Daily fluid intake will be calculated as the sum of all intravenous and oral fluids. The daily fluid 
output will be calculated as the sum of the volume of urine output, ultrafiltration fluid, drain 
fluid, and estimated gastrointestinal losses (including stools only in the presence of profound 
diarrhea). Insensitive losses will not be taken into account because they are difficult to assess 
reliably. Daily fluid balance (according to baseline patient weight) will be calculated by 
subtracting the total fluid output from the total intake. Day 1 is defined with start of IMP infusion 
(whatever time it is) unil the next ICU day change at the individual hospital.  Depending on IMP 
administration time day 1 can last more or less than 24 hours. 
 
8.7 
12-lead ECG 
A standard 12-lead ECG will be recorded at screening in supine or semi-supine position, if not 
already done at any time after diagnosis of septic shock. 
 
The ECG device will compute overall rhythm analysis, heart rate, P wave, PQ interval, QRS 
duration, QT and QTc intervals. The QT interval will be corrected for heart rate (QTc) using 
Bazett’s and Fridericia´s formula (QTcB and QTcF). Each original ECG recording will be 
evaluated by the investigator following automated measurement, and the interpretation of the 
results will follow the categories ‘normal’, ‘abnormal, not clinically significant’, or ‘abnormal, 
clinically significant’. ECG results will only be defined as an AE, if they are evaluated as 
‘abnormal, clinically significant’. The investigator will evaluate and assesst the print out with 
initials and date. The tracing must then be stored with the patient's source documents. 
 
ECG recording will be printed as an original rhythm strip with at least 5 evaluable ECG 
complexes (cardiac cycles) for each lead. To avoid any variability caused by relocation, self-
adhesive electrodes should be used for ECG recording. 
 
 

 
 
 
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8.8 
Local Laboratory Assessments 
Laboratory examinations are done locally as part of routine clinical care during stay in ICU and 
at the day 28 follow-up visit. In order to verify the patient’s eligibility for the study during 
screening, lab values can be used which have already been analysed for clinical routine (e.g. 
routine blood test at ICU) and not for study purposes specifically. However, only documentation 
from lab analyses should be considered, which is closest to the timepoint of IMP administration. 
 
A center specific table of the reference ranges for each of the laboratory parameter measured 
with a description of the methods will be available in the Investigator’s Site File and sent to the 
sponsor before the study starts. Changes in reference ranges or in the methodology during the 
course of the study are to be communicated to the sponsor by the investigator. 
 
Laboratory values outside the reference ranges require a written comment by the investigator 
regarding their clinical significance throughout the clinical study. Evaluation and assessment by 
the investigator will be documented by dated signature or initials. Any lab abnormality assessed 
as “CS” must be recorded as an AE if not explained by a coexisting condition (documented in 
the medical history or reported AE during the study). 
 
If clinically relevant abnormal values are obtained at any time during the course of the study 
additional blood samples for laboratory tests should be taken at the respective clinical unit. 
 
 
8.8.1 
Day 2 through day 7 or discharge (whatever comes first) 
Daily blood collection (taken at the morning routine) for assessment of safety laboratory 
markers (hematology – blood sample up to 2 mL blood, biochemistry – blood sample 
approximately 2,5 mL) will be performed. 
 
The following parameters will be assessed: 
BUN (calculated) or urea, sodium, potassium (at screening only), creatinine, total bilirubin, 
platelet count, hemoglobin, hematocrit, blood lactate concentration, whith blood count, 
differential blood count (at screening only). 
 
 
  
 
Blood Gas Analysis (BGA): 
PaO2/FiO2, arterial pH: Arterial blood collection (0,1 mL) will be performed for 
measurement/calculation of PaO2/FiO2 and arterial pH. Recordings are to be performed  prior 
to IMP administration (day 1), minimal value as well as maximal value and each day thereafter 
(until ICU discharge) or removal of arterial line. 
 
 
 
 
8.8.2 
Day 8 through Day 27 or discharge (whatever comes first): 
The following parameters will be measured daily: PaO2/FiO2 (if arterial line in place), arterial 
pH and creatinine. Total bilirubin, platelet count and blood lactate concentration will be 
measured every other day. 
 
 

 
 
 
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8.8.3 
Follow-up Day 28: 
For assessment of safety laboratory markers a blood sample (approximately 4,5 mL) will be 
collected for analysis of BUN (calculated) or urea, sodium, creatinine, total bilirubin, blood 
lactate concentration, platelet count, hemoglobin, hematocrit, white blood count. 
 
 
8.8.4 
Pregnancy test 
Pregnancy test (urine or serum ß-HCG ) will be performed in all women to assure that no 
pregnant women is included in the study. Female patients who are not of childbearing potential 
due to being postmenopausal (2 years without menstruation) or surgically sterilised 
(oophorectomy, hysterectomy and/or tubal ligation) do not need a pregnancy test. 
 
Pregnancy test will be performed before randomization and on day 28 (for patients still on ICU) 
or on day 28 follow-up (for patients discharged from ICU). Inquiry regarding a potential 
pregnancy will be made by the investigator at Day 90 (no test to be performed). 
 
 
8.9 
Blood Sampling for bio-ADM and Biomarker 
 
8.9.1 
Blood Sampling for measurement of bio-ADM ( screening) 
For measurement of bio-ADM concentation a 5 mL EDTA plasma  sample will be collected 
(derived from EDTA blood). For measurement of bioactive Adrenomedullin in human EDTA-
plasma the sphingotest® bio-ADMCDx, a immuno luminometric assay (ILMA) will be used. 
ADM measurement should be performed before randomization. Any ADM measurement 
performed after randomization will immediately exclude the patient from the study. 
 
Bio-ADM is stable for up to 24 hours in EDTA blood and plasma at room temperature. The 
sample will be centrifuged, marked with the patient identification number and the sphingotest® 
assay performed according to the sphingotest® bio-ADMCDx instruction manual. The remaining 
plasma will be stored at -20 ºC or below at the site until shipment to the central laboratory 
(Sphingotec GmbH in Hennigsdorf, Germany) for re-evaluation of the bio-ADM concentration. 
 
 
8.9.2 
Blood Sampling for Biomarker for central laboratory 
Blood samples for determination of the biomarkers MR-pro-ADM, inflammatory biomarkers 
PCT, IL-6 and penKid will be taken prior to start of IMP infusion (day 1) and within the time 
frame of 24 hours +/- 10 hours after end of IMP infusion (day 2). Further timepoints for blood 
sampling for determination of the biomarkers will follow as specified in Figure 2. 
 
All remainings of the blood samples are stored for future analysis of additional exploratory 
biomarkers suitable for the safety and efficacy evaluation of the study. Excluded are any genetic 
analyses. 
 
EDTA blood, 2 samples of 7 mL content (resulting in approximately half the volume of 
plasma) are collected at each time point. 
 
The samples will be centrifuged within 3 hours of blood collection, marked with the patient 
identification number and stored at -20 ºC or below (please refer to laboratory manual). 
 
All biological samples to be gained for the measurement of the biomarkers shall be shipped on 
dry ice to Sphingotec GmbH in Hennigsdorf, Germany. Sphingotec GmbH will be responsible 

 
 
 
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for organization of shipment and evaluation of samples at Sphingotec GmbH (bio-ADM, PCT, 
penKid) and at MVZ Gemeinschaftslabor Cottbus in Cottbus, Germany (MR-pro-ADM, IL-6). 
 
Shipments from the site to the central laboratory should be done according to sponsor request, 
by secure transportation company that will provide boxes and dry ice. 
 
 
8.10 
Organ Dysfunction Characterized by SOFA Score 
It is intended to calculate the SOFA score on each day the patient remains in the ICU from day 
1 (shortly before IMP administration) and daily from day 2 through day 28 or discharge 
(whatever comes first) as an expression for organ dysfunction. Therefore, kidney function, 
Glasgow Coma Score, invasive/non-invasive mechanical ventilation and blood gas, liver 
function and coagulation system and vasopressor use will be documented daily. The data entered 
for day 1 must all be pre-treatment in order to calculate the baseline score. Data to be recorded 
for day 2 to day 28 are always the worst values within 24 hours. Therefore minimum and 
maximum daily values are collected for vasopressor dose and the laboratory parameters 
PaO2/FiO2, creatinine, total bilirubin and platelet count. 
 
 
8.11 
Pharmacokinetic Analysis - Substudy 
Pharmacokinetic (PK) samples from 80 patients will be collected at designated sites 
participating in the PK substudy. 
 
Plasma samples for PK analysis from 80 patients receiving either ADRECIZUMAB 2 mg/kg 
body weight (treatment arm A) or ADRECIZUMAB 4 mg/kg body weight (treatment arm B) or 
placebo (control group) will be drawn at time points provided in Figure 2 for determination of 
plasma concentration of free ADRECIZUMAB. 
 
Blood samples (2 mL EDTA blood at each time point) will be obtained prior to IMP dosing and 
after 30 minutes  as well as  24 hours 48 hours, 96 hours, 144 hours and 648 hours after end of 
infusion (during stay in ICU or on day 28 follow-up, if patient is discharged from ICU prior to 
day 28). 
 
The allowed time windows for the respective time points are given in Figure 2.. Blood 
(approximately 2 ml) will be collected in EDTA plasma tubes. The samples will be centrifuged. 
Separated plasma will be split into two aliquots of at least 0,5 mL and transferred into two tubes 
labelled with the patient identification number to ensure blinding of the analytical data. The 
samples will be frozen and stored at -20 °C or below within 2 hours. 
 
One aliquot will be stored as back-up sample at the center up to finalization of laboratory 
measurements or will be shipped to the laboratory according to the sponsor’s decision. 
One aliquot will be shipped on dry ice based on an agreed schedule to 
 
ATRC Aurigon Toxicological Research Center Ltd. 
Pálya u. 2 
2120 Dunakeszi 
Hungary 
 
Details about procedures for collection, processing, labeling, storage, and shipment of PK 
samples will be provided separately in a laboratory manual. 
 

 
 
 
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8.12 
Contraception, Pregnancy, Breastfeeding 
 
8.12.1 
Contraception 
Female patients who are not of childbearing potential due to being postmenopausal (2 year 
without menstruations) or surgically sterilized (oophorectomy, hysterectomy and/or tubal 
ligation) do not need to use contraception to be eligible for the study. All other female patients 
are considered to be of childbearing potential. 
 
Women of childbearing potential and sexually active men must use highly effective 
contraception after randomization and until 6 months after the end of intravenous infusion. The 
following contraception methods are considered highly effective: 
 
• 
Hormonal (estrogen and progesterone) contraception (oral, intravaginal, trans-dermal) 
associated with inhibition of ovulation 
• 
Progesterone-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation 
• 
Intrauterine deviced (IUD) or intrauterine hormone releasing systems (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy 
 
Women who become pregnant while participating in the clinical study must discontinue 
immediately. The pregnancy must be reported following procedures detailed in Section 9.3.1. 
Also any pregnancy that occurs in a female partner of a male study participant must be reported 
and followed-up for its outcome. 
 
Patients should be informed that taking ADRECIZUMAB may involve unknown risks to the 
fetus if pregnancy were to occur during the study. In order to participate in the clinical study 
they must adhere to the contraception requirement (described above) for the duration of the 
study up to 6 months after the end of intravenous infusion of IMP. If there is any doubt whether 
a patient will reliably comply with the requirements for contraception, that patient should not 
be entered into the study. 
 
 
8.12.2 
Pregnancy 
The site will contact the patient at least monthly and document the patient’s status until the 
pregnancy has been completed or terminated. 
 
The outcome of the pregnancy will be reported to the safety department of the sponsor without 
delay and within 24 hours if the outcome is a serious adverse experience (e.g. death, abortion, 
congential anomaly, or other diabling or life-threatening complication to the mother or 
newborn). The investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to the sponsor (see Section 
9.4). 
 
 
8.12.3 
Breatfeeding Women 
It is unknown whether ADRECIZUMAB is excreted in human milk. Because of the potential 
for serious adverse reactions in the nursing infant, patients who are breast-feeding are not 
eligible for randomization. 

 
 
 
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8.13 
Patient Reported Outcomes 
Euro-QoL – 5 Quality of Life Short Form will be completed at the day of discharge from ICU 
(day 2 to day 28, whatever comes first), and on follow-up day 28. Patients will be called from 
the investigator’s site on follow-up day 90 after end of infusion of study medication for 
completion of the paper telephone Euro-QoL – 5 Quality of Life Short Form. 
 
 
8.14 
Echocardiography (optional) 
If transthoracic or transeosophageal echocardiography is performed at screening , left ventricle 
end-diastolic diameter, right ventricular end-diastolic diameter, inferior vena cava diameter (and 
respiratory variation) and left ventricular ejection fraction will be recorded. Each original 
echocardiography recording will be evaluated by the investigator following automated 
measurement, and the interpretation of the results will follow the categories “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant”. 
 
Results from echocardiography evaluated by routine clinical care at the ICU or through 
retrospective analysis close to IMP administration can also be used. 
 
 
 
 

 
 
 
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9. 
PHARMACOVIGILANCE 
 
9.1 
Definitions 
 
9.1.1 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a patient or clinical study patient 
administered a product and which does not necessarily have a causal relation-ship with this 
treatment. 
 
Examples of AEs include one of the following or a combination of two or more of these factors: 
 
• 
Any unfavourable and unintended  sign, symptom, illness, or syndrome 
• 
Abnormal laboratory values, if judged clinically significant in the opinion of the 
investigator 
• 
Worsening (change in nature, severity or frequency) of a concomitant or pre-existing illness 
• 
An adverse event of the IMP including comparator or concomitant medication 
• 
Drug interactions 
• 
An adverse event of an invasive procedure required by the protocol 
• 
An accident or injury 
 
Any new data that may lead to: 
• 
A re-evaluation of the benefit and risk ratio of the research or product being researched 
• 
Changes in the use of this product, in the research throughout study conduct, or research 
related to materials, or 
• 
Suspension or discontinuation or modification of the research protocol or similar research 
(even if the new data occurred in another country). 
 
For trials involving the first administration or use of a health product in persons with no 
conditions: any serious adverse reactions. 
 
 
All AEs fall into one of two categories: “non-serious” and “serious” (see Section 9.1.2). 
 
Pre-existing illness or symptoms of the sepsis should only be recorded as AEs if they worsen 
during the course of the treatment, i.e. either change by one degree of the CTCAE grading from 
baseline, or significant clinical change in severity (for CTCAE grading, please refer to Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03, June 14, 2010). 
 
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly. 
 
Planned surgical measures and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the period of observation and did not worsen during the 
trial. In the latter case the condition should be reported as medical history. 
 
 
9.1.2 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose (including overdose): 
 
• 
Results in death 

 
 
 
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• 
Is life-threatening 
“Life-threatening” means that the patient was at immediate risk of death at the time of the 
SAE; it does not refer to an SAE that hypothetically might have caused death if it were 
more severe. 
• 
Requires subject hospitalization or prolongation of existing hospitalization. 
This means that hospital patient admission or prolongation of hospital stay was required 
for the treatment of the AE, or that they occurred as a consequence of the event. Visits to a 
hospital by ambulance or to the emergency room without admission will not be regarded 
as hospitalization unless the event fulfils any other of the seriousness criteria. 
• 
Results in persistent or significant disability or incapacity 
“Persistent or significant disability or incapacity” means a permanent or significant and 
substantial disruption of a person’s ability to carry out normal life functions. 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above should also usually be considered 
serious. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not 
result in patient hospitalization, or the development of drug dependency or drug abuse. 
A diagnosis of cancer/malignant tumor during the course of a treatment should always be 
considered as medically important. 
 
Clarification of the difference in meaning between “severe” and “serious”: The term “severe” 
is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or 
severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as “serious”, which is based on the 
outcome or action criteria usually associated with events that pose a threat to life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
 
Other events to be reported on the SAE report form: 
 
• 
Misuse and overdose: 
Drug misuse and drug overdose should be reported in the same format and within the same 
timelines as an SAE, even if they may not result in an adverse outcome. If no SAE is 
associated, the case will be regarded as non-serious. 
An overdose is defined as any dose higher than the assigned treatment dose (i.e. if a patient 
assigned to a dose > 8 mg/kg body weight, this would qualify as “overdose”). 
• 
Exposure to drug during pregnancy or lactation: 
In the unlikely event of a pregnancy occurring during the course of this particular study, 
the patient should be withdrawn from study, but closely followed up during the entire 
course of the pregnancy and postpartum period. All recommendations described in the 
investigational drug brochure during pregnancy and lactation have to be carefully 
considered. 
 
The sponsor must be notified without delay. Parental and neonatal outcomes must be recorded 
even if they are completely normal and without Adverse Events. Offspring should be followed 
up for at least 8 weeks after delivery. 

 
 
 
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Longer observation periods may be determined by the sponsor if an adverse outcome of the 
pregnancy was observed. 
 
 
9.1.3 
Recommendations to Treat Overdosing and Intoxication with the Study Medication 
No drug-specific antidote is available. Other emergencies will be treated symptomatically 
according to standard medical practice. 
 
 
9.1.4 
Investigational Product Complaints 
Pharmaceutical technical complaints associated with the investigational product must be 
reported to the sponsor immediately: 
 
ADRENOMED AG 
Neuendorfstr. 15a 
16761 Hennigsdorf 
Germany 
 
The same reporting timelines as for serious adverse events apply. 
 
 
9.2 
Period of Observation 
For the purpose of this study, the period of observation for collection of AEs extends from 
screening until 90 days after end of IMP administration. 
 
If the investigator detects an AE in a study patient after the end of the period of observation, and 
considers the event possibly related to prior study treatment or procedures, he or she should 
contact the sponsor to determine how the AE should be documented and reported. 
 
All AEs that occur in the course of a clinical study regardless of the causal relationship must be 
monitored and followed up until the outcome is known (see also section 9.3.4 and 9.4). There 
must be documented reasonable attempts to get this information. 
 
It is the responsibility of the investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
 
 
9.3 
Documentation and Reporting of Adverse Events 
 
9.3.1 
Documentation and Reporting of Adverse Events by Investigator 
The investigator must document all AEs that occur during the observation period set in this 
protocol in the eCRF. Additional instructions may be provided in the Investigator Site File and 
in the eCRFs itself. 
 
The following approach will be taken for documentation: 
 
All AEs (whether serious or non-serious,) must be documented on the “adverse event” page of 
the eCRF. 
 

 
 
 
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If the AE is serious (see Section 9.1.2), the investigator must complete, in addition to the 
“adverse event” page in the eCRF, a “serious adverse event report form” at the time the SAE is 
detected. This form must be sent immediately, i.e. within 24 hours from the awareness of the 
SAE to the safety contact of the sponsor (spm² - safety projects & more GmbH). 
 
The investigator will document the date when any study team member had first been aware of 
the report and fax all SAE reports (initial and follow-up reports) even if they are incomplete 
within one working day upon receipt to the safety department of the sponsor: 
 
spm² - safety projects & more GmbH 
Aurum 05 
Goldbeckstr. 5 
69493 Hirschberg a. d. Bergstraße, Germany 
Fax: 0049 - 621 - 570 5971 
Email: Adrenomed-phv@spm2-safety.com 
 
When an “overdose” or “drug misuse” of the investigational product occurs without an AE or if 
a “pregnancy is detected without an adverse outcome”, the investigator should only complete a 
“serious adverse event report form” and send this to the sponsor’s safety contact. It should be 
clearly stated that no AE was observed. In this case, there is no need to complete the “adverse 
event” page in the eCRF. The event will not be considered as serious. 
 
Every attempt should be made to describe all AEs in terms of a diagnosis. If a clear diagnosis 
has been made, individual signs and symptoms should not be recorded unless they represent 
atypical or extreme manifestations of the diagnosis, in which case they should be reported as 
separate events. If a clear diagnosis cannot be established, each sign and symptom must be 
recorded individually. 
 
The initial report should be as complete as possible, including details of the current illness and 
(serious) AE, the reason why the event was considered serious, date of onset and stop date (if 
applicable), diagnostic procedures and treatment of the event, relevant medical history and 
concomitant medication and action taken with trial medication. 
 
 
9.3.2 
Assessment of Severity 
The investigator will also provide an assessment of the severity of the event and causal 
relationship between the event and the investigational product or trial procedures. 
 
The basis of assessing severity and causality is described as: 
 
• 
Grade 1 - mild event: Causing no limitations of usual activities; the subject may experience 
slight discomfort 
 
• 
Grade 2 - moderate event: Causing some limitation of usual activities; the subject may 
experience annoying discomfort 
 
• 
Grade 3 - severe event: Causing inability to carry out usual activities; the subject may 
experience intolerable discomfort or pain 
 
• 
Grade 4 - life-threatening or disabling event 

 
 
 
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• 
Grade 5 - death related to event 
 
 
9.3.3 
Assessment of Causality 
The investigator will use medical judgment to determine whether there is evidence for a causal 
relationship, including all relevant factors such as temporal course and latency, results from de-
challenge or re-challenge, pattern of the reaction, known pharmacological properties of the 
product, and alternative explanations (e.g. other drugs, medical history, concomitant diseases). 
The investigator will apply the terms “certain”, “probable/likely”, “possible”, “unlikely” or 
“unrelated” to determine causality. For regulatory E2B reporting, this assessment will be 
converted to the binary system of “reasonable possibility” and “no reasonable possibility” (see 
table below). The expression “reasonable possibility” means to convey in general that there is 
factual evidence or argument to suggest a causal relationship. The assessment will be 
documented on the AE and SAE form. 
 
The causality criteria will be used as described in the following. 
 
 
 

 
 
 
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Table 1: Mapping of Causality Categories to Binary Causality Assessment 
 
Causality 
term 
Assessment criteria* 
E2B 
(EudraVigilance 
Database / 
EMA) 
Certain 
• 
Event or laboratory test abnormality, with plausible 
time relationship to drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible 
(pharmacologically, pathologically) 
• 
Event definitive pharmacological or 
phenomenological (i.e. an objective and specific 
medical disorder or a recognized pharmacological 
phenomenon) 
• 
Re-challenge satisfactory, if necessary 
Reasonable 
possibility 
Probable /  
Likely 
• 
Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Re-challenge not required 
Possible 
• 
Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or 
unclear 
Unlikely 
• 
Event or laboratory test abnormality, with a time to 
drug intake that makes a relationship improbable 
(but not impossible) 
• 
Disease or other drugs provide plausible 
explanations 
No reasonable 
possibility 
Unrelated 
• 
There is no evidence or argument to suggest a causal 
relationship. 
 
* All points should be reasonably complied with 
 
 
9.3.4 
Follow-up of Missing Information 
Information not available at the time of the initial SAE report (e.g., an end date for the SAE or 
laboratory values received after the report) must be documented on a “Serious Adverse Event” 
form, with the box “Follow-up” checked under “Report type”. 
 
All subjects who have AEs, whether considered associated with the use of the investigational 
products or not, must be monitored to determine the outcome. The clinical course of the AE will 
be followed up according to accepted standards of medical practice, even after the end of the 
period of observation, until a satisfactory explanation is found or the investigator considers it 
medically justifiable to terminate follow-up. Should the AE result in death, all efforts should be 

 
 
 
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exercised to have an autopsy performed and a full pathologist’s report should be supplied, if 
possible. 
 
The sponsor will identify missing information for each SAE report. Requests for follow-up will 
be sent to the investigators for further processing. spm²will require follow-up information in 
regular intervals from the investigators until all queries are resolved or no further information 
can be reasonably expected. All responses to queries and supply of additional information by 
the investigator should follow the same reporting route and timelines as the initial report. 
 
 
9.3.5 
Determination of Expectedness, Reference Safety Information 
Expectedness will be determined by the sponsor according to the designated Reference Safety 
Information. Any updates or substantial amendments will be considered accordingly. The 
Reference Safety Information for the investigational medicinal product will be the chapter 
“Reference Safety Information” of the current IB version for ADRECIZUMAB. 
 
Unexpected: 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the Reference 
Safety Information or is not listed with the specificity or severity that has been observed. 
Unexpected, as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the Reference Safety Information as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
 
 
9.3.6 
Expedited Reporting of Adverse Events / SUSAR Reporting 
All AEs and SAEs will be classified according to severity and causality.The sponsor will report 
all those serious and unexpected AEs, which are judged by either the investigator or the sponsor 
as having a reasonable suspected causal relationship i.e. SUSAR, to the Competent Authority, 
the concerned EC and the investigators according to applicable law without any delay. 
 
Unblinding: 
If applicable treatment codes will be broken prior to submission to authorities and concerned 
IRB/IECs, by the sponsor’s safety group, which is an independent entity within the sponsor. The 
study team will be kept blinded regarding treatment assignment. 
 
Development Safety Update Reports: 
The sponsor will prepare and submit development safety update reports to the Competent 
Authority and concerned EC. 
 
 
9.4 
Follow-up of Adverse Events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow-up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
 
The Investigator is expected to record any case of unexpected pregnancy throughout the 
treatment and follow-up periods until 90 days after the end of treatment. With the consent of the 
patient, the Investigator should monitor any occurring pregnancy until delivery to record any 
abnormality. The Investigator must immediately communicate any case of pregnancy resulting 

 
 
 
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in an abnormal outcome (e.g. miscarriage, congenital anomaly, or stillbirth). Any such case is 
to be managed as SAE and reported within 24 h after awareness.  
 

 
 
 
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10. 
STATISTICAL CONSIDERATIONS 
A full statistical analysis plan will be drawn up before the trial database is locked and analyzed. 
Prior to performing any statistical tests or fitting statistical models, an exploratory analysis of 
the baseline variables and outcome measures will be completed. The level and pattern of missing 
data in the baseline variables and outcomes will analyzed and likely causes of any missing 
values will be investigated. 
 
 
10.1 
Demographic and Other Baseline Characteristics 
Demographic characteristics will be listed and summarized. 
 
 
10.2 
Statistical Methods for Safety Parameters 
All safety and tolerability assessment will be based on the safety analysis set, which is defined 
as all patients who have received study medication. 
 
 
10.3 
Handling of Withdrawals, Protocol Deviations and Missing Values 
Data from subjects who prematurely terminate the study will be used to the maximum extent 
possible. 
 
Missing data in the primary efficacy endpoint will be dealt with using sensitivity analysis. 
Details will be outlined in the statistical analysis plan. 
All protocol deviations will be listed. The deviations will be assessed as critical, major or minor 
with regard to their influence prior to locking the database. 
 
The reasons for exclusion of patients from any of the analysis sets will be listed and, where 
relevant, the data from these patients will be described separately. 
 
 
10.4 
Safety Analysis 
Safety monitoring will begin at the time the Informed Consent Form (ICF) is signed and will 
continue for 90 days after short-term infusion of study medication. 
 
All AEs will be listed. The number and percent of patients experiencing 1 or more AEs will be 
summarized by treatment arm / control group, relationship to study drug and severity/grade. 
 
SAE specific listings for each patient population will be generated on reported SAEs, but not 
as SUSARs . 
 
Endpoints relevant for the primary objective of safety and tolerability are 
• 
Mortality 
• 
Interruption of infusion  
• 
Treatmant-emergent adverse events  
• 
Severity and frequency of adverse events 
 
Demographic and medical background data, secondary endpoints and safety variables are to be 
analyzed by means of descriptive and exploratory methods. 
 

 
 
 
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Continuous variables are to be summarized by the number of patients, mean, SD, median, 
quartiles and range. 
 
Categorical variables are to be summarized using number and percentage by category. 
 
Medical terms and adverse events are to be coded using the MedDRA Version 19.1 and 
summarized according to system organ class and preferred term. 
 
Concomitant medications are to be coded using the WHO-Drug Dictionary and summarized to 
the therapeutically chemical (ATC) terminology. 
 
 
10.5 
Efficacy Analysis 
The primary analysis for efficacy will be based on combining both ADRECIZUMAB doses and 
comparing the treated groups versus the placebo group. A second-line analysis will compare the 
two doses for differences in efficacy. 
 
For the primary efficacy endpoints, a first analysis will determine whether the improvement due 
to treatment is > 0 with at least 80% probability, i.e. the lower bound of a 60% confidence 
interval must be larger than 0. Only if this is achieved, the classical p-value using the described 
methods will be calculated. 
 
The primary analysis of the primary efficacy endpoint will be done as intention-to-treat, i.e. 
patients will be analyzed with respect to the group they were randomized to. A per protocol 
analysis will be performed, excluding patients that did not receive the treatment according to 
protocol or that did not meet the inclusion criteria.  In case patients did not receive the treatment 
they were randomized to, an analysis based on the actual treatment (as-treated-analysis) will 
also be performed. 
 
 
10.5.1 
Sepsis Support Index (SSI) and Penalized Sepsis Support Index (pSSI) 
SSI as primary efficacy endpoint is defined as days with organ support or dead within 14 day 
follow up. Organ support days are defined as days with vasopressor, mechanical ventilation or 
renal replacement therapy (defined as renal SOFA = 4 due to expected heterogeneity in 
treatment for renal failure). The SSI is calculated as follows: In the time frame of 14 day follow-
up, each day on support with either vasopressor, and/or mechanical ventilation (defined as any 
mechanical ventilation received on this day, independent from the duration of mechanical 
ventilation), and/or renal dysfunction, or not alive, is counted as 1. The sum over the follow-up 
period is defined as SSI. SSI describes the effect of a given therapy in pre-defined patient 
population with sepsis at risk or septic shock. 
 
A penalized version of the Sepsis Support Index (pSSI) is defined as above, but patients who 
die get penalized, i.e. the pSSI is set to 14 days. SSI and pSSI will also be evaluated for 28 day 
follow-up. The individual SSI components (cardiac, respiratory and renal failure), as well as an 
SSI-Version excluding the renal component, will also be evaluated separately. 
 
The non-parametric Wilcoxon test will be used to test  the treatment effect.The effect measure, 
delta SSI, will be estimated by the Hodges-Lehmann estimator.  
 
A third version of a composite endpoint is also considered: Persistent organ dysfunction or death 
at 14 and 28 day follow up (as defined by [5]). 
 

 
 
 
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10.5.2 
All-cause Mortality at Follow-up Day 28 and Day 90 
All-cause mortality will be evaluated using Kaplan-Meier plots comparing treatment vs. placebo 
(log-rank test) and Cox regression modelling including covariates to adjust for potential 
confounders, e.g. severity, age and others. 
 
 
10.5.3 
SOFA Score 
The SOFA score will be evaluated daily for all patients over the entire stay on ICU (as long as 
the arterial line is in place) until day 28 or discharge (whatever comes first). 
 
In the calculation of the score, the worst values for each parameter in the 24 hours period will 
be used.  In sedated patients, the GCS at the time of intubation will be used. When sedation is 
removed, the GCS is recorded with actual values. In the rare event, that the patient exeriences a 
stroke or bleeding after the initial intubation the GCS estimation of 3 – 4 will be used. When 
the patient is stable, the estimation would be based on clinical experience. 
 
When using the SOFA score as an endpoint, patients deceased will be assigned the maximum 
SOFA score (24). If the patient has been transferred from ICU to another ward and / or home 
the SOFA score will be set to0. 
 
The total SOFA score will be calculated as the sum of daily SOFA scores during the ICU stay 
for each patient. The mean SOFA score is defined as the total SOFA score divided by the length 
of stay in the ICU. The highest SOFA score recorded during the ICU stay will also be recorded. 
The delta- SOFA score is defined as the difference between the maximum and minimum SOFA 
score during ICU hospitalization. The change in SOFA score is defined as the difference 
between the SOFA score 48h post admission and baseline. 
 
Appropriate parametric and or non-parametric methods will be applied for the various 
endpoints based on SOFA score. 
 
 
10.6 
Sample Size Determination / Power Analysis for Primary Efficacy Endpoint 
(SSI within  14 days) 
 
Power simulations are based on using real patient data on the combined endpoint from the 
ALBIOS study, and underlying assumptions were re-evaluated using results from the AdrenOSS 
observational study.. 
 
• 
Details of the simulation:1,000 simulations using real patient data from ALBIOS (n=539)  
• 
Simulated sample size: n=150 per group (sampling with replacement) 
• 
Simulated effect size: 10% average reduction in the treated group, irrespective of treatment 
dose 
• 
p-values, confidence intervals and point estimates [=pseudo-median] based on Wilcoxon 
rank test 
• 
Simulation includes interim futility stop 
• 
Patients may not have less than 1 day with organ support  (as vasopressor is given at day 1 
by definition) 
 
Power Analysis Assumptions 

 
 
 
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If n=300 early septic shock patients are randomized 1:1 (we assume that both doses can be 
combined) to placebo and ADRECIZUMAB and assuming that delta SSI is >10%, the power is 
> 80% to demonstrate an improvement of delta SSI of > 0 with at least 80% probability. The 
lower bound of the confidence interval will be determined based on the non-parametric 
Wilcoxon test. 
 
Interim Analysis with Futility Stop 
An interim analysis is planned after 50% of patients (n=150) completed study day 28. The study 
will be stopped if the probability of a positive outcome is below 40% once 50% of patients 
(n=150) completed study day 28. Power remains >80% if futility stop is included in simulation. 
“Positive outcome” of the study will be defined in the SAP. 
 
Power Considerations Summary 
Based on the described simulation, the probability of achieving our primary objective, i.e. that 
the delta SSI is > 0 with at least 80% probability, is 0.87 without interim analysis and 0.85 
with the planned interim futility stop (discontinue if the probability of success is less than 
40%). Details will be outlined in the SAP.  
 
 
10.7 
Statistical Methods for Pharmacokinetic Parameters 
The analysis plan for PK assessment for the study will be part of the SAP. 
 
PK of ADRECIZUMAB profile is studied after single administration of ADRECIZUMAB 
2 mg/kg and 4 mg/kg in order to determine key PK parameters, including peak plasma 
concentrations (Cmax), systemic exposure (AUC), volume of distribution (V), systemic clearance 
(CL), and elimination half-life (t½) (in 80 patients only). 
 
 
10.8 
Analysis of Observational Data and Exploratory Analysis 
Several post-hoc analyses using all patients included in the study are planned, such as analyzing 
the association between 28 day mortality rate/ vasopressor use/ ventilation and bio-ADM. 
 
Exploratory post-hoc analysis of efficacy endpoints in patient subgroups defined by severity, 
other biomarkers, concomitant medication or other clinical data will be performed, as well as 
interactions with other drugs, in order to identify subgroups which possibly benefit 
overproportionally from treatment with Adrecizumab.  
 

 
 
 
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11. 
DATA MANAGEMENT and DATA HANDLING  
 
11.1 
Data Management 
All data management activities will be done according to ICH-GCP as required by regulatory 
agencies. Responsibility for data management lies with the designated CRO following their 
internal standard operating procedures (SOPs). 
 
The designated CRO will be responsible for the activities associated with the data management 
of this study, including the production of an eCRF, setting up a relevant database, along with 
appropriate validation of data and resolution of queries. All data will be entered into an eCRF. 
Automated and manual checks will be made against the data to ensure completeness and 
consistency. 
 
AEs will be standardized for terminology and classification, using MedDRA dictionary. 
Concomitant medications will be classified by site of action, therapeutic and clinical 
characteristics using the WHO-DRUG dictionary. Clean data sets will be provided for statistical 
analysis and reporting. 
 
 
11.2 
Data Handling and Recording of Data 
All data collected during the study have to be recorded in an electronic CRF (eCRF) which is 
provided in an internet portal. This eCRF will be designed by M.A.R.C.O. GmbH & Co. KG 
(M.A.R.C.O) in the Amedon system. The Amedon system has been validated by Amedon 
GmbH for use in clinical studies. Validation checks will be implemented in the system or 
programmed with SAS®, Version 9.1 or higher according to the data validation plan set up by 
M.A.R.C.O. 
 
Personnel at the site will be trained on the use of the eCRF. All investigator site personnel 
seeking access must go through training process before they are granted access to the system. 
Training records are maintained. All access to the internet portal is password protected. 
 
All personnel with access to the system are supported by a Service Desk staffed with trained 
personnel to answer questions and ensure access is maintained such that data entry can proceed 
in a timely manner. 
 
The investigator is responsible for ensuring that all sections of each eCRF are completed 
correctly, and that entries can be verified against source data. If certain data are not available or 
not applicable this will be indicated as such on the appropriate space on the eCRF. The study 
monitor will review the eCRFs and check them for completeness. In case of any missing data, 
inconsistencies, implausible values or other imperfections the data manager or the monitor will 
supply the site with queries, so that the investigator can correct this. It will also be done within 
the electronic system. 
 
The system contains a system-generated audit trail that captures any changes made to a data 
filed, including who made the change and the date and time the change was made. 
 
Addenda of the eCRF (i.e. clinical laboratory reports, ECG printouts) should bear the patient 
identification number, allocated randomization code, study day and time, and signature of the 
investigator. 

 
 
 
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Clinical laboratory parameters will be provided in laboratory print-outs which are to be signed 
by the investigator. Comments on all clinically significant abnormal values should be given by 
the investigator on these print-outs and will then be transferred into the eCRF. 
 
 
11.3 
Source Data 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, pharmacy 
dispensing records, recorded data from automated instruments, consultant letters, screening and 
enrollment logs etc. 
 
The investigator is responsible to record all study related source data enabling the sponsor to 
reconstruct the complete course of the clinical study. Source data will be transcribed to and 
reported through the eCRF accordingly. 
 
 
 

 
 
 
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12. 
ETHICAL CONSIDERATIONS 
 
12.1 
Good Clinical Practice 
The investigator will ensure that this clinical study is conducted in accordance with the 
principles of the Good Clinical Practices (GCP), ICH Guidelines, and the Declaration of 
Helsinki and with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the patient. 
 
 
12.2 
Independent Ethic Committees (IEC) and Competent Authorities (CAs) 
The study will only start after approval of the study protocol and all relevant documentation by 
the IRB/IEC and CA of the participating countries. 
 
In addition, all local national legal requirements for the conduct of a clinical study have to be 
followed prior to the start and during the study. 
 
The CA and IECs of the participating countries will be informed about any changes in the study 
protocol, the end of the study, or the premature study termination as appropriate and within the 
requested time period. 
 
 
12.3 
Subject Insurance 
Insurance for patients included in this study will be arranged by ADRENOMED AG as sponsor 
of the clinical study according to country-specific requirements. A copy of the insurance 
certification will be held in the study master file at ADRENOMED AG. Patients are to be 
informed by the investigator of the existence of the insurance, and that they have the right to 
inspect the terms and conditions of said insurance or may receive a copy, if required per national 
legislation. 
 
 
12.4 
Steering Committee 
The Steering Committee oversees all aspects of the study and during the study will remain 
blinded to treatment group results. The Steering Committee has the authority to propose protocol 
amendments to the sponsor based on its monitoring of the progress of the study, including 
reports or recommendations received from the DSMB. 
 
The Steering Committee will be responsible for approval of the final protocol for the study, the 
substudy and the publication of study results. The Steering Committee will meet regularly to 
monitor the progress of the study using blinded tabulations based on all patients. The Steering 
Committee will also approve the interim and final analysis dates proposed by the DSMB on 
basis of event accrual. Based on recommendations from the DSMB, the sponsor in conjuction 
with the Steering Committee has the authority to stop the study for unexpected safety reasons. 
 
Membership will include one coordinating investigator for each involved country and 
representatives of the sponsor. Chairpersons are Prof. A. Mebazaa, France,  Prof. P.F. Laterre, 
Belgium, Prof. G. Marx, Germany and Prof. P. Pickkers, Netherlands. 
 
 
 

 
 
 
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12.5 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will be established  and serves as an 
independent group responsible for the ongoing review of a clinical trial and for making 
recommendations to the sponsor concerning the continuation, modification, and termination of 
the trial throughout the study conduct. The key responsibilities of the DSMB are to ensure 
patient safety by routine review of overall safety data including all SAEs, SUSARs, all severe 
AEs, AESIs and AEs leading to drug or study discontinuation and, where applicable, literature 
cases and information from Competent Authorities (CAs) and by judging the relevance of the 
events for patients’ safety. 
 
The DSMB will operate independently of the Steering Committee and the sponsor. 
 
 
The specific composition and working procedures are described in the Charter of the DSMB. 
The DSMB will be comprised two clinical experts in the field of sepsis, a biostatistician and a 
Pharmacovigilance representative. The DSMB Chair and committee members will be selected 
by the sponsor and the Steering Committee. 
 
The DSMB will monitor a subset of safety data on monthly intervals during the study. For these 
monitoring activities data on SAE & SUSAR (including fatal outcome) will be provided 
aggregated, stratified by treatment groups to the members of the DSMB. The data will be 
presented in semi-blinded fashion (assignment into group A, B or C). In addition the DSMB 
will routinely review severe AEs, AESIs and AEs leading to drug or study discontinuation. 
 
Based on the results of these monitoring activities, the DSMB is empowered to recommend to 
the Steering Committee any change in the design of the study required to ensure the safety of 
the enrolled patients and the scientific integrity of the study. 
 
 
 
 

 
 
 
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13. 
ADMINISTRATIVE STRUCTURE AND RESPONSIBILITIES 
 
13.1 
Study Monitoring 
This study will be monitored according to the monitoring plan which will be prepared and filed 
in the study master file prior to initiation of a study site. The monitor is responsible for routine 
review of the eCRFs at regular intervals throughout the trial to verify adherence to the protocol 
and the completeness, consistency, and accuracy of the data being entered into them. The 
monitor should have access to any patient records needed to verify the entries on the eCRFs. 
 
The investigator will allocate adequate time for such monitoring activities and ensure that the 
monitor has adequate space to conduct the monitoring visit. The investigator agrees to assist the 
monitor in resolving any problem that may be detected during the monitoring visit or data 
cleaning process. 
 
The investigator will be contacted by the study monitor on a regular basis. The monitor will 
have the responsibility of reviewing the ongoing study with the investigator to verify adherence 
to the protocol and to deal with any problems. eCRFs will be checked for completeness and 
consistency with the source data. At all times, the confidentiality of study-related documents 
will be maintained. 
 
The investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given direct access to study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.) and all the study-related documents (source data) which supports the data on the eCRFs for 
the study. Direct access is defined as the permission to examine, verify, and reproduce any 
records and reports that are important for evaluation of a clinical study. Any party allowed direct 
access to study source data and documents should take all reasonable precautions within the 
constraints of the applicable regulatory requirements to maintain the confidentiality of patient 
identities and sponsor proprietary. 
 
 
13.2 
Investigator Study File 
The investigator is responsible for keeping files of essential documents as defined by the ICH 
guidelines on GCP and local requirements. The Investigator’s Study File must be available at 
monitoring visits and during an audit or inspection. 
 
 
13.3 
Changes in Study Conduct 
For any change of the study conduct the sponsor must be contacted and must agree to such 
change. Substantial changes to the protocol during the study will be documented as protocol 
amendments. The amended protocol will be signed by the responsible personnel at 
ADRENOMED AG and the Principal investigator. 
 
Depending on the contents of the amendment and local legal requirements, the amendment will 
be submitted to the relevant IEC and, where necessary, to the relevant CAs. 
 
 
 

 
 
 
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13.4 
Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
 
 
13.5 
Protocol Deviations 
Sponsor does not allow any deviations or exemptions relating to protocol inclusion and 
exclusion criteria. All protocol deviations will be documented. This study will be conducted as 
described in this protocol except for emergency situations in which the protection, safety, and 
well-being of the patient requires immediate intervention based upon the judgment of the 
Investigator (or a responsible, appropriately trained and credentialed professional(s) designated 
by the Investigator). 
 
 
13.6 
Drug Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused investigational medicinal product and placebo. This 
includes acknowledgement of receipt of each shipment of IMP kits (quantity and condition), 
IMP administration records, and returned or destroyedkits of IMP. IMP records will document 
quantities received from the sponsor and quantities administered to patients, including date /time 
of administration, patient identification number and the initials of the person responsible for 
IMP administration. 
 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the monitor over the course of the study. 
 
 
13.7 
Audits and Inspections 
The investigator will permit study-related audits, and inspections by the IRB/IEC, the sponsor, 
and regulatory authorities of all study-related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). The investigator will ensure the 
availability of applicable study-related facilities (e.g. pharmacy, laboratory, etc.) for inspections. 
 
Audits and inspections will be performed in accordance with ICH-GCP, EU Directives, and 
applicable local regulations to ensure that the clinical study is conducted in compliance with the 
study protocol requirements. 
 
 
13.8 
Confidentiality 
The investigators, designated CRO and ADRENOMED AG and all other involved parties will 
preserve the confidentiality of all patients taking part in the study, in accordance with ICH-GCP 
and local regulations. The confidentiality of all patient identities will be maintained, except 
during source data verification, when monitors, auditors and other authorized agents of the 
sponsor or its designee, the IECs approving this research, as well as any other applicable 
regulatory authorities will be granted direct access to the study patients’ original medical 
records. No material bearing a patient’s name will be kept on file by designated CRO or 
ADRENOMED AG. 
 
 
 

 
 
 
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The data retained from this study will be protected in accordance with all applicable legal 
requirements. Information about study patients will be kept confidential and managed according 
to the requirements of the EU Directives 2001/20/EC, 2005/28/EC, and 2003/63/EC  and 
relevant national and local legislations. 
 
 
13.9 
Patient Data and Data Protection 
Permission for direct access to patient data will be sought in writing by the investigator and from 
the patient as part of the informed consent procedure. This gives permission to examine, analyse, 
verify and reproduce any records and reports that are important to the evaluation of the study. 
Any party (e.g., domestic and foreign regulatory authorities, clinical research associates and 
auditors) with direct access must take all reasonable precautions within the constraints of the 
applicable regulatory requirement(s) to maintain the confidentiality of the patient’s identity and 
sponsor’s proprietary information. 
 
It is the monitor’s responsibility to verify that each patient has consented, in writing, to direct 
access. It is to be ensured by the investigator that documents that are given to ADRENOMED 
AG or its representatives do not contain the name or address of the patient, or other information 
that would affect the anonymity of the patient. 
 
The EU General Data Protection Regulation (GDPR) will also be taken into consideration 
during the conduct of study.  
 
 
13.10 
Reports 
All reports to the sponsor will be written in English. All clinical, analytical and statistical results 
will be presented in a final clinical study report which will be structured in accordance with ICH 
Topic E3. 
 
The clinical study report will be the sole property of the sponsor. Publication of the clinical 
study report or of parts of it may only be allowed when authorized by the sponsor. Independently 
from the clinical study report, the data obtained in this clinical study will be published. 
 
Short reports to the CA and IEC after study termination will be provided as required by law, i.e. 
no later than 1 year after study completion defined as last patient last visit. 
 
 
13.11 
Publication of Study Results 
The investigator and the institution recognize that all data generated from this study are the 
proprietary and confidential information of the sponsor, along with all information supplied by 
the sponsor. The sponsor recognizes the investigator’s and the institution’s rights and 
obligations, as an academic partner, to publish the study results. The study results will be 
published in accordance with the good publication practice guideline of the international society 
for medical publication professionals. This includes but is not limited to the following 
principles: 
 
The sponsor confirms the authors’ freedom to make public or publish the study results and grants 
full access to the study data for this purpose. The investigator and the institution agree that they 
are not permitted to publish data related to the study independent of the sponsor and the other 
investigators. 
 

 
 
 
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The investigator and the institution plan and produce publications in a timely manner and avoid 
premature release of study information. 
 
The sponsor and the investigator and other individuals who have expertise in the area and who 
are willing to interpret the data and write or review articles and presentations will form a 
publication Steering Committee to oversee the preparation of articles and presentations from 
this study. 
 
Prior to any written or oral presentation of the study results or any part thereof, the investigator 
or the institution shall send the full text of the proposed disclosure to the sponsor (or, if 
applicable, the publication steering committee) for review and comments at least 60 business 
days prior to submission for publication or oral presentation. The sponsor reserves the right to 
have deleted from the proposed publication any confidential information of the sponsor with the 
exception for results or data generated on the basis of the study which are of scientific interest 
to the investigator and which may be published in compliance with this section. During the 
above mentioned period, sponsor in his sole discretion will take the steps he deems necessary 
to secure any intellectual property arising from the study results or data, including the filing or 
substantiating of one or more patent applications. The investigator or the institution shall follow 
customary principles related to scientific publications in determining and attributing authorship 
of any proposed publication, provided that any such publication shall acknowledge the 
sponsorship by the sponsor. 
 
 
13.12 
Study Documents and Record Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be significantly verified. These documents should 
be classified into two separate categories (although not limited to) the following: 
(1) investigator’s study file and (2) patient clinical source documents. 
 
The investigator’s study file contains the protocol and any amendments, eCRF and query 
records, IRB/IEC and regulatory approvals including all correspondence, informed consent 
forms, drug records, staff curriculum vitae and authorizations forms and other appropriate 
documents and correspondence. 
 
In compliance with GCP guidelines and regulations, the investigator will keep all clinical study 
documents until at least two years after the last approval of a marketing application in an ICH 
region (i.e. United States, Europe or Japan) and until there are no pending or contemplated 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and 
regulatory authorities have been notified. Investigators may be required to retain documents 
longer if required by applicable regulatory requirements or an agreement with ADRENOMED 
AG. 
 
No data should be destroyed without the consent of ADRENOMED AG. 
 
Should the investigator assign the study records to another party or move them to another 
location, ADRENOMED AG must be notified in advance. If the investigator cannot guarantee 
these archiving requirements at the study center for any or all of the documents, special 
arrangements must be made between the investigator and ADRENOMED AG to store these in 
sealed containers outside of the center so that they can be returned sealed to the investigator in 
case of a regulatory audit. Where source documents are required for the continued care of 
patient, appropriate copies should be made for storage outside of the center. 

 
 
 
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13.13 
Data Archiving 
The clinical center is responsible for the secure and restrictive archiving of source data for at 
least 15 years or until written notification from ADRENOMED AG that the documents are no 
longer required. During the required period, the clinical center will ensure that archived data 
and documents will be undamaged, legible and accessible to the sponsor and/or for regulatory 
purposes, if required. 
 
The study master file, the eCRFs, the code envelopes and other material supplied for the 
performance of the study will be retained by ADRENOMED AG according to applicable 
regulations and laws. 
 
 
 
 

 
 
 
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14. 
REFERENCES 
 
 
1) 
Blet et al.; Hemodynamics effects of adrecizumab in sepsis rat. Intensive Care Medicine 
Experimental 2015, 3 (Suppl 1): A618 
 
2) 
Caironi P. et al.; Albumin Replacement in Patients with Severe Sepsis or Septic Shock. 
NEJM 370:1412 – 1421, 2014 
 
3) 
Dellinger R. P. et al.; Surviving Sepsis Campaign: International Guidelines for 
Management of Severe Sepsis and Septic Shock. 2012, Intensive Care Medicine, 39: 
165–228, 2013 
 
4) 
Fleischmann, C. et al.; Hospital incidence and mortality rates of sepsis — an analysis of 
hospital episode (DRG) statistics in Germany from 2007 to 2013. Dtsch. Arztebl. Int. 
2016; 113(10): 159-66 
 
5) 
Heyland et al.; Persistent organ dysfunction plus death: a novel,composite outcome 
measure for critical care trials. Critical Care 2011, 15 
 
6) 
Hirata Y. et al.; Increased circulating Adrenomedullin, a novel vasodilating peptide, in 
sepsis. J. Clin. Endocrinol. Metab. 81: 1449 – 1453, 1996 
 
7) 
Lainchbury J.G. et al.; Adrenomedullin: a hypotensive hormone in man. Clin. Science 
1997; 92: 467 – 472 
 
8) 
Lainchbury J.G. et al.; Bioactivity and Interactions of Adrenomedullin and Brain 
Natriuretic Peptide in Patients with Heart Failure. Hypertension 1999; 34: 70 – 75 
 
9) 
Lainchbury J.G. et al.; Hemodynamic, Hormonal, and Renal Effects of Short Term 
Adrenomedullin Infusion in Healthy Volunteers. J. Clin. Endocrin. Metab. 85; 1016 – 
1020, 2000 
 
10) 
Nagaya N. et al.; Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin 
Infusion in Patients with Congestive Heart Failure. Circulation, 2000; 101: 498 – 503 
 
11) 
Nagaya N. et al.; J. Intravenous Adrenomedullin in Myocardial Function and Energy 
Metabolism in Patients After Myocardial InfarctionCardiol. Pharmacology 2002; 39: 
754 – 769 
 
12) 
Nicholls M.G. et al.; Adrenomedullin in Heart Failure. Hypertension Res. 2003; 26 
(suppl.): S135- 140 
 
13) 
Nishio K. et al.; Increased plasma concentrations of adrenomedullin correlate with 
relaxation of vascular tone  in patients with septic shock. Crit. Care Med. 25: 953 – 957, 
1997 
 
14) 
Marino R. et al.; Plasma adrenomedullin is associated with short-term mortality and 
vasopressor requirement in patients admitted with sepsis. Critical Care (London, 
England) 2014;18:R34 
 

 
 
 
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15) 
McCook O. et al.; Abstract at the Annual Conference of Shock, 2014 
 
16) 
Mebazaa A. et al.; Post-ICU discharge and outcome: rationale and methods of the The 
French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) 
observational study. BMC Anesthesiol. 2015 Oct 12;15:143 
 
17) 
Mebazza A. et al.; manuscript in preparation 
 
18) 
Meeran K. et al.;  Circulating Adrenomedullin Does Not Regulate Systemic Blood 
Pressure but Increases Plasma Prolactin after Intravenous Infusion in Humans: A 
Pharmacokinetic Study. J. Clin. Endocrinol. Metab. 82: 95 – 100, 1997 
 
19) 
Rademaker M.T. et al.; Hemodynamic, Hormonal, and Renal Actions of 
Adrenomedullin 2 in Experimental Heart Failure. Circ. Heart Fail. 2008; 1: 134 – 142 
 
20) 
Schürholz T. et al.; unpublished data 
 
21) 
Simon T.P. et al., Plasma Adrenomedullin in Critically Ill Patientswith Sepsis after Major 
Surgery - A pilot study. Journal of Critical Care (2016), doi: 10.1016/j.jcrc.2016.10.017. 
 
22) 
Singer P. et al.; Third International Consensus Definitions for Sepsis and Septic Shock 
(Sepsis - 3). JAMA. 2016;315(8):801-810 
 
23) 
Struck J. et al.; Epitope specificity of anti-Adrenomedullin antibodies determines 
efficacy of mortality reduction in a cecal ligation and puncture mouse model. Intensive 
Care Med. Exp. 2013 Dec;1(1): 22. doi: 10.1186/2197-425X-1-3 
 
24) 
Troughton R.W. et al.; Hemodynamic, Hormone, and Urinary Effects of 
Adrenomedullin Infusion in Essential Hypertension. Hypertension. 2000; 36: 588 – 593 
 
25) 
Ueda et al.; Increased Plasma Levels of Adrenomedullin in Patients with Systemic 
Inflammatory Response Syndrome. Am. J. Respir. Crit. Care Med. 160; 132 – 136, 
1999 
 
26) 
Wagner K et al.; Adrenomedullin binding improves catecholamine responsiveness and 
kidney function in resuscitated murine septic shock. Journal of Software Engineering 
Research and Development 2013, 1:2 
 
27) 
Watkins HA et al.; Identification of key residues involved in adrenomedullin binding to 
the AM1receptor. Br. J. Pharmacol. 2013 May: 169(1): 143-55 
 
 
 

 
 
 
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APPENDICES 
 
 
 

 
 
 
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Appendix 2: APACHE II Score 
 
 
 
A. Acute Physiology Score: 
 
 
PHYSIOLOGIC 
VARIABLE 
HIGH ABNORMAk RANGE 
LOW ABNORMAL RANGE 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
 
 
 
 
 
 
 
 
 
 
 
1 
Temperature – rectal (°C) 
> 41° 
39 - 40.9° 
 
38.,5 - 
38.9° 
36.0 - 38.4° 
34 - 35.9° 
32 - 33.9° 
30 - 31.9° 
< 29.9° 
2 
Mean Arterial  =  
(2 x diastolic + systolic)/3 
> 160 
130 - 159 
110 - 129 
 
70 - 109 
 
50 - 59 
 
< 49 
3 
Heart Rate (ventricular 
response) 
> 180 
140 - 179 
110 - 139 
 
70 - 109 
 
55 - 69 
40 - 54 
< 39 
4 
Respiratory Rate (non-
ventilated or ventilated) 
> 50 
35 - 49 
 
25 - 34 
12 - 24 
10 - 11 
6 - 9 
 
< 5 
5 
Oxygenation: 
A-aDO2 or PaO2 (mmHg) 
> 500 
350 -- 499 
200 - 349 
 
< 200 
 
 
 
 
a. FiO2 > 0.5 record A-aDO2 
 
 
 
 
 
 
 
 
 
 
b. FiO2 > 0.5 record PaO2 
 
 
 
 
> 70 
61 - 70 
 
55 - 50 
< 5 
6 
Arterial pH (*If no ABGs 
record Serum HCO3 below) 
> 7.7 
7.6 - 7.69 
 
7.5 - 7.59 
7.33 - 7.49 
 
7.25 - 7.32 
7.15 - 7.24 
< 7.15 
7 
Serum Sodium (mMol/L) 
> 180 
160 - 179 
155 - 159 
150 - 154 
130 - 149 
 
120 - 129 
111 - 119 
< 110 
8 
Serum Potassium (mMol/L) 
> 7 
6 - 6.9 
 
5.5 - 5.9 
3.5 - 5.4 
3 - 3.4 
2.5 - 2.9 
 
< 2.5 
9 
Serum Creatinine (mg/dl) 
Double point score for acute 
renal failure 
> 3.5 
2 - 3.4 
1.5 - 1.9 
 
0.6 - 1.4 
 
< 0.6 
 
 
10 
Hematocrit (%) 
> 60 
 
50 - 59.9 
46 - 49.9 
30 - 45.9 
 
20 - 29.9 
 
< 20 
11 
White Blood Count  
> 40 
 
20 - 39.9 
15 - 19.9 
3 - 14.9 
 
1 - 2.9 
 
< 1 
12 
Glasgow Coma Scale Enter 
15 minus actual GCS – see 
calculations in table below 
15-GCS = 
A 
Total Acute Physiology 
Score (APS) 
Sum of the 12 individual variable points = 
* 
Serum HCO3 (venous-
mMol/L) (Not preferred, use 
if no ABGs) 
> 52 
41 – 51.9 
 
32 – 40.9 
22 – 31.9 
 
18 – 21.9 
15 – 17.9 
< 15 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
CONFIDENTIAL 
 Trial Protocol – Version 4.2, 28-August 2019 
 
Page 76 of 79 
APACHE II Severity of Disease Classification System 
 
Glasgow Coma Score (GCS) 
(circle appropriate response) 
Eyes open (E) 
Motor response (M) 
Verbal-Response (V) 
4 – spontaneously 
6 – to verbal command 
5 – oriented and controversed 
3 – to verbal command 
5 – localizes to pain 
4 – confused and disoriented 
2 – to painful stimul 
4 – withdraw to pain 
3 – inappropriate words 
1 – no response 
3 – decorticate 
2 – incomprehensible sounds 
 
2 – decerebrate 
1 – no response 
 
1 – no response 
 
GLASGOW COMA SCORE+ = E + M + V 
 Subjects scoring 3 or 4 have an 85 % chance of dying or remaining vegetative, while scores above 11 indicate 5 
to 10 % likelihood of death or vegetative state and 85 % chance of moderate disability or good recovery. 
Intermediate scores correlate with proportional chances of subjects recovering. 
 
B. Age Points 
Age 
Points 
 
< 44 
0 
 
45 -54 
2 
 
55 – 64 
3 
 
65 – 74 
5 
 
> 75 
6 
 
 
Age points =   
__________ 
 
C. Chronic Health Points (CHE) 
If any of the 5 CHE categories is answered with yes give +5 points for nonoperative or emergency postoperative 
subjects, or +2 points for elective postoperative subjects  
Liver-Cirrhosis with Portal Hypertension (PHT) or encephalopathy  
Cardiovascular – NYHA Class IV angina at rest or with minimal self-care activities 
Pulmonary – chronic hypoxemia or hypercapnia or polycythemia or PHT > 40 mm Hg 
Kidney – chronic peritoneal dialysis or hemodialysis 
Immune – immune compromised host 
 
Chronic Health Points =  
____________ 
 
APACHE-II Score is sum of A+B+C 
APS points 
  A  
 
Age points 
+B  
 
Chronic Health Points 
+C  
 
 
Total APACHE-II Score = 
 
 
 
 
Source: Adapted from Knaus WA, Draper EA, Wagner DP, Zimmermann JE (1985).  
APACHE II: a severity of disease classification system. Critical Care Medicine 13 (10): 818-29 
 
 
 
 

 
 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________________________________________________________ 
 
 
CONFIDENTIAL 
 Trial Protocol – Version 4.2, 28-August 2019 
 
Page 77 of 79 
 
Appendix 3: SOFA Score 
 
SOFA Score 
 
 
1 
2 
3 
4 
Organ system 
 
Parameter 
 
 
 
 
Respiratory system 
PaO2 / FiO2 (mmHg) 
< 400 
< 300 
< 200 and mechanically 
ventilated 
< 100 and mechanically 
ventilated 
Nervous system 
 
Glasgow Coma Scale 
13-14 
10-12 
6-9 
< 6 
Cardiovascular system 
Mean arterial pressure OR 
administration of 
vasopressors required 
MAP < 70 mm/Hg 
dopamine < 5 µg/kg/min or 
dobutamine (any dose) 
dopamine > 5 µg/kg/min OR 
epinephrine < 0.1 µg/kg/min 
OR norepinephrine < 0.1 
µg/kg/min 
dopamine > 15 µg/kg/min 
OR epinephrine > 0.1 
µg/kg/min OR 
norepinephrine > 0.1 
µg/kg/min 
Liver 
 
Bilirubin (mg/dl) [µmol/L] 
1.2-1.9 [20-32] 
2.0-5.9 [33-101] 
6.0-11.9 [102-204] 
> 12.0 [> 204] 
Coagulation 
 
Platelets x103/µl 
< 150 
< 100 
< 50 
< 20 
Kidneys 
Creatinine (mg/dl) 
[µmol/l] (or urine output) 
1.2-1.9 [110-170] 
2.03-3.4 [171-299] 
3.5-4.9 [300-440] 
> 5.0 [> 440] 
(or< 200 ml/d) 
 
Use of vasopressors (dopamine, dobutamine, phenylephrine) in combination with catecholamine (adrenaline, noradrenaline*). 
* used equivalent to epinephrine and norepinephrin

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
 
 
CONFIDENTIAL 
 Trial Protocol – Version 4.2, 28-August 2019 
 
Page 78 of 79 
 
 
 
Appendix 4: IMP Body weight Adjustment 
 
IMP Bodyweight Adjustment 
 
Protocol Code: AdrenOSS-2 
 
Weight 
range 
IMP amount to use 
from EACH vial 
of the kit 
NaCl amount 
Weight 
range 
IMP amount to use 
from EACH vial 
of the kit 
NaCl amount 
kg 
ml 
ml 
kg 
ml 
ml 
50,0 - 50,4 
5 
40 
75,5 - 76,4 
7,6 
34,8 
50,5 - 51,4 
5,1 
39,8 
76,5 - 77,4 
7,7 
34,6 
51,5 - 52,4 
5,2 
39,6 
77,5  -78,4 
7,8 
34,4 
52,5 - 53,4 
5,3 
39,4 
78,5 - 79,4 
7,9 
34,2 
53,5 - 54,4 
5,4 
39,2 
79,5  -80,4 
8 
34 
54,5  -55,4 
5,5 
39 
80,5 - 81,4 
8,1 
33,8 
55,5 - 56,4 
5,6 
38,8 
81,5 - 82,4 
8,2 
33,6 
56,5 - 57,4 
5,7 
38,6 
82,5 - 83,4 
8,3 
33,4 
57,5  -58,4 
5,8 
38,4 
83,5- 84,4 
8,4 
33,2 
58,5 - 59,4 
5,9 
38,2 
84,5  -85,4 
8,5 
33 
59,5 - 60,4 
6 
38 
85,5  86,4 
8,6 
32,8 
60,5 - 61,4 
6,1 
37,8 
86,5 - 87,4 
8,7 
32,6 
61,5  -62,4 
6,2 
37,6 
87,5 - 88,4 
8,8 
32,4 
62,5 - 63,4 
6,3 
37,4 
88,5 - 89,4 
8,9 
32,2 
63,5 - 64,4 
6,4 
37,2 
89,5 - 90,4 
9 
32 
64,5 - 65,4 
6,5 
37 
90,5 - 91,4 
9,1 
31,8 
65,5  -66,4 
6,6 
36,8 
91,5 - 92,4 
9,2 
31,6 
66,5 - 67,4 
6,7 
36,6 
92,5 - 93,4 
9,3 
31,4 
67,5 - 68,4 
6,8 
36,4 
93,5 - 94,4 
9,4 
31,2 
68,5 - 69,4 
6,9 
36,2 
94,5 - 95,4 
9,5 
31 
69,5 - 70,4 
7 
36 
95,5 - 96,4 
9,6 
30,8 
70,5 - 71,4 
7,1 
35,8 
96,5 - 97,4 
9,7 
30,6 
71,5 - 72,4 
7,2 
35,6 
97,5 - 98,4 
9,8 
30,4 
72,5 - 73,4 
7,3 
35,4 
98,5 - 99,4 
9,9 
30,2 
73,5 - 74,4 
7,4 
35,2 
99,5- 120 
10 
30 
74,5  -75,4 
7,5 
35 
 
 
 

 
 
 
Protocol No. 
ADR-02 
EudraCT-No: 
2016-003883-38 
____________________________________________________________________________ 
 
 
 
 
 
CONFIDENTIAL 
 Trial Protocol – Version 4.2, 28-August 2019 
 
Page 79 of 79 
 
Appendix 5: Protocol History 
 
 
Version 
Date 
Comment 
 
 
 
Version 1.0 
 
01 December 2016 
Not submitted 
Version 2.0 
 
13 January 2017 
Submitted in Germany 
Version 2.1 
 
31 May 2017 
Not submitted 
Version 2.2 
 
14 June 2017 
Valid for Germany 
Version 3.0 
 
03 July 2017 
Valid for Belgium, The Netherlands 
Version 3.1 – France 
 
15 March 2018 
Valid for France 
Version 4.0 
 
19 March 2018 
Not submitted 
Version 4.1  
7-January 2019