Multicentre, Prospective, Randomized, Open-label, Assessor Blinded Study to Evaluate Granulox® Used as Adjunct Therapy to Defined Standard of Care vs. Defined Standard of Care for the Treatment of Predominantly Chronic Venous Leg Ulcers (VLUs)
Phase: NA
Conditions: Venous Leg Ulcer
Sponsor: Molnlycke Health Care AB



 
Clinical Investigation Plan (CIP) 
Document ID:  PD-568268 Rev: 02 
 
 
Title: CIP_Granulox01 
Page 2(38) 
Investigation Code Granulox01 
Final Version 
Approval date 2019-10-24 
 
Document template: F-167 Clinical Investigation Plan 
Rev: 11 
 
 
CLINICAL INVESTIGATION PLAN (CIP) SYNOPSIS 
 
INVESTIGATION TITLE:  
Multicentre, prospective, randomized, open-label, assessor blinded study to 
evaluate Granulox® used as adjunct therapy to defined standard of care vs. 
defined standard of care for the treatment of predominantly chronic venous leg 
ulcers (VLUs) 
 
Objectives 
Primary Objective 
The primary objective of this study is to compare wound healing of chronic venous leg ulcers 
(VLUs) managed using standard of care, with or without added Granulox®, at up to 20 weeks 
post therapy initiation. The main efficacy criteria is Confirmed Complete wound Closure (CCC). 
Secondary Objectives 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
Clinical Investigation Design 
This is a N = 254 patient, European, multi-centre, assessor blinded, 2-arm, randomised 
controlled study. The study will include multiple European countries (e.g. France, Germany, UK, 
Poland, Hungary, Croatia and Czech Republic), with approximately 2-7 clinics per country. 
The study will run with a two-phase set-up, with a 14 days run-in period and an up to 20 weeks 
treatment period starting with randomization and allocation of treatment. 
Endpoints 
Efficacy Endpoints 
The following efficacy endpoints will be assessed and evaluated in the study: 
• 
Confirmed Complete wound Closure (CCC); derived by two blinded quantifications of 
100% re-epithelialization by PictZar®, 15 days (+/- 3 days) apart. 
 
 
 
  

 
Clinical Investigation Plan (CIP) 
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Title: CIP_Granulox01 
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Document template: F-167 Clinical Investigation Plan 
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Safety Endpoints 
Adverse Events (AE) and Serious Adverse Events (SAE) will be collected in the study to 
measure safety associated to study treatments from ICF signature until study completion. AEs 
will be assessed according to criteria for Adverse Device Effect (ADE), SAE, Serious Adverse 
Device Effect (SADE), and Device Deficiencies (DD). 
Inclusion Criteria 
1. Signed consent to participate. 
2. No planned hospitalization in the forthcoming 20 weeks. 
3. Male or female (women of childbearing age must have an acceptable method of birth 
control). 
4. Age >18 years. 

 
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Document template: F-167 Clinical Investigation Plan 
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5. Recent (less than 12 months) doppler or duplex colour ultrasonography compatible with 
chronic venous insufficiency. 
6. ABPI (less than 3 months) ≥0.7 for both legs. If ABPI >1.4, then big toe pressure >60 
mmHg is required or an alternative measurement verifying normal distal arterial flow. 
7. At least one or more supra- or peri-malleolar leg ulcers and no foot ulcer or another 
chronic wound.  
8. In case of two ulcers, select ulcer with the highest PUSH score at randomization and treat 
the non-selected ulcer in the same way as ulcers in the control group.  
9. In case of two ulcers on the same limb, ensure that the distance between each ulcer is 3 
cm as measured from the margins of each ulcer that are closest to one another. 
10. Wound duration >8 weeks and <60 months. 
11. At randomization, the ulcer area should be 3 cm2 - 70 cm² and should not have decreased 
by more than 30% during the 2-week run-in period. 
12. Less than 50% of the wound area should be covered with fibrinous tissue at 
randomization and after debridement. 
13. Patients considered as compliant/adherent to the compression device during the run-in 
period (i.e. no more than 2 days without compression over the 2-week run-in period). 
14. No clinically significant comorbidities requiring the use of systemic steroids or any 
cytotoxic or immunosuppressive agents. 
Exclusion Criteria 
1. Infected ulcer according to the judgment of the investigator defined as any wound 
condition requiring the prescription or continuation of systemic antibiotic therapy at 
randomization. 
2. Circumferential wounds. 
3. Wound covered fully or partially by necrotic tissue (black tissue). 
4. Patients who will have problems following the protocol, especially compression therapy. 
5. Patients included in another on-going clinical investigation, or patients who have 
participated in a clinical investigation during the past 30 days. 
6. Wounds treated with dressings containing an active component (e.g. silver, nano-
oligosaccharide factor (NOSF), charcoal, chlorhexidine, iodine or ibuprofen) 14 days prior 
to study enrollment.  
7. Patient with a systemic infection not controlled by suitable antibiotic treatment. 
8. Current treatment with radiotherapy, chemotherapy, immunosuppressant drugs or high 
doses of oral corticosteroids (>10 mg Predinsolone or equivalent) if any.  
9. Patient with deep vein thrombosis within 3 months prior to inclusion. 
10. Known allergy/hypersensitivity to the ingredients of the dressings and/or Granulox®. 
11. Malignant wounds.  
12. Endovenous surgery planned or performed within the past 30 days. 

 
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13. Primary lymphoedema caused by congenital/developmental defect, i.e. Milroy's disease 
(congenital lymphedema), Meige's disease (lymphedema praecox), or Late-onset 
lymphedema (lymphedema tarda). 
Investigational Device and Comparator 
Granulox®  
Granulox® is a CE marked medical device manufactured by HÄLSA Pharma GmbH. It is a 
topical haemoglobin spray, which is designed to transport oxygen to the wound site. In the 
study, Granulox® will be used as intended, in addition to defined standard care. The following 
procedural steps should be followed: 
1. After wound bed preparation (e.g. debridement and cleaning) Granulox® should be sprayed 
onto the cleaned wound until the wound is completely coated with a thin film. That is, hold the 
nozzle about 5 to 10 cm from the wound and spray until the wound is completely coated with a 
thin film. 1 to 2 seconds are normally sufficient to cover a wound area of 2 x 3 cm. 
2. After Granulox® has been applied, the wound should be covered with a breathable wound 
dressing containing no active ingredients.  
3. Granulox® should be applied again every time the dressing is changed, but at least every 
three days.  
Standard of care:   
VLU standard of care treatment will be performed according to local practice requirements but 
reapplied at least every third day until complete epithelization. Standard of care will include the 
following:  
1. Wound bed preparation, i.e.:  
• 
Careful wound cleansing with water, saline, Ringer’s solution or preserved mechanical 
wound cleansers (i.e. polyhexanide (Prontosan, Lavanid), or hypochlorous (Granudacyn, 
Microdacyn) irrigation)  
• 
Wound debridement if necessary and as per standard of care (e.g. mechanical or 
surgical debridement) 
2. Application of appropriate breathable wound dressing which must be selected among the 
following categories and with regard to routine local care, level of exudate, and healing stage: 
• 
Hydrofiber: Exufiber, Aquacel Extra 
• 
Foam dressings: Mepilex XT, Mepilex Lite, Biatain Soft Hold, Biatain Silicone lite, 
Aquacel Foam, UrgoTul Lite  
• 
Wound Contact layer: Mepitel, Mepitel One, Adaptic Touch, UrgoTul 
• 
Superabsorbant: Mextra, Kiliniderm Superabsorber, Zetuvit Plus/Resposorb 
NB: Dressings including active components are not allowed. Within a clinic, there must be 
consistency in the choice in dressings, i.e. the same sequence of dressings should be kept for 
all the patients. 
3. Application of appropriate compression therapy which must be selected among the following 
categories and with regard to routine local care, level of exudate, and healing stage: 
• 
Multilayer compression: 
 
• 
Hosiery and stockings compression: 
 
 

 
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• 
Short stretch bandages 
NB: A multilayer compression system is preferred and consistency in compression therapy 
throughout the study is mandatory, unless patient compliance issues necessitate change. 
Patients must be withdrawn from study in case of severe non-compliance to compression 
therapy.  

 
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Document template: F-167 Clinical Investigation Plan 
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TABLE OF CONTENTS 
1. INTRODUCTION .................................................................................................... 12 
2. OBJECTIVES AND HYPOTHESES ....................................................................... 12 
2.1 
Primary Objective...................................................................................................................................... 12 
2.2 
Secondary Objectives .............................................................................................................................. 12 
3. INVESTIGATION PLAN AND PROCEDURES ...................................................... 13 
3.1 
Clinical Investigation Design ................................................................................................................. 13 
3.2 
Procedures and Assessments ............................................................................................................... 13 
3.2.1 
Flow Chart ................................................................................................................................................ 14 
3.3 
Efficacy and Safety ................................................................................................................................... 16 
3.3.1 
Subject Characteristics .......................................................................................................................... 16 
3.3.2 
Primary Efficacy Measurement and Variable ..................................................................................... 16 
3.3.2.1 
Confirmed Complete wound Closure (CCC) .................................................................................. 16 
3.3.3 
Secondary Efficacy Measurements and Variables ............................................................................ 16 
3.3.3.1 
Healing time......................................................................................................................................... 16 
3.3.3.2 
Wound status ...................................................................................................................................... 16 
3.3.3.3 
Wound Area Regression (WAR) ...................................................................................................... 17 
3.3.3.4 
Possible Complete wound Closure (PCC) ...................................................................................... 17 
3.3.3.5 
Healing trajectories ............................................................................................................................. 17 
3.3.3.6 
Pressure Ulcer Scale for Healing (PUSH) ...................................................................................... 17 
3.3.3.7 
Blind assessment of wound healing ................................................................................................ 17 
3.3.4 
Patient Reported Outcomes (PROs) .................................................................................................... 17 
3.3.5 
Acceptability and compliance ................................................................................................................ 18 
3.3.6 
Cost-effectiveness .................................................................................................................................. 18 
3.3.7 
Safety Measurements and Variables ................................................................................................... 18 
3.3.8 
Schedule of Assessment ....................................................................................................................... 19 
3.4 
Subject Population ................................................................................................................................... 21 
3.4.1 
Inclusion Criteria ..................................................................................................................................... 21 
3.4.2 
Exclusion Criteria .................................................................................................................................... 21 
3.4.3 
Method of Assigning Subjects to Treatment Groups ......................................................................... 22 
3.4.4 
Withdrawal of Subjects from Treatment or Assessment ................................................................... 22 
3.5 
Investigational Device .............................................................................................................................. 23 
3.5.1 
Summary description of the Investigational Device(s) and Comparator(s) .................................... 23 
3.5.1.1 
Investigational Device ........................................................................................................................ 23 
3.5.1.2 
Comparator .......................................................................................................................................... 24 
3.5.2 
Labelling ................................................................................................................................................... 24 
3.5.3 
Device Accountability ............................................................................................................................. 24 
3.5.4 
Storage conditions .................................................................................................................................. 25 
3.6 
Concomitant Treatments......................................................................................................................... 25 
3.7 
Risks and benefits of the Investigational Device and clinical investigation ............................. 25 
4. DATA QUALITY ASSURANCE .............................................................................. 26 

 
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4.1 
Monitoring, Audits and Inspections ..................................................................................................... 26 
4.2 
Training of Staff ......................................................................................................................................... 26 
4.3 
Data Management ..................................................................................................................................... 26 
4.3.1 
Data Retention ........................................................................................................................................ 27 
5. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE AND 
STATISTICAL ANALYSES ........................................................................................... 27 
5.1 
Determination of Sample Size ............................................................................................................... 27 
5.1.1 
Independent interim analysis review committee (IARC) ................................................................... 28 
5.1.2 
Sample size re-estimation ..................................................................................................................... 28 
5.2 
Statistical Analyses .................................................................................................................................. 28 
5.2.1 
Definition of Study Populations ............................................................................................................. 28 
5.2.2 
General statistical methodology............................................................................................................ 28 
5.2.2.1 
Primary efficacy analysis ................................................................................................................... 29 
5.2.2.2 
Secondary efficacy analyses ............................................................................................................ 29 
5.2.2.3 
Sub-group analyses ........................................................................................................................... 29 
5.2.2.4 
Interim analysis ................................................................................................................................... 30 
5.2.2.5 
Statistical Analysis Plan (SAP) ......................................................................................................... 30 
6. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ............................... 30 
7. DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN ............................. 30 
8. STATEMENTS OF COMPLIANCE ......................................................................... 31 
8.1 
Ethics ........................................................................................................................................................... 31 
8.1.1 
Ethics review............................................................................................................................................ 31 
8.1.2 
Ethical Conduct of the Investigation ..................................................................................................... 31 
8.1.3 
Subject Information and Consent Form ............................................................................................... 31 
8.2 
Regulatory and standards ...................................................................................................................... 31 
8.2.1 
Regulatory review ................................................................................................................................... 31 
8.2.2 
Standards and other ............................................................................................................................... 31 
8.2.3 
Subject Data Protection ......................................................................................................................... 31 
8.3 
SUBJECT PROTECTION PROCEDURES............................................................................................. 32 
8.3.1 
Procedures in Case of Medical Emergency ........................................................................................ 32 
8.3.2 
Insurance ................................................................................................................................................. 32 
9. INVESTIGATION TIMETABLE AND TERMINATION ............................................ 32 
10. 
PRINCIPAL INVESTIGATOR(S) AND INVESTIGATION ADMINISTRATIVE 
STRUCTURE ................................................................................................................ 32 
11. 
DEFINITIONS AND PROCEDURES FOR REPORTING OF ADVERSE EVENT, 
ADVERSE DEVICE EFFECT, SERIOUS ADVERSE EVENT, SERIOUS ADVERSE 
DEVICE EFFECT AND DEVICE DEFICIENCY ............................................................. 32 

 
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Document template: F-167 Clinical Investigation Plan 
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12. 
PUBLICATION POLICY ...................................................................................... 35 
13. 
LITERATURE REVIEW AND REFERENCES ..................................................... 35 
 
 
 

 
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LIST OF APPENDICES 
Appendix A  F-449 Clinical Investigation Plan Appendix A, Core Signatures 
 
F-583 Clinical Investigation Plan Principal Investigator Signature 
Appendix B  Master Subject  Information and Consent Form 
Appendix C F-542 All variables to be obtained during the Investigation 
Appendix D Assessment tools/questionnaires; PUSH, Wound-QoL, EQ-5D-5L, and NRS.  
Appendix E Instructions for use Granulox® 
LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CCC 
Confirmed Complete wound Closure 
CIP 
Clinical Investigation Plan 
CP 
Conditional Power 
CRF 
Case Report Form 
CVI 
Chronic Venous Insufficiency 
DD 
Device Deficiency 
EC 
Ethics Committee 
EQ-5D-5L 
EuroQol.org - 5 dimensions - 5 level instrument to describe and value health  
FAS 
Full Analysis Set 
HRQoL 
Health-Related Quality of Life 
IARC 
Interim analysis review committee 
IRB 
Institutional Review Board 
NRS 
Numerical Rating Scale 
PCC 
Possible Complete wound Closure 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PUSH 
Pressure Ulcer Scale for Healing 
RA 
Regulatory Authority 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
WAR 
Wound Area Regression 
50WAR 
50% Wound Area Regression 

 
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90WAR 
90% Wound Area Regression 
VLU 
Venous Leg Ulcer 
Wound-QoL Wound Quality of Life questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Document template: F-167 Clinical Investigation Plan 
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1. INTRODUCTION 
Venous leg ulcer (VLU) is a severe clinical manifestation of chronic venous insufficiency (CVI) 
and is responsible for about 70% of chronic ulcers in the lower limbs.1 VLUs are a major health 
problem because of their high prevalence and associated high cost of care.2 
Compression therapy is the most widely used conservative treatment for VLUs as the 
application of external pressure to the calf muscle raises the interstitial pressure resulting in 
improved venous return and reduction in the venous hypertension. Published healing rates of 
VLUs obtained with compression therapy vary widely from 40-88%.3-6 Over a quarter of patients 
with VLUs fails to heal despite standard of care including compression therapy, and those who 
do heal often take 6 months or longer.7 Risk factors, such as wound age and size, have been 
identified to be correlated with the failure of VLUs to heal, showing VLUs present for at least 5 
months prior to appropriate management and whose area is 10 cm² or larger, have less than 
20% chance to heal at 24 weeks.8  
Granulox® is a haemoglobin spray that can be added to standard of care of chronic wounds. It 
is expected to improve the tissue repair process by increasing tissue oxygen supply. In a 
previous randomized controlled trial (RCT) comparing Granulox® to a control group in VLUs, a 
significant mean reduction of the wound surface area was observed at 13 weeks with a 
decrease of 53.4% (p<0.0001) for Granulox® treated wounds.9 Use of Granulox® was 
associated with significant pain score reduction compared to standard wound care alone thus 
improving patients´ quality of life.9 Furthermore, use of Granulox® as an adjunct therapy led to a 
significant reduction of slough and recurrence compared with standard care alone.9 
This study is intended to assess the healing benefits of Granulox® therapy in combination with 
standard of care for the management of chronic VLUs over a period of 20 weeks, compared to 
VLU standard of care treatment without Granulox®.  
2. OBJECTIVES AND HYPOTHESES 
2.1 Primary Objective 
The primary objective of this study is to compare wound healing of chronic VLUs managed 
using standard of care, with or without added Granulox®, at up to 20 weeks post therapy 
initiation. The main efficacy criteria is Confirmed Complete wound Closure (CCC). 
2.2 Secondary Objectives 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Document template: F-167 Clinical Investigation Plan 
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3. INVESTIGATION PLAN AND PROCEDURES 
3.1 Clinical Investigation Design 
This is a N = 254 patient, European, multi-centre, assessor blinded, 2-arm, randomised 
controlled study. The study will include multiple European countries (e.g. France, Germany, UK, 
Poland, Hungary, Croatia and Czech Republic), with approximately 2-7 clinics per country. 
The study will run with a two-phase set-up, with a 14 days run-in period and an up to 20 weeks 
treatment period starting with randomization and allocation of treatment. 
3.2 Procedures and Assessments 
This study starts with a 14 days run-in period to verify two of the required inclusion criteria, i.e. 
that the wound area does not decrease more than 30% during run-in period and compliance to 
compression therapy part of standard of care.  
After the 14-days run-in period during which time patients will receive standard of care, (D-14 to 
D0) patients meeting the selection criteria will be randomly allocated (on D0) to experimental 
(i.e. standard of care plus Granulox®) or control (i.e. standard of care only) groups. 
Randomization will be stratified on study site, wound duration (<5 months; ≥5 months), and 
wound area after run-in period (<10; ≥10 cm²), to ensure equal distribution of test and control in 
these sub-groups. This, as wound duration and wound area may significantly impact outcomes, 
and as minor variations in standard of care between study sites may still be present in spite of 
the measures taken to ensure standardization. See details on standardization of standard of 
care in Section 3.5.  
Each patient will be followed to wound closure, or up to 20 weeks (whichever occurs first), with 
scheduled clinical visits at 1 week (W1), 4 weeks (W4), 8 weeks (W8), 12 weeks (W12), 16 
weeks (W16), and 20 weeks (W20). Additional visits are allowed in between the per-protocol 
scheduled visits. If suspected wound closure occurs at any point during the study, a final 
assessment visit will be scheduled 15 days (±3 days) subsequent to the suspected wound 
closure observation to verify CCC. If wound closure is confirmed, the study is completed for this 
patient. If wound closure is not confirmed, the patient should continue to be followed according 
to the schedule of assessments. See study Flow Chart at Section 3.2.1 and Schedule of 
Assessment at section 3.3.8. 
In between clinical visits, wound management will follow standard of care. Home visits will be 
performed by study nurses who are responsible for changing dressing, reapplying Granulox® 
(for patients randomized to the treatment group only), and reapplying compression therapy. See 
details in Section 3.5.1.1. Home visits frequency will follow local practice requirements but must 
take place at least every 3rd day until epithelization is complete. The study nurse will record 
information in the patient-specific diary. If considered necessary, nurses can ask for an 
additional patient visit to the investigating centre. This is mandatory at suspected complete 
wound closure. 
If at any time, a wound graft is required (it usually requires at 24-48 hours hospitalization), study 
will not be considered as completed and patients will still be followed according to the schedule 
of assessments (even if experimental treatment is no longer applied) up to CCC occurrence or 
up to W20 (whichever occurs first). 
The study will be stopped before W20 for a given patient in the event of: 
• 
Consent withdrawal 
• 
Impossibility to follow the patient (i.e. lost to follow-up) 

 
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NB. Wound management as per standard of care, at least every 3rd day until complete epithelization, will take place 
between visits D0-W20. Extra clinical visits between visits D0-W20 are allowed and should be issued in the event of 
suspected wound closure. 
 
 

 
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3.3 Efficacy and Safety 
3.3.1 Subject Characteristics 
Demography and background data with potential impact on wound healing will be collected at 
the initial visit, i.e. :  
• 
Date of birth 
• 
Gender 
• 
Ethnicity 
• 
Mobility 
• 
Vital signs (e.g. height/weight) 
• 
Social profile (e.g. autonomy, lifestyle, social support) 
• 
Relevant medical history (general and with regard to venous disease/VLU) 
• 
Relevant surgical history (general and with regard to venous disease/VLU) 
• 
Current wound management treatment 
• 
Current wound status 
3.3.2  Primary Efficacy Measurement and Variable 
Digital photographs, taken after wound bed preparation at each clinical visit, will be used as a 
basis for the primary and secondary efficacy measurements and variables.    
3.3.2.1 
Confirmed Complete wound Closure (CCC) 
CCC is the primary variable and main efficacy criterion. It is defined as an blinded assessment 
and observation of 100% re-epithelialization, confirmed by a second visit 15 days later (+/- 3 
days). If a wound graft is required, patients will be followed to observation of CCC. 
Blinded quantification of each wound picture will be made using PictZar® Digital Planimetry 
Software. 
CCC will be derived from two measurements of 100% re-epithelialization by PictZar®, 15 days 
(+/- 3 days) apart.   
3.3.3 Secondary Efficacy Measurements and Variables 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 

 
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3.3.7 Safety Measurements and Variables 
Adverse Events (AE) and Serious Adverse Events (SAE) will be collected in the study to 
measure safety associated to study treatments from ICF signature until study completion. 
 
The definition of AE, Adverse Device Effect (ADE), SAE, Serious Adverse Device Effect 
(SADE), and Device Deficiencies (DD) and procedures for reporting SAE and SADE and DD 
that could have led to a SADE are presented in section 11 of this CIP. All AE, ADE, SAE, SADE 
and DD must also be recorded in the appropriate section of the CRF. It is of utmost importance 
that all staff involved in the clinical investigation is familiar with the content of section 11. It is the 
responsibility of the Principal Investigator to ensure this. 

 
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3.4 Subject Population 
The study population is comprised of N = 254 adult patients presenting with VLUs who meet the 
study’s inclusion and exclusion criteria. Approximately equal proportions of male and female 
patients will be enrolled in the study.   
3.4.1 Inclusion Criteria 
All of the following criteria need to be fulfilled for inclusion in the study:  
 
1. Signed consent to participate. 
2. No planned hospitalization in the forthcoming 20 weeks. 
3. Male or female (women of childbearing age must have an acceptable method of birth 
control). 
4. Age >18 years. 
5. Recent (less than 12 months) doppler or duplex colour ultrasonography compatible with 
chronic venous insufficiency. 
6. ABPI (less than 3 months) ≥0.7 for both legs. If ABPI >1.4, then big toe pressure >60 
mmHg is required or an alternative measurement verifying normal distal arterial flow. 
7. At least one or more supra- or peri-malleolar leg ulcers and no foot ulcer or another 
chronic wound.  
8. In case of two ulcers, select ulcer with the highest PUSH score at randomization and treat 
the non-selected ulcer in the same way as ulcers in the control group.  
9. In case of two ulcers on the same limb, ensure that the distance between each ulcer is 3 
cm as measured from the margins of each ulcer that are closest to one another. 
10. Wound duration >8 weeks and <60 months. 
11. At randomization, the ulcer area should be 3 cm2 - 70 cm² and should not have decreased 
by more than 30% during the 2-week run-in period. 
12. Less than 50% of the wound area should be covered with fibrinous tissue at 
randomization and after debridement. 
13. Patients considered as compliant/adherent to the compression device during the run-in 
period (i.e. no more than 2 days without compression over the 2-week run-in period). 
14. No clinically significant comorbidities requiring the use of systemic steroids or any 
cytotoxic or immunosuppressive agents.  
3.4.2 Exclusion Criteria 
If any of the following criteria applies, the patient will be excluded from participation:  
1. Infected ulcer according to the judgment of the investigator defined as any wound 
condition requiring the prescription or continuation of systemic antibiotic therapy at 
randomization. 
2. Circumferential wounds. 

 
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3. Wound covered fully or partially by necrotic tissue (black tissue). 
4. Patients who will have problems following the protocol, especially compression therapy. 
5. Patients included in another on-going clinical investigation, or patients who have 
participated in a clinical investigation during the past 30 days. 
6. Wounds treated with dressings containing an active component (e.g. silver, nano-
oligosaccharide factor (NOSF), charcoal, chlorhexidine, iodine or ibuprofen) 14 days prior 
to study enrollment.  
7. Patient with a systemic infection not controlled by suitable antibiotic treatment. 
8. Current treatment with radiotherapy, chemotherapy, immunosuppressant drugs or high 
doses of oral corticosteroids (>10 mg Predinsolone or equivalent) if any.  
9. Patient with deep vein thrombosis within 3 months prior to inclusion. 
10. Known allergy/hypersensitivity to the ingredients of the dressings and/or Granulox®. 
11. Malignant wounds.  
12. Endovenous surgery planned or performed within the past 30 days. 
13. Primary lymphoedema caused by congenital/developmental defect, i.e. Milroy's disease 
(congenital lymphedema), Meige's disease (lymphedema praecox), or Late-onset 
lymphedema (lymphedema tarda). 
3.4.3 Method of Assigning Subjects to Treatment Groups 
At initial screening and after an informed consent signature is obtained (day-14), an enrolment 
number is assigned to each patient who agrees to take part in the study. Following the run-in 
period, and after all eligibility criteria have been confirmed (day 0), randomisation is initiated and 
treatment allocated to either standard of care only (control group) or standard of care and 
Granulox® (test group).  
Randomisation is centralized and stratified according to: 
• 
Wound duration (<5 months; ≥5 months) 
• 
Wound area after run-in period (<10 cm²; ≥10 cm²) 
• 
Country 
3.4.4 Withdrawal of Subjects from Treatment or Assessment 
Subjects are free to discontinue participation in the study at any time, and without prejudice to 
further treatment. Subjects who withdraw from the study should always be asked about the 
reason(s) for their discontinuation and about the presence of any Adverse Event/Adverse Device 
Effect or Device Deficiency and, if possible, be assessed by the Principal Investigator. Each 
reported Adverse Event/Adverse Device Effect will be followed up.  
Subjects may be withdrawn from the study at any time, at the discretion of the Principal 
Investigator. 
Incorrectly enrolled or randomised subjects will be withdrawn from the study. A subject may, 
however, continue study involvement under special circumstances (i.e. if continuation of study-
related treatment or follow-up actions are necessary for the subject’s safety and well-being, or if 
only a follow-up period remains, and the continuation of the subject’s study involvement is not 
expected to be associated with any risk or discomfort for the subject). 

 
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3.5 Investigational Device 
3.5.1 Summary description of the Investigational Device(s) and Comparator(s) 
3.5.1.1 
Investigational Device 
The investigational device is Granulox®, a topical haemoglobin spray, which is designed to 
transport oxygen to the wound site. Granulox® is intended to increase oxygen supply to the 
wound. Granulox is a CE marked medical device manufactured by HÄLSA Pharma GmbH 
(report number: 12911FS06F). It is an innovative product for the treatment of chronic wounds, 
such as venous leg ulcer, arterial leg ulcer, mixed leg ulcer, diabetic foot ulcers, secondary 
healing of surgical wounds and pressure sores. Granulox can also be used on sloughy and 
infected wounds. 
 
The mode of action is that once Granulox® is sprayed, the haemoglobin starts to bind oxygen 
from the atmosphere and the process of oxygen transportation begins. Oxygen promotes the 
formation of new blood vessels and subsequently the growth of new skin. Granulox provides the 
wound with the required oxygen by means of diffusion. The active substance haemoglobin 
supplies the base of the wound with external oxygen. The improved oxygen supply to the base 
of the wound supports wound healing.  
Granulox® should not be used simultaneously with topical medicines for your wound, such as 
application of local antibiotics, as interactions have not yet been studied sufficiently. 
Disinfectants are known to impair the efficacy of Granulox®. Therefore, after application of a 
disinfectant, the area must be subsequently flushed thoroughly with a physiological solution. 
Thorough flushing with a physiological solution is necessary after use of proteolytic (enzymatic) 
debridement. 
In this study, Granulox® will be used as intended, in combination with an appropriate foam or 
wound contact layer wound dressing and in addition to defined standard care. 
Granulox®:  
The instructions for use for Granulox® should be consulted before initiating treatment. The 
following procedural steps should be followed: 
1. After wound bed preparation (e.g. debridement and cleaning) Granulox® should be 
sprayed onto the cleaned wound until the wound is completely coated with a thin film. 
That is, hold the nozzle about 5 to 10 cm from the wound and spray until the wound is 
completely coated with a thin film. 1 to 2 seconds are normally sufficient to cover a 
wound area of 2 x 3 cm. 
2. After Granulox® has been applied, the wound should be covered with a breathable 
wound dressing containing no active ingredients.  
3. Granulox® should be applied again every time the dressing is changed, but at least 
every three days.  
Defined standard of care:   
VLU standard of care treatment will be performed according to local practice requirements but 
reapplied at least every third day until complete epithelization. Standard of care will include the 
following:  
1. Wound bed preparation, i.e.:  

 
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• 
Careful wound cleansing with saline/water or Ringer’s solution or preserved mechanical 
wound cleansers (i.e. polyhexanide (Prontosan, Lavanid), or hypochlorous (Granudacyn, 
Microdacyn) irrigation)  
• 
Wound debridement if necessary and as per standard of care (e.g. mechanical or 
surgical debridement) 
2. Application of appropriate breathable wound dressing which must be selected among the 
following categories and with regard to routine local care, level of exudate, and healing stage: 
• 
Hydrofiber: 
 
• 
Foam dressings: 
 
  
• 
Wound Contact layer: 
 
• 
Superabsorbant: 
 
NB: Dressings including active components are not allowed. Within a clinic, there must be 
consistency in the choice in dressings, i.e. the same sequence of dressings should be kept for 
all the patients. 
3. Application of appropriate compression therapy which must be selected among the following 
categories and with regard to routine local care, level of exudate, and healing stage: 
• 
Multilayer compression: 
 
• 
Hosiery and stockings compression: 
 
 
• 
Short stretch bandages 
 
NB: A multilayer compression system is preferred and consistency in compression therapy 
throughout the study is mandatory, unless patient compliance issues necessitate change. 
Patients must be withdrawn from study in case of severe non-compliance to compression 
therapy.  
All performed local care has to be documented in patients’ medical records. 
3.5.1.2 
Comparator 
The control group will use the same defined standard of care as the treatment group (see 
section 3.5.1.1) but without Granulox®. 
3.5.2 Labelling 
3.5.3 Device Accountability 
Mölnlycke and the Principal Investigator will keep records documenting the location of all 
investigational devices from shipment of investigational devices to the investigation site until 
return. This will be documented by a shipment log stored by Mölnlycke and in a device 
accountability log at the investigation site. The device accountability log at each investigational 
site will include information on; date, serial and batch number of delivered devices, date and 
subject identification for used devices, date, serial and batch numbers of devices returned. 
The Site Monitor will verify the accountability process at each site during the site monitoring 
visits. 

 
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3.5.4 Storage conditions 
During use, Granulox® can be stored at room temperature (max. 25 °C) until it is empty or up to 
6 weeks. For long-term storage, place Granulox® in a refrigerator at temperatures from 2 °C to 
8 °C.  
Storage conditions for other components used in the study should follow instructions for use 
specific to each component. 
3.6 Concomitant Treatments 
Medication and treatment, which is considered necessary for the subject’s safety and well-
being, may be given at the discretion of the Principal Investigator. All concomitant medication 
and relevant treatment must be recorded in the appropriate section of the Case Report Form 
(CRF).  
The following restrictions and specific considerations apply for the study: 
• 
No use of local antiseptics will be authorized. 
• 
Peri-wound skin cares may use emollients if necessary. 
• 
Use of antibiotics and analgesics must be recorded on the appropriate CRF during the 
study. 
3.7 Risks and benefits of the Investigational Device and clinical 
investigation 
The following events have been identified as anticipated effects of Granulox®: 
• 
In the overall evaluation of safety, the use of Granulox® for the treatment of chronic 
hypoxic wounds with poor blood supply as well of burn wounds and infected or 
critically colonized wounds is found to be safe and well-tolerated.14-18 
• 
Tests for cytotoxicity, sensitization, irritation and subcutaneous reactivity did not 
identify any hazardous properties and thus confirmed the safety of the topical 
haemoglobin spray.19 Tissue tolerability has also been tested using the semi-in-vivo 
method HET-CAM (hen's egg test on the chorioallantoic membrane) without any 
signs of irritation.20 The risk of inhaling aerosols when using Granulox® spray has 
been evaluated by Holzer et al. who concluded that there is no risk of inhaling 
nanoparticles or being exposed to harmful concentrations and that all ingredients can 
be degraded and excreted by the human body through natural pathways.21 
• 
Only one of the reviewed publications from previous clinical trials reported of adverse 
events (one event of infection) associated with topical administration of Granulox®.18 
The majority of the evaluated publications explicitly stated no occurrence of adverse 
events.e.g.15,22,23 
• 
Within the framework of the clinical investigation carried out at the Hospital Civil de 
Ciudad Victoria by the Mexican health government, the haemoglobin spray was 
applied almost 1,500 times on chronic wounds. In all cases, the spray was well 
tolerated and there were no undesirable events that might have resulted due to the 
application of the haemoglobin spray. In addition, Granulox® was rated as very easy 
to handle from the participants of the clinical trials under review.17,24 
The possible benefits associated with Granulox® are as follows:   
• 
Higher healing rate / wound closure. 
• 
Pain reduction. 

 
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Reduced recurrence of slough.  
• 
Improved health-related quality of life.  
In summary, the single ingredients of Granulox® are established as safe for use in topical 
applications and the general safety and tolerability of Granulox® is assessed as very good. 
4. DATA QUALITY ASSURANCE 
4.1 Monitoring, Audits and Inspections 
During the investigation, the Site Monitor will have regular contacts with the investigation site. 
These contacts will include monitoring visits, conducted in accordance with a clinical 
investigation specific monitoring plan, to confirm that the facilities remain adequate to specified 
standards and that the investigation site team is carrying out the procedure as stated in the 
Clinical Investigation Plan and supporting the Principal Investigator appropriately. All data must 
be accurately recorded in the CRF. Source data verification (a comparison of data in the CRF 
with the subject’s hospital/practice and other records at the investigation site) with direct access 
to records will also be performed. 
The Site Monitor or other Mölnlycke personnel will be available between visits if the Principal 
Investigator or other staff at the site needs information and/or advice. 
Authorised representatives of Mölnlycke and/or a Regulatory Authority (RA) and/or the Ethics 
Committee (EC)/Institutional Review Board (IRB) may visit the investigation site to perform 
audits/inspections, including source data and informed consent verification. 
4.2 Training of Staff 
The Principal Investigator will ensure that appropriate training relevant to the investigation is 
given to the medical, nursing and other staff at the sites involved and that new information of 
relevance to the performance of this investigation is forwarded to the staff involved in a timely 
manner. 
4.3 Data Management 
The Data Management process includes all activities related to data handling regarding: 
• 
Compilation of a CRF  
• 
Randomisation 
• 
Set-up of eCRF/database  
• 
Specification of on-line checks 
• 
Data entry/data editing 
• 
Export of data from eCRF/database to analysis software 
• 
Creation of post-entry checks and listings 
• 
Reconciliation of Serious Adverse Event  (SAE), Serious Adverse Device Effect 
(SADE), Adverse Devise Effect (ADE) and Device Deficiency (DD) 
• 
Clean-file process including execution of post-entry checks and listings 
• 
Post clean-file tasks 
A web based electronic CRF system, will be used to capture data in this investigation. The 
eCRF system complies with FDA Title 21 CFR part 11 (ER/ES) requirement. 
eCRF training will be given to appropriate personnel at initiation of the investigation site(s).  

 
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The Principal Investigator and other authorized personnel at the site(s) will perform data entry. 
When entering data on-line checks are incorporated for consistency and validation. Support will 
be provided for system user questions. 
When data has been entered, authorized personnel at Mölnlycke can immediately view the 
data, send queries if necessary and lock eCRF pages when correct data entry has been 
verified.  
Photos will be uploaded in the eCRF and are marked with the subject code. Uploaded photos 
shall not contain any information that can reveal the identity of the subject. All uploaded photos 
will be reviewed by personnel at Mölnlycke and stored in the company database. All data 
entered in the eCRF will be encrypted. The physical database will be stored in Sweden. 
Programs for post-entry checks and data listings will be created and executed for validation of 
data.  
Authorized personnel at Mölnlycke will check each finalised eCRF for completeness so that 
there are no unexplainable empty fields in the eCRF. This is done in order to prevent 
incomplete data entry. 
A clean-file meeting will be held prior to database lock. All decisions on the evaluability of the 
data from each individual subject will be made and documented before locking the database for 
the statistical analysis. 
4.3.1 Data Retention 
The medical records of clinical investigation subjects must be retained in accordance with local 
legislation and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
The Principal Investigator must retain all clinical investigation records during the clinical 
investigation and for the period required by the applicable regulatory requirements or for at least 
20 years after the premature termination or completion of the clinical investigation, whichever is 
the longer. The Principal Investigator must take measures to prevent accidental or premature 
destruction of these documents. The Principal Investigator should contact Mölnlycke prior to 
destruction of any records or reports pertaining to the clinical investigation in order to ensure 
they no longer need to be retained. In addition, if the Principal Investigator leaves the hospital, 
he/she should provide Mölnlycke with the name and address of the person who will look after 
and be responsible for the clinical investigation-related records. If the records will be transferred 
to another person/party, the transfer must be documented at the investigation site or at 
Mölnlycke. 
5. STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE AND STATISTICAL ANALYSES 
5.1 Determination of Sample Size 
 
 
 
  
 
 
 
 

 
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5.1.1 Independent interim analysis review committee (IARC) 
An independent interim analysis review committee (IARC) will be appointed to follow the safety 
monitoring and sample size adjustment of the study. 
5.1.2 Sample size re-estimation 
After approximately 110 patients have completed the study, the IARC will perform an unblended 
interim analysis on the primary efficacy variable CCC incidence. From this analysis, the IARC 
will calculate the conditional power (CP). 
The IARC will form a recommendation to either terminate, continue, or adjust sample size,  
based on the following guidelines: 
• 
Futility: If CP ≤30%, then terminate the study for futility. 
• 
Promising outcome: If 30%< CP% <80%, then adjust the sample size so that CP = 0.80. 
The sample size could be increased to maximum 600 subjects. 
• 
Favorable outcome: If CP% >80%, then do not adjust the sample size. 
The sample size re-estimation analysis will not require adjustments of the final primary statistical 
analysis.28 
5.2 Statistical Analyses 
5.2.1 Definition of Study Populations 
Full Analysis Set (FAS): All randomized patients with at least one ordinary follow-up visit will be 
included in the FAS. The final decisions regarding the FAS population will be taken at the Clean 
File meeting before database lock. 
Per-Protocol (PP) Population: All patients in FAS with no significant protocol violations will be 
included in the PP population. The final decisions regarding the PP population will be taken at 
the Clean File meeting before database lock. 
Safety Population: All enrolled subjects who received at least application of randomized 
investigational product (IP) will be included in the safety population. 
5.2.2 General statistical methodology 
This study will use confirmative and explorative analyses. All confirmative analyses will be 
based on FAS. Confirmative analysis of primary variables will also be performed based on PP. 
Imputing of missing data in outcome variables will generally be used. For confirmative analyses, 
multiple imputations with Fully Conditional Specification (FCS) will be used for primary efficacy 
analysis. Confirmative secondary analysis and exploratory analyses will use stochastic 
imputation with FCS. Missing data on demography and background variables will not be 
replaced.  
The study include testing analysis of the primary variable and sequential testing of selected 
secondary variables for confirmative analysis.  

 
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The study utilized stratified randomization based on site, wound size, and wound duration. This 
is reflected by a stratified primary analysis adjusted for these variables. For adjusted 
comparison between the two randomized groups, multivariable logistic regression will be used 
for dichotomous variables and analysis of covariance for continuous variables. 
Continuous variable will be described with mean, SD, median, minimum and maximum and 
categorical variables with numbers and percentages. For unadjusted and adjusted analyses, 
mean differences with 95% CI will be calculated. For dichotomous variables, for descriptive 
purpose, relative risk with 95% CI will also be calculated. All significance analyses will be two-
sided and conducted at the 5% significance level.  
For unadjusted comparison between the two randomized groups Fisher’s exact test will be used 
for dichotomous variables, Fisher’s non-parametric permutation test for continuous variables, 
Mantel-Haenszel chi-square test for ordered categorical variables, and Chi-Square test for non-
ordered categorical variables. 
Applicable descriptive statistics and non-parametric statistical test methods are used to describe 
and explore secondary variables. For explorative analyses, no multiple-test considerations are 
made. For time to endpoint outcomes the Kaplan-Meier model and logrank test are used 
unadjusted and Cox proportional hazard model for adjusted analyses. 
5.2.2.1 
Primary efficacy analysis 
The primary analysis of comparison of CCC between the two randomized groups will be using 
binary logistic model at significance level 0.05, on FAS with multiple imputation including the 
following covariates: 
1. Country (as fixed effect) 
2. Wound duration (<5 months; ≥5 months) 
3. Wound area after run-in period (<10 cm2; ≥10 cm2) 
Sensitivity analysis will be comparison between the two randomized groups unadjusted on CCC 
with Fisher’s exact test without imputation. 
5.2.2.2 
Secondary efficacy analyses 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
5.2.2.3 
Sub-group analyses 
Preplanned sub-group analyses will be performed for the primary analysis variables on the 
following variables:  

 
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- Country 
- Wound duration at inclusion (<5 months; ≥5 months) 
- Wound area at inclusion (<10 cm2; ≥10 cm2) 
Additional explorative sub-group analyses will be defined in SAP.  
5.2.2.4 
Interim analysis 
Interim analyses will only be performed by the IARC group. 
5.2.2.5 
Statistical Analysis Plan (SAP) 
A Statistical Analysis Plan (SAP) will be written with detailed description of all statistical 
analysis. 
6. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
No change in the clinical investigation procedure will be implemented without the mutual 
agreement of the Principal Investigator and Mölnlycke. 
An amendment to the Clinical Investigation Plan may require notification or approval from an 
EC/IRB and, in many countries, also the RA before implementation. Local requirements must be 
followed. 
Mölnlycke will distribute Clinical Investigation Plan amendments to the Principal Investigator 
who is responsible for the distribution of these documents to the EC/IRB and staff concerned at 
his/her site. The distribution of these documents to the RA will be handled according to local 
practice. 
7. DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN 
A deviation is a failure to follow, intentionally or unintentionally, the requirements of the Clinical 
Investigation Plan. Every effort should be made to comply with the requirements of the Clinical 
Investigation Plan and the Principal Investigator is not allowed to deviate from the plan. 
Furthermore, the use of waivers from the Clinical Investigation Plan is prohibited. 
As required by national regulations, or guidelines, requests for deviations and reports of 
deviations will be provided to the EC/IRB if the deviation affects subject’s rights, safety or well-
being, or the scientific integrity of the clinical investigation. 
Under emergency circumstances deviations from the Clinical Investigation Plan may proceed 
without prior approval by Mölnlycke and the EC/IRB if the rights, safety and well-being of human 
subjects need to be protected. Such deviations will be documented and reported to the 
Mölnlycke and EC/IRB as soon as possible in accordance with national regulations. 
When the Site Monitor or Mölnlycke identifies that the Principal Investigator is out of 
compliance, this will be communicated to the Principal Investigator in writing, with a request to 
correct the source of the deviation immediately. Corrective action(s) will be implemented to 
avoid repeated non-compliance, which will usually include re-training and may include 
terminating the clinical investigation at the site. 
Mölnlycke is responsible for analysing deviations and assessing their significance. Corrective 
action will be implemented to avoid repeated deviations, which may include suspending the 
clinical investigation, and/or disqualifying the Principal Investigator. 

 
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8. STATEMENTS OF COMPLIANCE 
8.1 Ethics 
8.1.1 Ethics review  
The final Clinical Investigation Plan, including the final version of the Subject Information and 
Consent Form, must be approved or given a favourable opinion in writing by an EC/IRB before 
enrolment of any subject into the clinical investigation. The Principal Investigator is responsible 
for informing the EC/IRB of any amendment to the Clinical Investigation Plan as per local 
requirements. 
Any additional requirements imposed by the EC/IRB or RA must be followed. 
8.1.2 Ethical Conduct of the Investigation 
This clinical investigation will be performed in accordance with the ethical principles that have 
their origin in the most recent version of the Declaration of Helsinki, and applicable regulation. 
8.1.3  Subject Information and Consent Form 
The Principal Investigator must ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risks and benefits of the clinical 
investigation and must verify that the subject has understood the information. Subjects must 
also be notified that they are free to discontinue participation in the investigation at any time. 
The withdrawal of the informed consent must not affect the activities already carried out and the 
use of data obtained based on informed consent before its withdrawal. The subject must be 
given the opportunity to ask questions and adequate time for consideration prior to providing 
their consent to take part in the study. The subject’s signed informed consent has to be 
obtained before conducting any procedure specifically for the investigation. The original signed 
copy of the Informed Consent Form must be filed by the Principal Investigator. A copy of the 
Subject Information including a copy of the signed Consent Form should be given to the subject. 
A sample of the Master Subject Information and Consent Form is enclosed (Appendix B). If 
modifications are made to either of these documents according to local requirements, Mölnlycke 
must approve amended version(s) of the document(s). 
If any new important information occurs during the clinical investigation the subject will be 
informed both orally and in writing. 
8.2 Regulatory and standards 
8.2.1 Regulatory review 
If applicable, the final Clinical Investigation Plan, including the final version of the Subject 
Information and Consent Form, must be approved or given a favourable opinion in writing by a 
RA before enrolment of any subject into the clinical investigation. Mölnlycke is responsible for 
informing the RA of any amendment to the Clinical Investigation Plan as per local requirements. 
8.2.2 Standards and other 
The most recent version of ISO 14155 is followed in addition to national regulations.  
8.2.3 Subject Data Protection 
The written Subject Information explains that the data will be stored in a computer database, 
maintaining confidentiality in accordance with national data legislation and that authorised 
representatives of Mölnlycke and/or a RA and/or EC/IRB, may require direct access to those 

 
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parts of the hospital/practice records relevant to the clinical investigation, including medical 
history, for verification of data. All data computerized by Mölnlycke will be identified by subject 
number only. 
8.3 SUBJECT PROTECTION PROCEDURES 
8.3.1 Procedures in Case of Medical Emergency 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the clinical investigation. 
8.3.2 Insurance 
Mölnlycke Health Care AB has product liability insurance, which also covers devices being 
investigated in a clinical investigation.  
9. INVESTIGATION TIMETABLE AND TERMINATION 
The study duration per patients is approximately 22 weeks, i.e. treatment duration of  up to 20 
weeks and follow up 2 weeks after closure. 
Planned investigation start: Q4 2019 
Planned inclusion completion: Q3 2022 
Planned last subject out: Q4 2022 
The clinical investigation could be prematurely discontinued if the dropout rate is higher than 
20% and/or the investigation site is unable to fulfil the inclusion period according to the Clinical 
Investigation Agreement. 
10. PRINCIPAL INVESTIGATOR(S) AND INVESTIGATION 
ADMINISTRATIVE STRUCTURE 
Specified in separate list.  
11. DEFINITIONS AND PROCEDURES FOR REPORTING OF 
ADVERSE EVENT, ADVERSE DEVICE EFFECT, SERIOUS 
ADVERSE EVENT, SERIOUS ADVERSE DEVICE EFFECT 
AND DEVICE DEFICIENCY 
DEFINITIONS 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance. 
Note: Device Deficiencies include malfunctions, use errors, and inadequate labelling.  
All Device Deficiencies that might have led to a Serious Adverse Device Effect shall be reported 
in accordance with Serious Adverse Event reporting procedures, as specified below. 
Adverse Event (AE)  

 
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Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
Note:  
• 
This definition includes events related to the investigational medical device or the 
comparator. 
• 
This definition includes events related to the procedures involved. 
• 
For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
Adverse Device Effect (ADE)  
Adverse Event related to the use of an investigational medical device  
Note:  
a) This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, or operation, or any malfunction of 
the investigational medical device. 
b) This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device. 
Serious Adverse Event (SAE) 
Means any adverse event that led to any of the following: 
a) 
death, 
b) 
serious deterioration in the health of the subject, that resulted in any of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) hospitalization or prolongation of patient hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, or 
5) chronic disease 
c) 
foetal distress, foetal death or a congenital physical or mental impairment or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without serious deterioration in health, is not considered a serious adverse 
event. 
Serious Adverse Device Effect (SADE) 
Adverse Device Effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event.   
PROCEDURES FOR SAE AND/OR SADE REPORTING OR REPORTING OF DD THAT 
COULD HAVE LED TO A SADE 
The investigator is responsible for the reporting of AEs, ADEs; SAEs, SADEs and DD that occur 
in the control group in accordance with local requirements to authorities and if applicable 
manufacturers of these products. 

 
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Document template: F-167 Clinical Investigation Plan 
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The Principal Investigator must inform Mölnlycke, within 1 calendar day of awareness of the 
event. When a SAE/SADE has been entered into the eCRF by the Principal 
Investigator/authorised site staff, the eCRF system will automatically generate a report to: 
Clinical Investigations Event Reporting@molnlycke.com. 
In case of problem with the eCRF, a paper-based version of the SAE/SADE report form 
(available in the Investigator Site File) shall be used and sent by email to: 
Clinical Investigations Event Reporting@molnlycke.com. 
All SAEs/SADEs that occur during the Clinical Investigation shall be reported, whether or not 
they are considered causally related to the investigational device. 
Device Deficiencies that might have led to SADE if either a) suitable action had not been taken, 
b) if intervention had not been made, or c) if circumstances had been less fortunate must be 
reported as a SADE. 
The Principal Investigator is responsible for informing the EC/IRB and/or the RA of the 
SAE/SADE as per local requirements. 
PROCEDURES FOR DD REPORTING  
All DD shall be reported to Mölnlycke as soon as possible, without unjustified delay. If the DD 
might have led to a SADE the reporting requirements for SADE described above must be 
followed. DDs can be either subject related or non-subject related depending on if the 
investigational device was used by a subject or not. Separate forms are used for subject related 
and non-subject related DDs. 
When a subject related DD has been entered into the eCRF by the Principal 
Investigator/authorised site staff, the eCRF system will automatically generate a report to: 
Clinical Investigations Event Reporting@molnlycke.com  
Non-subject related DDs are reported using the paper-based report form located in the 
Investigator Site File. The completed form shall be sent by email to: 
Clinical Investigations Event Reporting@molnlycke.com  
PROCEDURES FOR ADE REPORTING 
All ADE shall be reported by the Principal Investigator to Mölnlycke as soon as possible without 
unjustified delay. When an ADE has been entered into the eCRF by the Principal 
Investigator/authorised site staff, the eCRF system will automatically generate a report to: 
Clinical Investigations Event Reporting@molnlycke.com 
This includes also ADEs occurring in the comparator arm. 
CAUSALITY ASSESSMENT 
The relationship between the use of the investigational device and the occurrence of each 
AE/SAE shall be assessed by the Principal Investigator and Mölnlycke and classified as device 
related or not related to the device. 
 
Report by Mölnlycke Health Care to Regulatory Authorities 
Mölnlycke will report to RA where the clinical investigation has commenced in accordance with 
the local requirements for market authorised medical devices. 

 
Clinical Investigation Plan (CIP) 
Document ID:  PD-568268 Rev: 02 
 
 
Title: CIP_Granulox01 
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Approval date 2019-10-24 
 
Document template: F-167 Clinical Investigation Plan 
Rev: 11 
 
 
12. PUBLICATION POLICY 
The clinical investigation will be registered in a publicly accessible database before recruitment 
of the first subject. 
A final Clinical Investigation Report (CIR) of the investigation will be completed, even if the 
clinical investigation is prematurely terminated. The CIR will be prepared by Mölnlycke in 
accordance with the guideline presented in Annex D of ISO 14155. 
All publications and presentations must be based upon the CIR. 
All information supplied by Mölnlycke in connection with this investigation will remain the sole 
property of Mölnlycke and is to be considered confidential information. No confidential 
information will be disclosed to other parties not involved in this clinical study without obtaining 
prior written consent from Mölnlycke. Confidential information associated with this study will not 
be used except in the performance of this investigation. 
Mölnlycke may choose to publish or present data from this clinical investigation. If a Principal 
Investigator is offered first authorship, he/she will be asked to comment and approve the 
publication. Mölnlycke has the right to use the results of this study for registration, internal 
presentation, and for promotion. 
 
13. LITERATURE REVIEW AND REFERENCES 
In order to determine the scientific background for this clinical investigation as well as to assess 
risks/benefits of the device, a literature review was conducted. The below literature is listed as 
references and was critically evaluated before serving as background information.1-12,14-19,22,23,30-
35 
1. 
Bergqvist D, Lindholm C, Nelzen O. Chronic leg ulcers: the impact of venous disease. J 
Vasc Surg. 1999;29(4):752-755.https://www.ncbi.nlm.nih.gov/pubmed/10194512 
2. 
Purwins S, Herberger K, Debus ES, et al. Cost-of-illness of chronic leg ulcers in 
Germany. Int Wound J. 2010;7(2):97-
102.https://www.ncbi.nlm.nih.gov/pubmed/20529149 
3. 
Blecken SR, Villavicencio JL, Kao TC. Comparison of elastic versus nonelastic 
compression in bilateral venous ulcers: a randomized trial. J Vasc Surg. 
2005;42(6):1150-1155.https://www.ncbi.nlm.nih.gov/pubmed/16376207 
4. 
Brown A, Augustin M, Junger M, et al. Randomized standard-of-care-controlled trial of a 
silica gel fibre matrix in the treatment of chronic venous leg ulcers. Eur J Dermatol. 
2014;24(2):210-216.https://www.ncbi.nlm.nih.gov/pubmed/24839984 
5. 
Kantor J, Margolis DJ. A multicentre study of percentage change in venous leg ulcer 
area as a prognostic index of healing at 24 weeks. Br J Dermatol. 2000;142(5):960-
964.https://www.ncbi.nlm.nih.gov/pubmed/10809855 
6. 
Partsch H, Damstra RJ, Tazelaar DJ, et al. Multicentre, randomised controlled trial of 
four-layer bandaging versus short-stretch bandaging in the treatment of venous leg 
ulcers. Vasa. 2001;30(2):108-113.https://www.ncbi.nlm.nih.gov/pubmed/11417280 
7. 
Alavi A, Sibbald RG, Phillips TJ, et al. What's new: Management of venous leg ulcers: 
Treating venous leg ulcers. J Am Acad Dermatol. 2016;74(4):643-664; quiz 665-
646.https://www.ncbi.nlm.nih.gov/pubmed/26979355 

 
Clinical Investigation Plan (CIP) 
Document ID:  PD-568268 Rev: 02 
 
 
Title: CIP_Granulox01 
Page 36(38) 
Investigation Code Granulox01 
Final Version 
Approval date 2019-10-24 
 
Document template: F-167 Clinical Investigation Plan 
Rev: 11 
 
 
8. 
Kirsner RS, Baquerizo Nole KL, Fox JD, Liu SN. Healing refractory venous ulcers: new 
treatments offer hope. J Invest Dermatol. 2015;135(1):19-
23.https://www.ncbi.nlm.nih.gov/pubmed/25501380 
9. 
Arenbergerova M, Engels P, Gkalpakiotis S, Dubska Z, Arenberger P. Effect of topical 
haemoglobin on venous leg ulcer healing. EWMA Journal. 2013;13(2):25-
30.https://pdfs.semanticscholar.org/b7e1/c5052e1e7a94eb02e39de095b689bca545b9.p
df 
10. 
Hon J, Lagden K, McLaren AM, et al. A prospective, multicenter study to validate use of 
the PUSH in patients with diabetic, venous, and pressure ulcers. Ostomy Wound 
Manage. 2010;56(2):26-36.https://www.ncbi.nlm.nih.gov/pubmed/20200443 
11. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life 
Res. 2013;22(7):1717-1727.https://www.ncbi.nlm.nih.gov/pubmed/23184421 
12. 
Augustin M, Conde Montero E, Zander N, et al. Validity and feasibility of the wound-QoL 
questionnaire on health-related quality of life in chronic wounds. Wound Repair Regen. 
2017;25(5):852-857.https://www.ncbi.nlm.nih.gov/pubmed/29080332 
13. 
Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing Numerical Rating 
Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain 
intensity in adults: a systematic literature review. J Pain Symptom Manage. 
2011;41(6):1073-1093.https://www.ncbi.nlm.nih.gov/pubmed/21621130 
14. 
Arenbergerova M, Engels P, Gkalpakiotis S, Dubska Z, Arenberger P. [Topical 
hemoglobin promotes wound healing of patients with venous leg ulcers]. Hautarzt. 
2013;64(3):180-186.https://www.ncbi.nlm.nih.gov/pubmed/23354657 
15. 
Hunt SD, Elg F. Clinical effectiveness of hemoglobin spray (Granulox((R))) as adjunctive 
therapy in the treatment of chronic diabetic foot ulcers. Diabet Foot Ankle. 
2016;7:33101.https://www.ncbi.nlm.nih.gov/pubmed/27829487 
16. 
Petri M, Stoffels I, Griewank K, et al. Oxygenation Status in Chronic Leg Ulcer After 
Topical Hemoglobin Application May Act as a Surrogate Marker to Find the Best 
Treatment Strategy and to Avoid Ineffective Conservative Long-term Therapy. Mol 
Imaging Biol. 2018;20(1):124-130.https://www.ncbi.nlm.nih.gov/pubmed/28702902 
17. 
Arenberger P, Engels P, Arenbergerova M, et al. Clinical results of the application of a 
hemoglobin spray to promote healing of chronic wounds. GMS Krankenhhyg Interdiszip. 
2011;6(1):Doc05.https://www.ncbi.nlm.nih.gov/pubmed/22242086 
18. 
Haycocks S, McCardle J, Findlow AH, Guttormsen K. Evaluating the effect of a 
haemoglobin spray on size reduction in chronic DFUs. Br J Nurs. 2016;25(6 Suppl):S54-
62.https://www.ncbi.nlm.nih.gov/pubmed/27019186 
19. 
Dissemond J, Kroger K, Storck M, Risse A, Engels P. Topical oxygen wound therapies 
for chronic wounds: a review. J Wound Care. 2015;24(2):53-54, 56-60, 62-
53.https://www.ncbi.nlm.nih.gov/pubmed/25647433 
20. 
Harnoss JC, Elrub QMA, Jung JO, et al. Irritative potency of selected wound antiseptics 
in the hen's egg test on chorioallantoic membrane to predict their compatibility to 
wounds. Wound Repair Regen. 2019;27(2):183-
189.https://www.ncbi.nlm.nih.gov/pubmed/30520197 

 
Clinical Investigation Plan (CIP) 
Document ID:  PD-568268 Rev: 02 
 
 
Title: CIP_Granulox01 
Page 37(38) 
Investigation Code Granulox01 
Final Version 
Approval date 2019-10-24 
 
Document template: F-167 Clinical Investigation Plan 
Rev: 11 
 
 
21. 
Holzer JC, Birngruber T, Mautner S, Graff A, Kamolz LP. Topical application of 
haemoglobin: a safety study. J Wound Care. 2019;28(3):148-
153.https://www.ncbi.nlm.nih.gov/pubmed/30840547 
22. 
Bateman SD. Topical haemoglobin spray for diabetic foot ulceration. Br J Nurs. 
2015;24(12):S24-29.https://www.ncbi.nlm.nih.gov/pubmed/26110985 
23. 
Hunt S, Elg F. The clinical effectiveness of haemoglobin spray as adjunctive therapy in 
the treatment of chronic wounds. J Wound Care. 2017;26(9):558-
568.https://www.ncbi.nlm.nih.gov/pubmed/28880758 
24. 
Pötzschke H. Zusammenfassender Bericht zur klinischen Studie "Efficacy of 
Hämoglobin-Spray Treatment of Chronic Lower Leg Wounds" at the Hospital Civil de 
Cd. Victoria, Tamaulipas, Mexico. 2011. 
25. 
Ashby RL, Gabe R, Ali S, et al. Clinical and cost-effectiveness of compression hosiery 
versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer 
Study IV, VenUS IV): a randomised controlled trial. Lancet. 2014;383(9920):871-
879.https://www.ncbi.nlm.nih.gov/pubmed/24315520 
26. 
Edmonds M, Lazaro-Martinez JL, Alfayate-Garcia JM, et al. Sucrose octasulfate 
dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers 
(Explorer): an international, multicentre, double-blind, randomised, controlled trial. 
Lancet Diabetes Endocrinol. 2018;6(3):186-
196.https://www.ncbi.nlm.nih.gov/pubmed/29275068 
27. 
Game F, Jeffcoate W, Tarnow L, et al. LeucoPatch system for the management of hard-
to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, 
randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(11):870-
878.https://www.ncbi.nlm.nih.gov/pubmed/30243803 
28. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Med. 2011;30(28):3267-
3284.https://www.ncbi.nlm.nih.gov/pubmed/22105690 
29. 
Dmitrienko A, D'Agostino RB, Sr. Multiplicity Considerations in Clinical Trials. N Engl J 
Med. 2018;378(22):2115-2122.https://www.ncbi.nlm.nih.gov/pubmed/29847757 
30. 
Brüggenjürgen B, Hunt SD, Eberlein T. Wundversorgung des diabetischen Fuß-Ulkus 
(DFU) – Inkrementelle Kostenanalyse der mit einem Hämoglobinspray erweiterten 
Therapie der diabetisch-neuropathischen Fußläsion in Deutschland. Gesundh ökon Qual 
manag. 2018;23(06):320-327.https://www.thieme-
connect.com/products/ejournals/abstract/10.1055/s-0043-120204 
31. 
Fischer D, Stewart AL, Bloch DA, Lorig K, Laurent D, Holman H. Capturing the patient's 
view of change as a clinical outcome measure. Jama. 1999;282(12):1157-
1162.https://www.ncbi.nlm.nih.gov/pubmed/10501119 
32. 
Gottrup F, Dissemond J, Baines C, et al. Use of Oxygen Therapies in Wound Healing. J 
Wound Care. 2017;26(Sup5):S1-s43.https://www.ncbi.nlm.nih.gov/pubmed/28475468 
33. 
Hunt S. Exploring the effectiveness of topical haemoglobin therapy in the acute care 
setting on diabetic foot ulceration. Diabetic Foot Journal. 2017;20(3):176-
183.https://www.woundsinternational.com/resources/details/exploring-effectiveness-
topical-haemoglobin-therapy-acute-care-setting-diabetic-foot-ulceration 

 
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Document ID:  PD-568268 Rev: 02 
 
 
Title: CIP_Granulox01 
Page 38(38) 
Investigation Code Granulox01 
Final Version 
Approval date 2019-10-24 
 
Document template: F-167 Clinical Investigation Plan 
Rev: 11 
 
 
34. 
Hunt SD, Elg F, Percival SL. Assessment of clinical effectiveness of haemoglobin spray 
as adjunctive therapy in the treatment of sloughy wounds. J Wound Care. 
2018;27(4):210-219.https://www.ncbi.nlm.nih.gov/pubmed/29637828 
35. 
Healthcare Improvement Scotland. Innovative Medical Technology Overview: Number 
006/2016. Granulox®haemoglobin spray. 2016; 
http://www.healthcareimprovementscotland.org/our work/technologies and medicines/t
opics assessed/imto 006-2016.aspx.