Clinical trial NCT04962503
Conditions: Arterial Ischemic Stroke
Sponsor: Clinuvel Pharmaceuticals Limited
Start date: 2021-06-03; Completion date: 2022-02-04
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary study objective is to assess the safety of afamelanotide while the secondary objective is to assess whether the therapy affects the size of the penumbra, by increasing blood flow, restoring oxygen supply to the brain, and reducing the amount of cerebral oedema (fluid) which is seen as a result of the stroke. Positive findings would indicate that the drug is able to support brain tissue-at-risk and provide overall neuroprotection and benefit to stroke patients.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Afamelanotide
Intervention descriptions: intervention 1: Six adult patients with clots located in the higher segments of the brain and who are ineligible for alternative treatments will be enrolled in the study and evaluated for six weeks. The study will assess patients' brain injury with computed tomography (CT) scans and magnetic resonance imaging (MRI), as well as using recognised methods of clinical evaluation to measure changes in patients' neurological and cognitive function following treatment.

Protocol documents:
Prot_SAP_000.pdf: 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 2 of 65 
 
 
SIGNATURES OF AGREEMENT FOR PROTOCOL AND AMENDMENTS 
 
A Proof of Concept, Phase IIa, Open Label Study to Evaluate the Safety of Afamelanotide in Patients with Arterial 
Ischaemic Stroke (AIS) due to Distal [M2 segment and beyond] Arterial Large Vessel Occlusion (LVO) or 
Perforator Occlusion and who are ineligible for Intravenous Thrombolysis (IVT) or Endovascular Thrombectomy 
(EVT) 
 
  [Short Title: Phase IIa Stroke Study] 
 
 
Protocol Final Version 3.0: 04 May 2021 
 
Principal Investigator (PI):  
 
I have read this protocol and agree to conduct the study as outlined herein, complying with the 
obligations and requirements of clinical investigators and ICH Guidelines. 
 
Name of Principal Investigator (PI): Prof Geoffrey Cloud 
 
Investigational Site Name: Department of Neurology  
                                           Alfred Hospital Melbourne 
 
Investigational Site Address: 99 Commercial Road 
                                               Melbourne, 3000 VIC 
 
 
Signature:                                                                              Date: 
 
 
 
 
 
Study Director, Sponsor:  
 
Name of Sponsor Representative: Dr Dennis Wright 
 
Title of Sponsor Representative: 
Chief Scientific Officer 
 
 
Signature:                                                                              Date: 
 
 
 
 
 
 












 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 8 of 65 
 
TABLE OF CONTENTS   
 
SIGNATURES OF AGREEMENT FOR PROTOCOL AND AMENDMENTS ........................................................ 2 
PROTOCOL SYNOPSIS ................................................................................................................................................. 3 
STUDY FLOW CHART .................................................................................................................................................. 7 
TABLE OF CONTENTS ................................................................................................................................................. 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................ 11 
1.0 
ETHICS.................................................................................................................................................................. 13 
1.1 
Human Research Ethics Committee (HREC) ..................................................................................................... 13 
1.2 
Ethical Conduct of the Study .............................................................................................................................. 13 
1.3 
Participant Information and Informed Consent Form ....................................................................................... 13 
1.4 
Protocol Amendments ......................................................................................................................................... 14 
1.5 
Confidentiality .................................................................................................................................................... 14 
2.0 
STUDY PERSONNEL AND STUDY ADMINISTRATION ............................................................................. 15 
3.0 
INTRODUCTION AND STUDY RATIONALE ................................................................................................ 16 
4.0 
STUDY OBJECTIVES ......................................................................................................................................... 21 
4.1 
Primary Objective .............................................................................................................................................. 21 
4.2 
Secondary Objectives ......................................................................................................................................... 21 
5.0 
INVESTIGATIONAL PLAN ............................................................................................................................... 21 
5.1 
Overall Design and Plan of the Study ................................................................................................................ 21 
5.2 
Selection of Study Population ............................................................................................................................. 22 
5.2.1 
Inclusion Criteria ...................................................................................................................................... 22 
5.2.2 
Exclusion Criteria ..................................................................................................................................... 23 
5.2.3 
Recruitment Management ......................................................................................................................... 23 
5.2.4  
Withdrawals and Replacement of Patients ............................................................................................... 24 
5.3 
Study Medication ................................................................................................................................................ 24 
5.3.1 
Description of Study Medication ............................................................................................................... 24 
5.3.2 
Treatment Groups ..................................................................................................................................... 24 
5.3.3 
Dosage and Administration of Study Medication ..................................................................................... 25 
5.3.4 
Packaging and Labeling of Study Medication .......................................................................................... 25 
5.3.5 
Storage and Accountability ....................................................................................................................... 25 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 9 of 65 
 
5.3.6 
Compliance ............................................................................................................................................... 26 
5.4 
Prior and Concomitant Therapy ........................................................................................................................ 26 
5.4.1 
Prior Therapy ........................................................................................................................................... 26 
5.4.2 
Concomitant Therapy................................................................................................................................ 26 
5.5 
Study Procedures ................................................................................................................................................ 26 
5.5.1 
Description of Study Days ........................................................................................................................ 27 
5.5.1.1 
Screening Period .................................................................................................................................................... 27 
5.5.1.2 
Study Period ........................................................................................................................................................... 27 
5.5.2 
Study Procedures Flowchart ..................................................................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
5.6 
Data Quality Assurance ..................................................................................................................................... 40 
5.6.1 
Data Collection, Monitoring and Auditing ............................................................................................... 40 
5.6.2 
Database Management and Quality Control ............................................................................................ 41 
5.7 
Statistical Methods, Exploratory Statistics ......................................................................................................... 41 
 
 ................................................................................................................ 41 
5.7.2 
Efficacy Assessment .................................................................................................................................. 41 
5.7.2.1 
Specification of Efficacy Endpoints ....................................................................................................................... 41 
5.7.3 
Safety Assessment ..................................................................................................................................... 43 
5.7.3.1 
Specification of Safety Endpoint (Primary Endpoint) ............................................................................................ 43 
5.7.4 
Sample Size ............................................................................................................................................... 43 
5.7.5 
Analysis Plan ............................................................................................................................................ 43 
5.7.5.1   Safety Population ..................................................................................................................................................... 43 
5.7.5.2    ITT Population ........................................................................................................................................................ 43 
5.7.5.3 
Handling of Missing and Incomplete Data............................................................................................................. 43 
5.7.5.4    Per Protocol Analysis (PPA) Population ................................................................................................................. 44 
5.7.5.5     Demographic and Initial Characteristics ................................................................................................................ 44 
5.7.5.6     Efficacy .................................................................................................................................................................. 44 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 10 of 65 
 
5.7.5.7     Safety ..................................................................................................................................................................... 44 
5.7.5.8     Adverse Events ...................................................................................................................................................... 44 
5.7.5.9     Clinical Laboratory Data ........................................................................................................................................ 45 
5.7.5.10   Other Clinical Data Analyses ................................................................................................................................. 45 
5.7.5.11    Interim Evaluations ............................................................................................................................................... 45 
5.8 
Premature Termination of the Study .................................................................................................................. 46 
6.0 
STUDY REPORT, PUBLICATION POLICY & ARCHIVING OF STUDY DOCUMENTATION ............ 47 
7.0 
AMENDMENTS AND UPDATES ...................................................................................................................... 49 
8.0 
STUDY TIMETABLE .......................................................................................................................................... 49 
9.0 
REFERENCES ...................................................................................................................................................... 50 
10.0 
APPENDICES .................................................................................................................................................. 52 
APPENDIX 1: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ............................................... 52 
 
 
 
 
TOTAL (0–6): ................................................................................................................................................................. 58 
APPENDIX B: National Institutional Health Stroke Scale (NIHSS) ........................................................................... 59 
 
 
 
 
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 12 of 65 
 
 
 
 
 
 
 
LPI 
Last-patient-in  
LPLV 
Last-patient-last-visit 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
Mg 
Milligram 
Mm 
Millimeter 
 
 
 
 
mRS 
Modified Rankin Scale 
MRI 
Magnetic resonance imaging 
 
 
 
 
 
NIHSS  
National Institutional Health Stroke Scale 
PI 
Principal Investigator 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
SOM 
Study operating manual 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 13 of 65 
 
 
1.0 ETHICS 
1.1 
Human Research Ethics Committee (HREC) 
An appropriate HREC will approve the protocol and the Informed Consent Form before the study is 
initiated at the study center.  Documentation of this approval will be provided to the Sponsor and/ or 
the Sponsor’s designee. The Investigator(s) will have the following responsibilities: 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the Declaration of Helsinki (see Appendix 1), its 
revisions and ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and 
all applicable local regulations including the National Statement on Ethical Conduct in Human 
Research of the NHMRC. 
 
 
 
 
1.3 
Participant Information and Informed Consent Form 
Prior to any study specific screening procedures, the Investigator will explain to each participant or 
medical treatment decision maker the nature of the study, its purpose, procedures to be performed, 
the necessity for withdrawal of prohibited medication, expected duration, and the benefits and risks 
of study participation. After this explanation and before any study specific procedures are performed, 
the subject or medical treatment decision maker must voluntarily sign an informed consent statement 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 14 of 65 
 
in the presence of a witness, if applicable (see Appendix 2). The inclusion and exclusion criteria will 
be reviewed at Day 0 prior to study medication administration. 
1.4 Protocol Amendments 
Changes in any portion of this protocol will be documented in the form of a protocol amendment and 
signed revision, signed by the appropriate CLINUVEL PHARMACEUTICALS LIMITED personnel 
and the Investigator. 
 
Depending on the requirements of the study center’s HREC and the relevant Competent Authority, 
where applicable, protocol amendment(s) will either need to be submitted for approval or advised by 
notification. Where formal approval is required, the revision(s) will not be implemented until 
approval has been obtained. 
1.5 
Confidentiality 
All information provided to the Investigator by the Sponsor, including clinical observations at the 
study center, are held strictly confidential and confined to the clinical personnel involved in 
conducting the study, under the supervision of the Investigator. 
 
 
 
 
 
 
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 16 of 65 
 
3.0 INTRODUCTION AND STUDY RATIONALE 
Stroke is the second commonest cause of death globally and the leading cause of adult neurological 
disability1. Acute arterial ischaemic stroke (AIS), due to arterial occlusion, accounts for 85% of all 
acute strokes whilst 15% of acute strokes are caused by an acute hemorrhage2.  
The outcome of AIS, both in terms of disability and survival, can be improved by reperfusion therapy 
using intravenous thrombolysis3 (IVT) and, or thrombectomy4 (mechanical endovascular removal of 
thrombus), in selected patients, where occlusion involves a proximal vessel of the circle of Willis. 
Both treatments are time dependent5 and at best only a significant minority of patients with AIS, 
 are eligible for reperfusion treatments. 
 
 
 Perfusion brain imaging, with 
computed tomography (CT) or Magnetic resonance imaging (MRI), has become the cornerstone of 
selecting AIS patients for reperfusion therapy and as such individualized patient treatment by using 
imaging as a surrogate for a ‘brain tissue clock,’ as opposed to arbitrary time since last seen well, in 
treatment decision paradigms6–9. 
Stroke unit care has been shown to reduce mortality and dependence in AIS 
 
 
 
   
More than ever, effective neuroprotection – that may either facilitate more patients being suitable for 
timely reperfusion therapy by slowing the conversion of penumbra to core, or intrinsically attenuate 
the size of a threatened area of cerebral infarction is needed to aid assist in treating the global burden 
of disease due to AIS. 
 
BLOOD BRAIN BARRIER (BBB) 
 
It is well published that after a cerebrovascular accident (stroke) the damage to the blood-brain-barrier 
(BBB) includes decreased expression and altered organization of tight junction constituent proteins 
but also modulation of functional expression of endogenous BBB transporters.  


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 17 of 65 
 
Several hallmarks of pathology following ischaemic stroke is breakdown of the BBB, resulting in 
increased paracellular solute leak, modulation of transport proteins and endocytotic transport 
mechanisms, and inflammatory damage. Such barrier breakdown leads to a significant increase in 
paracellular permeability at the level of the cerebral microvasculature. These pathological 
derangements variably result in cognitive and motor impairments.  
One of the most significant contributors to BBB breakdown in stroke is activation of proteinases such 
as matrix metalloproteinases (MMPs). This includes MMPs that are activated by hypoxia-inducible 
factor-1α (HIF-1α)-dependent mechanisms (i.e., MMP-2) and MMPs whose activation is triggered 
by cytokines (i.e., TNF-α, IL-1β) such as MMP-3 and MMP-9.  
Integrins, transmembrane glycoprotein receptors for the extracellular matrix, also play a significant 
role in BBB breakdown. Physiologically, integrins interact with constituents of the basement 
membrane (i.e., collagen IV, fibronectin, laminin, heparin sulfate proteoglycans such as perlecan) to 
regulate BBB permeability and transport. In ischaemic stroke, integrins are rapidly degraded, which 
leads to BBB breakdown and subsequent edema, inflammation, and exacerbation of stroke injury. 
 
 
 
  
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 18 of 65 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 19 of 65 
 
 
  
In 111 patients a longitudinal study showed that the effect of early plasma α-MSH on stroke outcome 
was more than a reflection of the stress response related to stroke severity and that maintenance of 
plasma α-MSH after stroke onset could be protective. Furthermore, a growing body of experimental 
data has shown that exogenous administration of α-MSH decreases infarct volume and improves 
stroke outcome16. There are numerous mechanisms by which α-MSH (and related neuropeptides) 
could improve stroke outcome, and these effects are mediated through 5 different melanocortin 
receptors (MCRs). Potent antipyretic properties of α-MSH, which could potentially be capitalized on 
in the treatment of stroke, are mediated through the MCR3/MCR4 receptor complex in the brain. 
 
OBJECTIVES 
The objective of this pilot study is to evaluate the safety of afamelanotide, identify changes in 
reperfusion in AIS patients, specifically the ischaemic core and/or the penumbral ischaemic zone 
(salvageable tissue) and assess neurological functions and activities of daily living in AIS patients. 
 
SCIENTIFIC HYPOTHESIS 
The scientific hypothesis is that the pharmacologic intervention with afamelanotide would positively 
affect the infarcted area in patients with AIS 
 
  
Afamelanotide is a potent synthetic analogue of the naturally occurring hormone, alpha melanocyte 
stimulating hormone (α-MSH).  
 
 
 
 
 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 20 of 65 
 
 
 
 
Afamelanotide 16mg has been shown to be effective in providing systemic photoprotection in EPP 
and has obtained marketing authorization in the European Union (October 2014) and the United 
States (October 2019) for the prevention of phototoxicity and endothelial damage incurred by adult 
EPP patients. The results of the clinical trials conducted by CLINUVEL, as well as of one long term 
observational study and the ongoing post-authorization pharmacovigilance activities, confirm the 
positive safety profile of afamelanotide to date17–19. 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
It is proposed for AIS patients diagnosed with an acute stroke - and not eligible for intravenous 
thrombolysis (IVT) or endovascular thrombectomy (EVT) - originating from distal occlusion (M2 
and beyond) of the large vessels be enrolled 
 
 
  
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 21 of 65 
 
 
 
 
 
 
 
4.0 STUDY OBJECTIVES 
4.1 
Primary Objective 
The objective of this pilot study is to evaluate the safety of afamelanotide in AIS patients.  
4.2 
Secondary Objectives 
The secondary objectives of this pilot study CUV801 are to identify changes in reperfusion of the 
ischaemic core and ischaemic penumbra (salvageable tissue) in AIS patients with distal occlusion of 
the large vessels and who are ineligible to receive IVT or EVT, and to monitor changes in neurological 
function, cognitive functions and changes of daily activities in these patients.  
 
5.0 INVESTIGATIONAL PLAN 
5.1 
Overall Design and Plan of the Study 
This is an open label phase IIa pilot study to be conducted in six (6) patients with acute AIS during a 
6-weeks period 
   
 
To determine eligibility for entry into the study, 
 
 Eligible 
patients will be enrolled and will be administered 
 
  
 
 
 
   
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 23 of 65 
 
• Male or female subjects with a diagnosis of first Arterial Ischaemic Stroke (AIS) due to distal 
[M2 segment and beyond] occlusion or perforator occlusion   
• 
 
  
• Mild to moderate stroke 
  
• 
 
• Aged 18-85 years  
• Written informed consent obtained from patient and/or medical treatment decision maker prior to 
study-start (upon admission). 
5.2.2 Exclusion Criteria 
Any of the following exclusion criteria will exclude the patient from the study: 
• Administration of intravenous thrombolytic therapy in distal occlusion as etiology of AIS 
• Intervention by endovascular thrombectomy (EVT) 
• 
 
 
• Any evidence of hepatic (defined as three times standard range) or renal impairment (defined as 
  
• 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
5.2.3 Recruitment Management 
 the patients will be recruited through 
the PI’s acute stroke service. 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 25 of 65 
 
The groups consist of:  
 
 Six (6) stroke patients with acute distal (M2 and beyond) LVO or perforator occlusion. 
 
Open label study: Six (6) patients receiving afamelanotide.  
5.3.3 Dosage and Administration of Study Medication 
Afamelanotide 
 will be administered 
on the designated 
study days. 
 
. Please refer to the CUV801 SOM for further 
details.  
 
 
always within 24 hours of onset of symptoms or last seen well. 
5.3.4 Packaging and Labeling of Study Medication 
The implant formulation will be packaged in amber glass vials. The label will include information in 
compliance with the local regulatory requirements for clinical trials/investigational medicinal 
products. 
5.3.5 Storage and Accountability 
Study medication will be maintained in a safe and secure (locked, restricted access) location and kept 
at 2-8°C. The expiry or retest date for each afamelanotide vial will be printed on the label. The 
Investigator will agree not to supply study drug to any persons other than those enrolled in the study. 
Current and accurate drug receipts, inventory, accountability and dispensing records will be kept for 
all study drug in the Pharmacy/Investigator Site File(s), and upon study completion, a final inventory 
and reconciliation of all study drug will be compiled. 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 26 of 65 
 
5.3.6 Compliance 
Data related to the administration of the study drug will be recorded on the CRF.  
5.4 
Prior and Concomitant Therapy 
5.4.1 Prior Therapy 
All subjects (or medical treatment decision makers) will be instructed to report to the Investigator any 
treatments, prescribed medicines, over-the-counter medications, dietary supplements or 
nutraceuticals that are being used. Use of any other prior and concomitant therapy which may interfere 
with the objective of the study, 
 
  
5.4.2 Concomitant Therapy 
The Investigator must be informed as soon as possible about any medication taken from the time of 
screening (Day 0, Day of Admission) until the end of the study (Day 42) and these will be fully 
documented in the patients’ medical records and CRF. In the event that a subject has taken a 
medication which has not been pre-approved, the Investigator will make a decision to continue or 
discontinue the subject, based on whether the medication may interfere with the objectives of the 
study.  
 
For complete information, during the study, contraceptive therapy must not be changed.  
 
5.5 
Study Procedures 
This will be an inpatient study (during hospital admission). 
 
 Patients may be discharged and will be asked 
to return to hospital for the rest of study visits. Patients will participate for a total of up to nine visits.   
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 27 of 65 
 
5.5.1 Description of Study Days 
5.5.1.1 
Screening Period 
 
 
Screening Visit (Day 0) – Day of Admission 
 
The Screening Visit and Admission Visit and related procedures on the Day 0 will only occur after 
the informed consent process is performed and a signed and dated informed consent form has been 
obtained from the patient (or medical treatment decision maker).  
The Investigator will assess eligibility for the study after the following procedures are performed and 
information collected: 
• 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
5.5.1.2 
Study Period 
 
Visit 1 (Day 0) 
 
Once all screening evaluations at Visit 1 (Day 0) have been completed and the Investigator has 
confirmed patient’s eligibility, the following procedures will be performed: 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 29 of 65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 31 of 65 
 
5.5.2 Study Procedures Flowchart 
Please refer to the section Study Flow Chart of the protocol. 
5.5.3 Methods of Assessment 
5.5.3.1 Efficacy Variables 
 
The Efficacy of the treatment will be assessed by: 
5.5.3.1.1 
Evaluation of MRI imaging (CTP and DWI-FLAIR)  
 
Background 
For patients with acute arterial occlusion, 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI diffusion weighted imaging (DWI) is accurate in the identification of acutely infarcted tissue. 
 
 
 
 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 32 of 65 
 
Imaging Protocol 
 
Standard care multimodal computed tomography (CT) will be performed on Day 0. 
 
 
 
 
 
 
 
 
 
 
 
MRI will be performed at Days 3(±1) and 9(±1) 
 
 
 
 
 
 
Efficacy of treatment 
 
 
  
 
 
 
 
 
 
 
 








 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 36 of 65 
 
 
Weight and Height 
Weight in kilograms will be recorded 
 
 
 
 
5.5.3.2.3 Neurological examination 
Neurological examination using a NIHSS will be conducted in a standardized manner 
 
 
 
 
5.5.3.2.4 Vital Signs Measurements 
Vital signs (blood pressure, temperature and pulse rate) will be recorded 
 
 
 
5.5.3.2.5  Adverse Events 
An adverse event (AE) is defined as any untoward medical event (clinical or laboratory) experienced 
by a patient during the course of a clinical trial, whether or not it is related to the investigational 
product. An AE may be a symptom, sign, or abnormal finding or test result. Whenever possible, the 
Investigator will group together into a single term, signs and symptoms that constitute a single 
diagnosis. For example, cough, rhinitis and sneezing might be grouped together as "upper respiratory 
tract infection”.  
 
The Investigator will monitor each patient closely for the development of AEs, and any adverse 
experience spontaneously reported by or elicited from the patient or observed by the Investigators 
(physician or study staff) will be recorded in the patient’s medical notes and on the appropriate AE 
page of the CRF, when applicable. 
 
 
 
 
It is the responsibility of any member of the 
study site staff to immediately report any suspected AE to the Investigator. 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 37 of 65 
 
The Investigator will assess the AE(s) in the patient’s medical notes and provide the date and time of 
onset, severity, seriousness, action taken, outcome, date of resolution (or comment that the event is 
still continuing) and relationship to study medication. 
 
If a laboratory value is outside the normal range, the Investigator must comment on the findings in 
the laboratory report. For any clinical laboratory abnormality, the Investigator will make a judgment 
as to clinical significance. All clinically significant laboratory abnormalities will be recorded as an 
AE in the patient’s medical notes and on the AE page of the CRF.  
 
All AEs will be followed up in accordance with GCP. AEs will be graded for severity as defined 
below: 
• Mild - The AE is transient and easily tolerated by the patient. Specific action is optional; 
• Moderate - The AE causes the patient discomfort and interrupts the patient’s usual activities; 
• Severe - The AE causes considerable interference with the patient’s usual activities and may be 
incapacitating or life-threatening. 
 
Outcome of the event must be described as one of the following: 
• Recovered without sequelae; 
• Recovered with sequelae; 
• Recovering; 
• Not recovered; 
• Death. 
 
The Investigator will be asked to document his/her opinion of the relationship of the event to the 
study drug as follows: 
• Related - There are facts or arguments to suggest a causal relationship, i.e. there is a reasonable 
possibility of a causal relationship between the drug and the AE(s); 
• Not Related - There is not a reasonable possibility that the AE(s) is/are related to the drug – 
alternative aetiology, diagnosis, or explanations for the AE(s) exist, or the time from suspect drug 
intake make a relationship improbable; 
• Not Assessable - Report suggesting an adverse reaction BUT cannot be judged because 
information is insufficient or contradictory OR cannot be supplemented or verified. 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 38 of 65 
 
 
Serious Adverse Events (SAE) 
A Serious Adverse Event (SAE) is any adverse event occurring at any dose that results in any of the 
following outcomes: 
• Death (due to any cause); 
• Is life-threatening; 
• Requires a prolongation of an existing hospitalization. 
• Results in a persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; 
• Important medical events that may not be immediately life threatening, result in death or require 
prolonged hospitalization but may be considered a SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition above. 
 
Reporting: Any SAE, including death due to any cause, which occurs during this study, has to be 
reported to CLINUVEL within 24 hours of the Investigator or their delegate becoming aware of the 
event, even if only limited information regarding the event is available. The CLINUVEL safety team 
will follow up on any missing information or any other information needed and it is expected that the 
investigator responds to these queries as the information becomes available. 
 
An SAE report form must be completed and sent to CLINUVEL Safety Team at 
 
or sent by fax to the number provided in the form within 24 hours of the event occurring or within 24 
hours of becoming aware of the event. In addition to completing the SAE report form (one form 
completed for each SAE), additional supporting information should be provided as appropriate, such 
as photocopies of pertinent test results and medical notes, trial records, consultant report(s), hospital 
discharge summary and autopsy report (if relevant and as soon as available to the Investigator). All 
SAEs will be recorded in the patient’s medical notes and on the AE page of the CRF. 
 
The Investigator will determine whether the seriousness of the event warrants removal of any patient 
from the study. The Investigator will institute appropriate diagnostic and therapeutic measures and 
keep the patient under observation for as long as is medically indicated. 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 39 of 65 
 
Certain AEs and/or SAEs, including suspected unexpected serious adverse reactions (SUSARs), may 
warrant expediting to HRECs, according to the regulatory requirements for the individual countries 
or sites involved, either by the Investigator or the Sponsor. The modalities for reporting and filing 
relevant documentation will be detailed in the CUV801 SOM. 
 
 
 
 
Pregnancy and/or Breastfeeding 
The following situations must be reported to CLINUVEL within 24 hours of the Investigator or their 
delegate becoming aware of the event, even if only limited information regarding the event is 
available. 
• Pregnancy occurring in a female patient, when dose was administered less than three months 
after the last afamelanotide; 
• Pregnancy occurring in the female partner of a male patient treated, when the start of the 
pregnancy is less than three months after the last afamelanotide dose was administered to the 
male patient; 
• Female patient breastfeeding when less than three months after the last afamelanotide dose 
was administered; 
• Birth of a child from a female patient, when the start of the pregnancy was less than three 
months after the last afamelanotide dose was administered; 
• Birth of a child from the female partner of a male patient, when the start of the pregnancy is 
less than three months after the last afamelanotide dose was administered to the male patient. 
 
 Report Form and/or a Pregnancy Outcome/Breastfeeding Report form will be completed 
and sent to the CLINUVEL Safety Team at 
 or faxed to the number provided in 
the forms within 24 hours of becoming aware of the event. All pregnancies will be followed from the 
date of pregnancy detection until pregnancy outcome and/or lactation (when applicable). 
 
Female patients who become pregnant, give birth or begin breastfeeding during the treatment period 
will be withdrawn from treatment and complete the Premature Termination Visit.  
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 40 of 65 
 
For male patients of female partners who become pregnant, the responsible Investigator will 
determine whether the event warrants removal of any patient from the study. 
 
5.6 
Data Quality Assurance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 41 of 65 
 
 
 
 
5.6.2 Database Management and Quality Control 
The study will be monitored by the Clinical Monitor, and/or representatives of CLINUVEL, or its 
delegated representative, as frequently as is necessary to determine that data recording and protocol 
adherence are satisfactory. 
 
 
 
The detailed procedures for data entry, data coding, cleaning and electronic data transfer will be 
provided in the Data Management Plan. 
 
5.7 
Statistical Methods, Exploratory Statistics 
 
Descriptive and exploratory statistics (non-parametric analyses) will be performed 
 
 
  
5.7.2 Efficacy Assessment 
 
5.7.2.1 
Specification of Efficacy Endpoints 
 
Primary Endpoints 
 
(i)     Evaluate the safety of afamelanotide by monitoring and recording TEAEs (on all days of 
administration and up to day 42). 
TEAEs will be recorded and coded as MedDRA Preferred Terms. 
 
Secondary Endpoints  
 
(i)       Evaluate changes in the reperfusion of the ischaemic core and the penumbral ischaemic  
         zone (salvageable tissue) by quantitative analysis of hemodynamics: 
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 43 of 65 
 
5.7.3  Safety Assessment 
5.7.3.1 
Specification of Safety Endpoint (Primary Endpoint) 
 
The safety endpoint will be the incidence of TEAEs occurring during the study period, including 
clinically significant changes in laboratory parameters, will be listed by intensity, seriousness, 
outcome, and relationship to study drug. 
5.7.4 Sample Size 
While this is a phase IIa study of common indication, the sample size is based on availability of 
patients. A total of six (6) patients are planned to be enrolled in this study. This constitutes an open-
label exploratory study. 
5.7.5 Analysis Plan 
5.7.5.1   Safety Population 
 
The Safety Population will include all enrolled patients. Patients screened but not enrolled will be 
shown in separate listings. 
 
5.7.5.2    ITT Population 
 
The ITT population will include all treated patients, who provide at least one post dose efficacy 
assessment. This will be the main population for all efficacy analyses. 
 
5.7.5.3 Handling of Missing and Incomplete Data 
 
 
 
 
  
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 44 of 65 
 
5.7.5.4    Per Protocol Analysis (PPA) Population 
 
 
  
 
5.7.5.5     Demographic and Initial Characteristics 
 
Demographic and baseline characteristics will be summarized using descriptive statistics.  
 
 
5.7.5.6     Efficacy 
 
Primary and secondary efficacy endpoints are described under section 5.5.3.1 Efficacy variables of 
the Study Protocol. 
 
 
 
 
  
 
 
 
5.7.5.7     Safety 
 
Descriptive methods will be used to summarize the safety data. These will be based upon the safety 
population. 
 
5.7.5.8     Adverse Events 
 
All AEs, including non-TEAEs, will be listed. A TEAE is defined as: 
• An event that was not present prior to or on the day of the first study medication administration 
but was present after study medication was administered. 
• An event that was present prior to first administration of study medication and continued to 
occur after the administration of the first dose at an increased level of severity. 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 45 of 65 
 
• An event that was present prior to administration of study medication and was documented as 
completely resolved and re-emerged after the administration of the first dose. 
 
The MedDRA AE dictionary will be used to map verbatim AE terms to preferred terms and body 
systems. The number of patients with TEAEs will be summarized by preferred term and body system. 
TEAEs will be further summarized by intensity, seriousness and relationship to study medication. 
The number of patients who terminate treatment early due to AEs related to study medication will be 
tabulated. Summaries of the incidence of toxicities will be prepared, as appropriate. 
 
SAEs, SUSARs, and AEs of special interest will be listed individually. Any SAE that occurs prior to 
the first dose of the study medication, will be documented in the study report. 
 
5.7.5.9     Clinical Laboratory Data 
 
 
 
 
 
 
5.7.5.10   Other Clinical Data Analyses 
 
 
 
 
 
 
 
 
 
5.7.5.11    Interim Evaluations 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 46 of 65 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments (review of AEs) will be carried out at each study visit and in between, if required 
for safety-related reasons, at the Investigator’s discretion. 
 
5.8 
Premature Termination of the Study 
 
The study may be terminated early if the Sponsor, Investigator or Clinical Monitor discovers 
conditions arising during the course of the study which indicate that the clinical investigation should 
be halted. The study may then be terminated after appropriate consultation and discussion. 
 
Conditions that may warrant study termination include, but are not limited to, the discovery of a 
significant, unexpected, and unacceptable risk to the patients, failure of the Investigator to enroll 
patients at an acceptable rate, insufficient adherence to the protocol requirements, completion of study 
objectives or at the discretion of the Sponsor. 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 47 of 65 
 
6.0 STUDY 
REPORT, 
PUBLICATION 
POLICY 
& 
ARCHIVING 
OF 
STUDY 
DOCUMENTATION 
 
Investigators are required to maintain all study documentation, including copies of CRFs, Informed 
Consents, and adequate records for the receipt and disposition of study medications, for a period of 
15 years following study close-out. 
 
The Investigator will ensure to make all study data accessible to the Clinical Monitor, Sponsor, or 
other authorized representatives of the Sponsor and Regulatory Agencies during the conduct of the 
study as well as during the archiving period. A file for each patient will be maintained that includes 
the signed Informed Consent form and copies of all source documentation related to that patient. The 
Investigator will ensure the availability of the source documents from which the information on the 
CRF is derived (conform industry standards, patient details will be pseudonymized). 
 
All information provided to the Investigator dealing with this study drug or the methodologies used 
in the protocol, as well as information obtained during the course of the study will be regarded as 
strictly confidential and proprietary to the Sponsor ("Proprietary Information"). The Investigator 
agrees not to disclose any information supplied by the Sponsor in any way without written permission 
as outlined in the Confidentiality section of this protocol. For the purposes of this section, 
"Investigator" includes, but is not limited to, the PI and/or his/her agents, designees, sub-investigators, 
or other individuals involved in the running, administration, or collection/handling of patients/data 
for this study. 
 
 
 
 
 
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 48 of 65 
 
 
 
 
 
 
 




 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 50 of 65 
 
] 
9.0 
REFERENCES 
1. Strong, K., Mathers, C. & Bonita, R. Preventing stroke: saving lives around the world. The 
Lancet Neurology 6, 182–187 (2007). 
2. Benjamin Emelia J. et al. Heart Disease and Stroke Statistics—2019 Update: A Report From 
the American Heart Association. Circulation 139, e56–e528 (2019). 
3. Wardlaw, J. M., Murray, V., Berge, E. & del Zoppo, G. J. Thrombolysis for acute ischaemic 
stroke. Cochrane Database of Systematic Reviews (2014) 
doi:10.1002/14651858.CD000213.pub3. 
4. Goyal, M. et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-
analysis of individual patient data from five randomised trials. The Lancet 387, 1723–1731 
(2016). 
5. Emberson, J. et al. Effect of treatment delay, age, and stroke severity on the effects of 
intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of 
individual patient data from randomised trials. The Lancet 384, 1929–1935 (2014). 
6. Hill, M. D. & Goyal, M. Treat fast but abandon time from ischaemic stroke onset as a criterion 
for treatment: The DAWN and DEFUSE-3 trials. International Journal of Stroke 13, 344–347 
(2018). 
7. Román, L. S. et al. Imaging features and safety and efficacy of endovascular stroke treatment: a 
meta-analysis of individual patient-level data. The Lancet Neurology 17, 895–904 (2018). 
8. Campbell, B. C. V. et al. Penumbral imaging and functional outcome in patients with anterior 
circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a 
meta-analysis of individual patient-level data. The Lancet Neurology 18, 46–55 (2019). 
9. Ma, H. et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N 
Engl J Med 380, 1795–1803 (2019). 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 51 of 65 
 
10. Cheatwood, J. L., Emerick, A. J. & Kartje, G. L. Neuronal Plasticity and Functional Recovery 
After Ischaemic Stroke. Topics in Stroke Rehabilitation 15, 42–50 (2008). 
11. Wu, X. et al. NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and 
BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice. 
Journal of Neuroinflammation 16, 192 (2019). 
12. Rinne, P. et al. α-Melanocyte-stimulating hormone regulates vascular NO availability and 
protects against endothelial dysfunction. Cardiovascular Research 97, 360–368 (2013). 
13. Giuliani, D. et al. Broad therapeutic treatment window of [Nle4, D-Phe7]α-melanocyte-
stimulating hormone for long-lasting protection against ischaemic stroke, in Mongolian gerbils. 
European Journal of Pharmacology 538, 48–56 (2006). 
14. Chen, G. et al. Reduction of ischaemic stroke in rat brain by alpha melanocyte stimulating 
hormone. Neuropeptides 42, 331–338 (2008). 
15. Bitto, A. et al. Protective effects of melanocortins on short-term changes in a rat model of 
traumatic brain injury*. Crit. Care Med. 40, 945–951 (2012). 
16. Zierath, D., Tanzi, P., Cain, K., Shibata, D. & Becker, K. Plasma α-melanocyte stimulating 
hormone predicts outcome in ischaemic stroke. Stroke 42, 3415–3420 (2011). 
17. Minder, E. I. Afamelanotide. Drugs of the Future 35, 365 (2010). 
18. Langendonk, J. G. et al. Afamelanotide for Erythropoietic Protoporphyria. N. Engl. J. Med. 
373, 48–59 (2015). 
19. Biolcati, G. et al. Long-term observational study of afamelanotide in 115 patients with 
erythropoietic protoporphyria. Br. J. Dermatol. 172, 1601–1612 (2015). 
  
 
 
 
 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 52 of 65 
 
10.0 APPENDICES 
APPENDIX 1: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient’s best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician’s knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with the 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 53 of 65 
 
physician or other health care professionals and never with the research subjects, even though they 
have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 54 of 65 
 
Scientific Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other undue 
influence and must be duly qualified. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as applicable international norms 
and standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events 
(SAE). No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may be enrolled in a research study unless 
he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, post-study provisions and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the methods used 
to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 55 of 65 
 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only minimal 
risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent should 
be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research  group. In such circumstances 
the physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the research must be obtained 
as soon as possible from the subject or a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 56 of 65 
 
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorised representative, may use an unproven intervention if 
in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating 
suffering. This intervention should subsequently be made the object of research, designed to evaluate 
its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made 
publicly available. 
 


 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
Page 57 of 65 
 
APPENDIX 2: ELEMENTS OF INFORMED CONSENT DOCUMENTATION 
In seeking informed consent, the following information shall be provided to each patient: 
1. 
A statement that the study involves research, an explanation of the purposes of the research and 
the expected duration of the patient's participation, a description of the procedures to be 
followed, and identification of any procedures which are experimental; 
2. 
A description of any reasonably foreseeable risks or discomforts to the patient; 
3. 
A description of any benefits to the patient or to others which may reasonably be expected from 
the research; 
4. 
Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the patient; 
5. 
A statement describing the extent, if any, to which confidentiality of records identifying the 
patient will be maintained; and, 
6. 
An explanation of whom to contact for answers to pertinent questions about the research and 
participants' rights. It is the Sponsor's policy to reimburse an institution or Investigator for 
expenditures for the medical treatment of normal and patient volunteers who are injured as a 
direct result of their participation in the Sponsor's protocol as long as the Investigator has 
complied with the provisions of the protocol. Therefore, the consent form should reflect this in 
its explanation of the institution's policy. Further details on whom the volunteer should contact 
in case of injury should also be included. 
7. 
An explanation of whom to contact for answers to pertinent questions about the research and 
research patient's rights and whom to contact in the event of a research-related injury to the 
patient. 
8. 
A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the patient is otherwise entitled, and that the patient may discontinue 
participation at any time without penalty or the loss of benefits to which the patient is otherwise 
entitled. 
When appropriate, one or more of the following elements of information shall also be provided to 
each patient (required under ICH): 
1. 
A statement that the particular treatment or procedure may involve risks to the patient (or to the 
embryo or foetus, if the patient is or may become pregnant) which are currently unforeseeable; 
2. 
Anticipated circumstances under which the patient's participation may be terminated by the 
Investigator without regard to the patient's consent; 
3. 
Any additional costs to the patient that may result from participation in the research; 
4. 
The consequences of a patient's decision to withdraw from the research and the procedures for 
the orderly termination of participation by the patient; 
5. 
A statement that significant new findings that develop during the course of the research which 
may relate to the patient's willingness to continue participation will be provided to the patient; 
and, 
6.  
The approximate number of participants involved in the study. 






 
 
 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
3. Visual: Visual fields (upper and lower quadrants) are tested by 
confrontation, using finger counting or visual threat, as appropriate. 
Patients may be encouraged, but if they look at the side of the moving 
fingers appropriately, this can be scored as normal. If there is unilateral 
blindness or enucleation, visual fields in the remaining eye are scored. 
Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. 
If patient is blind from any cause, score 3. Double simultaneous 
stimulation is performed at this point. If there is extinction, patient 
receives a 1, and the results are used to respond to item 11. 
0 = No visual loss. 
1 = Partial hemianopia. 
2 = Complete hemianopia. 
3 = Bilateral hemianopia (blind including cortical blindness). 
 
4.  Facial Palsy:  Ask – or use pantomime to encourage  – the patient to 
show teeth or raise eyebrows and close eyes. Score symmetry of grimace 
in response to noxious stimuli in the poorly responsive or non- 
comprehending patient. If facial trauma/bandages, orotracheal tube, tape 
or other physical barriers obscure the face, these should be removed to 
the extent poss ble. 
0 = Normal symmetrical movements. 
1 = Minor paralysis (flattened nasolabial fold, asymmetry on 
smiling). 
2 = Partial paralysis (total or near-total paralysis of lower face). 
3 = Complete paralysis of one or both sides (absence of facial 
movement in the upper and lower face). 
 
5. Motor Arm: The limb is placed in the appropriate position: extend  the 
arms (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift 
is scored if the arm falls before 10 seconds. The aphasic patient is 
encouraged using urgency in the voice and pantomime, but not noxious 
stimulation. Each limb is tested in turn, beginning with the non-paretic 
arm. Only in the case of amputation or joint fusion at the shoulder, the 
examiner should record the score as untestable (UN), and clearly write 
the explanation for this choice. 
0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. 
1 = Drift; limb holds 90 (or 45) degrees, but drifts down before 
full 10 seconds; does not hit bed or other support. 
2 = Some effort against gravity; limb cannot get to or maintain 
(if cued) 90 (or 45) degrees, drifts down to bed, but has 
some effort against gravity. 
3 = No effort against gravity; limb falls. 
4 = No movement. 
UN = Amputation or joint fusion, explain:   
 
5a. Left Arm 
5b. Right Arm 
5a 
 
5b   
 
6. Motor Leg: The limb is placed in the appropriate position: hold the leg 
at 30 degrees (always tested supine). Drift is scored if the leg falls before 
5 seconds. The aphasic patient is encouraged using urgency in the voice 
and pantomime, but not noxious stimulation. Each limb is tested in turn, 
beginning with the non-paretic leg. Only in the case of amputation or joint 
fusion at the hip, the examiner should record the score as untestable 
(UN), and clearly write the explanation for this choice. 
0 = No drift; leg holds 30-degree position for full 5 seconds. 
1 = Drift; leg falls by the end of the 5-second period but does 
not hit bed. 
2 = Some effort against gravity; leg falls to bed by 5 seconds, 
but has some effort against gravity. 
3 = No effort against gravity; leg falls to bed immediately. 
4 = No movement. 
UN = Amputation or joint fusion, explain:   
 
6a. Left Leg 
6b. Right Leg 
6a 
 
6b   
 


 
 
 
 
CLINUVEL                                                                -Confidential-                                                           
 
 
 
7. Limb Ataxia: This item is aimed at finding evidence of a unilateral 
cerebellar lesion. Test with eyes open. In case of visual defect, ensure 
testing is done in intact visual field. The finger-nose-finger and heel-shin 
tests are performed on both sides, and ataxia is scored only if present 
out of proportion to weakness. Ataxia is absent in the patient who cannot 
understand or is paralysed. Only in the case of amputation or joint fusion, 
the examiner should record the score as untestable (UN), and clearly 
write the explanation for this choice. In case of blindness, test by having 
the patient touch nose from extended arm position. 
0 = Absent. 
1 = Present in one limb. 
2 = Present in two limbs. 
UN = Amputation or joint fusion, explain:   
 
 
8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal 
from noxious stimulus in the obtunded or aphasic patient. Only sensory 
loss attributed to stroke is scored as abnormal and the examiner should 
test as many body areas (arms [not hands], legs, trunk, face) as needed 
to accurately check for hemisensory loss. A score of 2, “severe or total 
sensory loss,” should only be given when a severe or total loss of 
sensation can be clearly demonstrated. Stuporous and aphasic patients 
will, therefore, probably score 1 or 0. The patient with brainstem stroke 
who has bilateral loss of sensation is scored 2. If the patient does not 
respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are 
automatically given a 2 on this item. 
0 = Normal; no sensory loss. 
1 = Mild-to-moderate sensory loss; patient feels pinprick is 
less sharp or is dull on the affected side; or there is a loss of 
superficial pain with pinprick, but patient is aware of being 
touched. 
2 = Severe to total sensory loss; patient is not aware of being 
touched in the face, arm, and leg. 
 
9. Best Language: A great deal of information about comprehension will 
be obtained during the preceding sections of the examination. For this 
scale item, the patient is asked to describe what is happening in the 
attached picture, to name the items on the attached naming sheet and to 
read from the attached list of sentences. Comprehension is judged from 
responses here, as well as to all of the commands in the preceding 
general neurological exam. If visual loss interferes with the tests, ask the 
patient to identify objects placed in the hand, repeat, and produce 
speech. The intubated patient should be asked to write. The patient in a 
coma (item 1a=3) will automatically score 3 on this item. The examiner 
must choose a score for the patient with stupor or limited cooperation, but 
a score of 3 should be used only if the patient is mute and follows no one-
step commands. 
0 = No aphasia; normal. 
1 = Mild-to-moderate aphasia; some obvious loss of fluency or 
facility of comprehension, without significant limitation on 
ideas expressed or form of expression. Reduction of speech 
and/or comprehension, however, makes conversation about 
provided materials difficult or impossible. For example, in 
conversation about provided materials, examiner can 
identify picture or naming card content from patient’s 
response. 
2 = Severe aphasia; all communication is through fragmentary 
expression; great need for inference, questioning, and 
guessing by the listener. Range of information that can be 
exchanged is limited; listener carries burden of 
communication. Examiner cannot identify materials 
provided from patient response. 
3 = Mute, global aphasia; no usable speech or auditory 
comprehension. 
 
10. Dysarthria: If patient is thought to be normal, an adequate sample of 
speech must be obtained by asking patient to read or repeat words from 
the attached list. If the patient has severe aphasia, the clarity of 
articulation of spontaneous speech can be rated. Only if the patient is 
intubated or has other physical barriers to producing speech, the 
examiner should record the score as untestable (UN), and clearly write 
an explanation for this choice. Do not tell the patient why he or she is 
being tested. 
0 = Normal. 
1 = Mild-to-moderate dysarthria; patient slurs at least some 
words and, at worst, can be understood with some difficulty. 
2 = Severe dysarthria; patient's speech is so slurred as to be 
unintelligible in the absence of or out of proportion to any 
dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain:  
 
 
11. Extinction and Inattention (formerly Neglect): Sufficient 
information to identify neglect may be obtained during the prior testing. If 
the patient has a severe visual loss preventing visual double 
simultaneous stimulation, and the cutaneous stimuli are normal, the 
score is normal. If the patient has aphasia but does appear to attend to 
both sides, the score is normal. The presence of visual spatial neglect or 
anosognosia may also be taken as evidence of abnormality. Since the 
abnormality is scored only if present, the item is never untestable. 
0 = No abnormality. 
1 = Visual, tactile, auditory, spatial, or personal inattention 
or extinction to bilateral simultaneous stimulation in one of 
the sensory modalities. 
2 = Profound hemi-inattention or extinction to more than 
one modality; does not recognise own hand or orients to 
only one side of space. 
 




 
 
 
CLINUVEL                                                                -Confidential-                                                           
 
You know how. 
 
Down to earth. 
 
 
 
I got home from work. 
 
Near the table in the dining 
room. 
 
They heard him speak on the 
radio last night.