Conditions: Variegate Porphyria
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The primary objective is to evaluate the impact of afamelanotide on the severity of skin disease in patients with Variegate Porphyria (VP). The secondary objectives are to evaluate the safety and tolerability of afamelanotide in patients with VP and evaluate the impact of afamelanotide on the quality of life of patients with VP.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Afamelanotide 16 MG
Intervention descriptions: intervention 1: Eligible patients will receive one dose of afamelanotide 16mg every 28 days (up to six doses), as a controlled-release formulation.

Protocol document:
Prot_SAP_001.pdf: 
 
A Proof of Concept, Phase IIa, Open Label Study to Evaluate the Safety 
and Efficacy of Afamelanotide in Patients with Variegate Porphyria (VP)-
related skin disease. 
 
Protocol No: CUV040 
ClinicalTrials.gov ID: NCT05854784 
EudraCT Number: 2018-004164-60 
Document Date: 14 December 2022 


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Page 1 of 83 
                               
 
 
 
A Proof of Concept, Phase IIa, Open Label Study to Evaluate the 
Safety and Efficacy of Afamelanotide in Patients with Variegate 
Porphyria (VP)-related skin disease. 
[Short Title: Phase IIa VP Study] 
 
Protocol No: CUV040 
 
 
14 December 2022 
 
 
SPONSOR 
CLINUVEL (UK) LTD 
Wesley House, Bull Hill 
Leatherhead, KT22 7AH 
United Kingdom 
 
This study will be conducted in compliance with Good Clinical Practices (GCP)  
and ICH guidelines, and all patient study documents will be archived by CLINUVEL (UK) LTD. 
 
 
CONFIDENTIAL 
Part or all of the information in this protocol may be unpublished material. Accordingly, this protocol is to be treated as 
confidential and restricted to its intended use. If any portion of this material is required for purposes of publication, 
authorisation must be obtained from CLINUVEL (UK) LTD and must not be disclosed or used except as authorised in 
writing by CLINUVEL (UK) LTD. This material is the property of CLINUVEL (UK) LTD and must not be disclosed 
or used except as authorised in writing by CLINUVEL (UK) LTD. 




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PROTOCOL SYNOPSIS 
Name of company: 
CLINUVEL (UK) LTD 
Name of finished product: 
SCENESSE® 
Name of active ingredient: 
Afamelanotide  
Title of study: A Proof of Concept, Phase IIa, Open Label Study to Evaluate the Safety and 
Efficacy of Afamelanotide in Patients with Variegate Porphyria (VP)-related skin disease  
Study number: CUV040 
Phase of development: IIa 
Study period: 8 months including the screening and follow-up period. 
Objectives: 
Primary objective  
• Evaluate the impact of afamelanotide on the severity of skin disease in patients with VP.  
 
Secondary objectives 
• Evaluate the safety and tolerability of afamelanotide in patients with VP.  
• Evaluate the impact of afamelanotide on the quality of life of patients with VP.  
 
Methodology:  
This is an 8-month open label study in adult patients with confirmed VP-related skin disease. To 
determine eligibility for entry 
 
 Eligible patients will be 
enrolled 
 
 
 
 
Clinical evaluations will be performed by the same Investigator over the course of the study during 
the Screening period (Day -28 and Day 0) and on Days 28, 56, 84, 112, 140, 168 and 196 or 
Premature Termination (if applicable). 
 
The evaluations will include assessments of disease severity using an 11-point Likert-type Visual 
Analogue Scale (VAS), a 5-point Investigator’s Global Assessment (IGA) scale and a clinical 
global impression of change (CGIC) as well as a count of skin lesions 
 
 
  
A mapping of the skin lesions will be performed at the same time using digital photography. 
 
The patient will also assess disease severity during the Screening period (Day -28 and Day 0) and 
on Days 28, 56, 84, 112, 140, 168 and 196 or Premature Termination (if applicable) through a 
VAS and a patient global impression of change (PGIC). Quality of life will be evaluated at the 
same time 
 Outdoors light exposure and 
trauma will be recorded daily by the patient 
. 
 
Safety assessments (including laboratory evaluations, review of adverse events) will be carried 
out at each study visit and in between, if required for safety-related reasons, at the Investigator’s 
discretion. 
 
 
 
 


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No. of participants planned: 6 
Treatment: 
Afamelanotide 
 
Diagnosis and main criteria for entry: 
To be eligible to enter the study, patients must meet the following inclusion criteria: 
• Male or female patients with a biochemically and/or molecular-genetically confirmed 
diagnosis of VP. 
• Patients with VP-related skin symptoms. 
 
 
  
• Aged 18-70 years. 
• Providing written Informed Consent prior to the performance of any study-specific 
procedure. 
• Willing and able to comply with the conditions specified in the protocol and study 
procedures, in the opinion of the Investigator.  
 
To be eligible to enter the study, patients must not meet any of the following exclusion criteria: 
• 
 
 
 
• Had two or more acute attacks of hepatic porphyria, as defined by the occurrence or acute 
porphyric symptoms 
 
lasting more than two days, within 12 months prior to the 
Screening period. 
• 
 
 
 
 
 
 
 
 
• Presence of severe hepatic disease 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Test product:  
Afamelanotide 
   
Dose:  
  
Mode of administration: 
Subcutaneous injection 
Reference therapy: 
Not applicable 
Criteria for evaluation: 
Efficacy Endpoints: 
Efficacy of the treatment will be assessed by: 
• Clinical Global Impression of Change (CGIC) 
• IGA of disease severity using an 11-point VAS (VAS IGA); 
• Static IGA of disease severity on a 5-point scale (5-point IGA);  
• Patient’s Global Assessment of disease severity evaluating skin fragility using a VAS; 
• Patient Global Impression of Change (PGIC) 
• Number of new skin lesions (blisters/wounds) 
 
 as counted by the Investigator and mapped by 
standardised digital photography; 
• Quality of Life, 
 
 
 
 
 
 
 
 
 
• Patient records 
 of outdoors light exposure and trauma. 
 
Safety and Tolerability Endpoints: 
Safety and tolerability will be assessed by measuring treatment-emergent adverse events (TEAEs) 
(coded as MedDRA Preferred Terms).   
 
Statistical Methods: 
 
Efficacy analysis:  
Primary efficacy endpoint:  
• The change in severity 
 
 as measured by the CGIC. 
The null hypothesis is formulated as: 
H0: there is no change in CGIC score at one or more timepoints after treatment. 
 
 
Secondary efficacy endpoints:  
• The change in severity 
 
 as measured by: 
o 5-point IGA; 
o 11-point VAS IGA; 
o The Patient’s Global Assessment of disease severity using a VAS; 
o The Patient Global Impression of Change using PGIC. 


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• The change in the number of new skin lesions 
 
 as 
counted by the Investigator.  
• The change in Quality of Life 
 
 
 
 
 
 
 
 
• Change in outdoors light exposure over time 
 Trauma events will be 
tabulated. 
 
 
 
 
 
 
 
 
 
 
 
All the applied instruments will be analysed using appropriate methods to evaluate their suitability 
to assess changes in skin disease severity, 
 
 
The patient-related outcome (PRO) instruments will be assessed 
based on the judgement of the patients on their suitability to document their skin disease. 
 
Safety Analyses: 
The number of participants with TEAEs will be summarised by MedDRA preferred term and 
body system. TEAEs will be further summarised by intensity, seriousness, outcome and 
relationship to study drug. Participants who prematurely terminate treatment due to adverse events 
related to study medication will be summarised. 


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TABLE OF CONTENTS 
SIGNATURES OF AGREEMENT FOR PROTOCOL AND AMENDMENTS ........................................................ 2 
PROTOCOL SYNOPSIS ................................................................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................................................. 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................ 10 
1.0 
ETHICS.................................................................................................................................................................. 12 
1.1 
Human Research Ethics Committee (HREC) ..................................................................................................... 12 
1.2 
Ethical Conduct of the Study .............................................................................................................................. 12 
1.3 
Participant Information and Informed Consent ................................................................................................. 12 
1.4 
Protocol Amendments ......................................................................................................................................... 13 
1.5 
Confidentiality .................................................................................................................................................... 13 
2.0 
STUDY PERSONNEL AND STUDY ADMINISTRATION ............................................................................. 14 
3.0 
INTRODUCTION AND STUDY RATIONALE ................................................................................................ 15 
4.0 
STUDY OBJECTIVES ......................................................................................................................................... 20 
4.1 
Primary Objective .............................................................................................................................................. 20 
4.2 
Secondary Objectives ......................................................................................................................................... 20 
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 Patient Recruitment Management .................................................................................................................. 24 
5.2.4 Withdrawals and Replacement of Participants .............................................................................................. 24 
5.3 
Study Medication ................................................................................................................................................ 25 
5.3.1 
Description of Study Medication ............................................................................................................... 25 
5.3.2 
Treatment Group ....................................................................................................................................... 25 
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 
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 


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5.5.1 
Description of Study Days ........................................................................................................................ 26 
5.5.1.1 Screening Period ...................................................................................................................................................... 26 
5.5.1.2 Study Period ............................................................................................................................................................. 28 
5.5.1.3 Follow-Up Period ..................................................................................................................................................... 31 
5.5.2 
Study Procedures Flowchart ..................................................................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.3.2 
Safety variables ...................................................................................................................................................... 34 
5.5.3.2.1 
Clinical Laboratory Evaluations .................................................................................................................. 34 
5.5.3.2.2 
Physical Examination .................................................................................................................................. 35 
5.5.3.2.3 
Weight and Height....................................................................................................................................... 36 
5.5.3.2.4 
Vital Signs Measurements ........................................................................................................................... 36 
5.5.3.2.5 
Dermatology Examination and Full Body Photography .............................................................................. 36 
5.5.3.2.6 
Adverse Events ............................................................................................................................................ 36 
5.6 
Data Quality Assurance ..................................................................................................................................... 41 
5.6.1 
Data Collection, Monitoring and Auditing ............................................................................................... 41 
5.6.2 
Database Management and Quality Control ............................................................................................ 42 
5.7 
Statistical Methods and Determination of Sample Size ...................................................................................... 42 
 
 
5.7.2 
Efficacy Assessment .................................................................................................................................. 42 
5.7.2.1 
Specification of Efficacy Endpoints ....................................................................................................................... 42 
5.7.3 
Safety Assessment ..................................................................................................................................... 43 
5.7.3.1 
Specification of Safety 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 
Intention To Treat (ITT) Population ...................................................................................................................... 43 
5.7.5.3 
Handling of Missing and Incomplete Data............................................................................................................. 44 
5.7.5.4 
Per Protocol Analysis (PPA) Population ................................................................................................................ 44 


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5.7.5.5 
Demographic and Initial Characteristics ................................................................................................................ 44 
5.7.5.6 
Efficacy .................................................................................................................................................................. 44 
5.7.5.7 
Safety ..................................................................................................................................................................... 45 
5.7.5.8 
Adverse Events ...................................................................................................................................................... 46 
5.7.5.9 
Clinical Laboratory Data ........................................................................................................................................ 46 
5.7.5.10 
Other Clinical Data Analyses ........................................................................................................................... 46 
5.7.5.11 
Interim Evaluation ............................................................................................................................................ 47 
5.8 
Early Termination of the Study ........................................................................................................................... 47 
6.0 
STUDY REPORT, PUBLICATION POLICY & ARCHIVING OF STUDY DOCUMENTATION ............ 48 
7.0 
STUDY TIMETABLE .......................................................................................................................................... 49 
8.0 
REFERENCES ...................................................................................................................................................... 50 
9.0 
APPENDICES ....................................................................................................................................................... 53 
APPENDIX 1: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ............................................... 53 
APPENDIX 2: ELEMENTS OF INFORMED CONSENT DOCUMENTATION ......................................................... 59 
APPENDIX 3: STUDY FLOW CHART........................................................................................................................ 60 
APPENDIX 4: CLINICAL GLOBAL IMPRESSION OF CHANGE (CGIC) ................................................................ 62 
APPENDIX 5: INVESTIGATOR’S GLOBAL ASSESSMENT USING AN 11-POINT LIKERT-TYPE VISUAL 
ANALOGUE SCALE (VAS IGA) .................................................................................................................................. 63 
APPENDIX 6: STATIC INVESTIGATOR’S GLOBAL ASSESSMENT USING A 5-POINT SCALE (5-POINT IGA) .. 64 
APPENDIX 7: PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) .................................................................. 65 
 
APPENDIX 9: SKIN LESIONS COUNT ...................................................................................................................... 67 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
 
  
 
 
 
 
 
 
 
 
β-HCG 
Beta Human Chorionic Gonadotropin 
CGIC 
Clinical Global Impression of Change 
 
 
CRF 
Case report form 
 
 
 
  
 
 
 
 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
 
  
HREC 
Human Research Ethics Committee 
ICH 
International Council for Harmonization 
IGA 
Investigator global assessment 
 
 
ITT 
Intention-to-treat 
kg 
Kilogram 
LPI 
Last patient in 
 
 
LPLV 
Last patient last visit 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
 
 
 
 
 
 
 
 
PGIC 
Patient Global Impression of Change 
PPIX 
Protoporphyrin IX 
 
 
 
 
PRO 
Patient reported outcome 
QoL 
Quality of life 
 
 
 
 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 


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SOM 
Study Operating Manual 
 
 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAEs 
Treatment-emergent adverse events 
UK 
United Kingdom 
 
 
 
 
VP 
Variegate porphyria 
 
  
WMA 
World Medical Association 
 
  
 


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1.0 ETHICS 
1.1 Human Research Ethics Committee (HREC) 
An appropriate HREC will approve the protocol and the Participant Information and Informed 
Consent Form before the study is initiated at each study centre. 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 International Council for Harmonization (ICH) guidelines for Good Clinical Practice 
(GCP) governing the conduct of studies, and all applicable local regulations. 
 
 
 
 
 
1.3 Participant Information and Informed Consent 
The treating physician will make the initial contact with the patient. Prior to any study specific 
screening procedures, the Investigator will explain to each participant 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 screening procedures are performed, the subject must voluntarily sign an informed consent 


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statement in the presence of a witness, if applicable. The inclusion and exclusion criteria will be 
reviewed at Days -28 and 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 by the appropriate CLINUVEL (UK) LTD personnel and the Investigator(s). 
 
Depending on the requirements of the study centre's HREC and relevant Competent Authority (where 
applicable), protocol amendments will either need to be submitted for approval or advised by 
notification. Where formal approval is required, the revision 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 
investigative centre, are held strictly confidential and confined to the clinical personnel involved in 
conducting the study, under the supervision of the Investigator.
 
 
 
 
 
 
 
 


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2.0 STUDY PERSONNEL AND STUDY ADMINISTRATION 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.0 
INTRODUCTION AND STUDY RATIONALE 
Variegate porphyria (VP) is a rare autosomal dominant inherited disorder characterised by the 
deficiency of the mitochondrial enzyme protoporphyrinogen oxidase (PPOX), the penultimate 
enzyme in the haem biosynthesis pathway. VP presents with phototoxicity, leading to chronic 
blistering and fragility of sun/light-exposed areas of the skin, acute attacks of neurovisceral 
symptoms, or both cutaneous and acute symptoms1,2. Manifestations of VP appear typically in 
adulthood, and rarely before puberty1. Although the acute neurovisceral attacks can respond to 
treatment used for other acute porphyrias, at present there is no effective intervention for the chronic 
skin symptoms1,2. SCENESSE® (afamelanotide 16mg) was granted marketing authorisation in the 
European Union in December 2014 and in Australia in October 2020 for the prevention of 
phototoxicity in adult patients with erythropoietic protoporphyria (EPP) and in the United States in 
October 2019 to increase pain free light exposure in adult patients with a history of phototoxic 
reactions from EPP, another cutaneous porphyria. In VP and EPP patients present with phototoxicity 
due to accumulation of protoporphyrin. 
 
 
  
 
The reported prevalence of VP varies from 0.3 to 2 cases per 100,000 inhabitants but has been 
reported as more common in the Caucasian South African population (up to 1 in 300 people) due to 
a founder effect. In Europe, the prevalence varies from 0.32 to 1 cases per 100,000 inhabitants3, 4. 
The occurrence of skin disease in VP patients varies; studies from Finland, France, the UK and 
Switzerland reported that symptomatic patients had either cutaneous symptoms only, acute attacks 
only or both acute attacks and cutaneous symptoms5,6,7.  
 
Phototoxicity in VP leads to chronic fragility and blistering, 
 
 
 
 
 
 
 The lesions result from sun/light exposure that activates 
porphyrins and makes the skin fragile as well as prone to blister formation and damage to the 
superficial layers from minor mechanical trauma (e.g. slight knock on the back of the hand). The 
subepidermal vesicles, bullae, and erosions crust over and heal slowly 
 When 
blisters rupture they may become infected and result in pigmented or, more rarely, depigmented scars. 
 
 Pain occurs from the superficial wounds and secondary infections8. Some patients develop 


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progressive pseudosclerodermatous changes in the hands and fingers8. Other chronic skin findings 
include milia (more commonly seen in porphyria cutanea tarda; PCT), scarring, thickening, and areas 
of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may also 
occur8,9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
With the exception of haem arginate for the treatment of acute attacks, there are no authorised 
medicinal products for VP, in particular for the prevention of phototoxicity and related skin- 
manifestations. Current advice for the skin complaints of VP patients includes protective clothing and 
avoidance of sunlight exposure. Analgesics and antibiotics may be used for treating painful and 
superimposed infections. Topical steroids have been found to have little or no benefit1. Advice 
regarding the avoidance of exacerbating factors such as some drugs, smoking and excessive alcohol 
consumption has been shown to be effective in reducing the number of acute neurovisceral attacks in 
VP, although the effect of such measures on phototoxicity and skin complaints has been limited5. 
 
VP and EPP share similar clinical features. In both forms, patients experience phototoxicity and suffer 
episodes most severely in spring and summer when the atmospheric intensity of light increases. 
Phototoxicity is due to overproduction and accumulation of protoporphyrin IX (PPIX). Light 
exposure of the skin will result in activation of protoporphyrin in plasma and in interstitial fluids. The 
activated porphyrins will induce activated oxygen and reactive oxygen species, which in turn induce 


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lipid- and DNA damage, damage to macromolecules, degranulation of mast cells, inflammatory 
reaction and endothelial damage. VP and EPP share very similar histopathological changes, with 
abnormal superficial dermal vessels which are often tube-like with thickened walls containing 
periodic acid Schiff (PAS)-positive material. In both forms of porphyria, the histological changes are 
to be found in light and sun-exposed areas23,24,25. 
 
Afamelanotide is a potent analogue of α-MSH which stimulates the production of eumelanin in the 
skin (epidermis) without the specific cell damage that usually occurs when melanin production is 
stimulated by UV radiation20,21. Melanin, in the form of eumelanin, is a photoprotective agent. The 
mechanisms proposed for photoprotection include, but are not limited to, the absorption and scattering 
of UV light, free radical scavenging and quenching of UV light16,17. There is also increasing evidence 
that melanogenesis represents a major antioxidant defense mechanism in melanocytes, neutralising 
the deleterious effects of free radicals and active oxygen species18. Eumelanin acts as a neutral density 
filter and, unlike most sunscreens, reduces all wavelengths of light equally so that the photoprotection 
provided by epidermal melanin pigmentation is essentially independent of wavelength19. Moreover, 
alpha-MSH signalling induces antioxidative enzymes and improves DNA repair processes22. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Afamelanotide 16mg has been shown to be effective in the prevention of phototoxicity in EPP and 
had obtained marketing authorisation in the European Union and to increase pain free light exposure 
in adult patients with a history of phototoxic reactions from EPP in the United States for this 




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This study aims to extend knowledge of the photoprotective effects of afamelanotide in the cutaneous 
porphyria patients. 
 
 
 
 


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4.0 
STUDY OBJECTIVES 
4.1 
Primary Objective 
The primary objective of this study is to evaluate the impact of afamelanotide on the severity of the 
skin disease in patients with VP. 
4.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate the safety and tolerability of afamelanotide in patients with VP; 
• Evaluate the impact of afamelanotide on the quality of life of patients with VP. 
 
 
 


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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 6 patients with VP skin disease during 
an 8-month period 
 
 
To determine eligibility for study inclusion, 
 
 Eligible patients will be enrolled 
and will receive 
 
 
 
 
Clinical evaluations will be performed by the same Investigator over the course of the study during 
the Screening period (Day -28 and Day 0) and on Days 28, 56, 84, 112, 140, 168 and 196 or Premature 
Termination (if applicable). 
 
The evaluations will include assessments of disease severity using an 11-point Likert-type Visual 
Analogue Scale (VAS IGA), a 5-point Investigator’s Global Assessment (IGA) scale and a clinical 
global impression of change (CGIC) as well as a count of skin lesions 
 
 
  
A mapping of the skin lesions will be performed at the same time using digital photography. 
The patient will also assess disease severity during the Screening period (Day -28 and Day 0) and on 
Days 28, 56, 84, 112, 140, 168 and 196 or Premature Termination (if applicable) through a VAS and 
a patient global impression of change (PGIC). Quality of life will be evaluated at the same time 
 
Outdoors light exposure and trauma will be recorded 
daily by the patient 
 
 
 
Safety assessments (including laboratory evaluations, 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. 
 


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5.2 
Selection of Study Population 
The target population consists of male and female patients with VP who have chronic skin changes 
including blisters, wounds and infected wounds. 
 
  
  
 
  
 
 
  
 
 
 
 
The following inclusion and exclusion criteria must be met by each patient before enrolment in the 
study. 
5.2.1 Inclusion Criteria 
The participants have to fulfil all of the following inclusion criteria for study participation: 
• Male or female patients with a biochemically and/or molecular-genetically confirmed 
diagnosis of VP. 
• Patients with VP-related skin symptoms. 
 
 
• Aged 18-70 years. 
• Providing written Informed Consent prior to the performance of any study-specific procedure. 
• Willing and able to comply with the conditions specified in the protocol and study procedures, 
in the opinion of the Investigator.  


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5.2.2 Exclusion Criteria 
To be eligible to enter the study, patients must not meet any of the following exclusion criteria: 
 
 
 
 
• Had two or more acute attacks of hepatic porphyria, as defined by the occurrence or acute 
porphyric symptoms 
 
 lasting more than two days, within 12 months prior to the Screening period. 
 
 
 
 
 
 
 
 
 
• Presence of severe hepatic disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.2.3 Patient Recruitment Management 
Patients known to the principal investigator to potentially fulfil inclusion criteria, will be contacted 
and asked for study participation. Please refer to the CUV040 Study Operating Manual (SOM) section 
5 for a detailed description of the method for patient recruitment management. 
5.2.4 Withdrawals and Replacement of Participants 
Patient discontinuation occurs when a patient does not complete the study as required by the study 
protocol. Participants will be free to discontinue their participation in this trial at any time for any 
reason. In addition, participants may be withdrawn from the trial at the discretion of the Sponsor, the 
Investigator or medically qualified nominee. A patient may withdraw for any of, but not limited to, 
the following reasons: 
• Informed consent withdrawn by the patient; 
• AE requiring study discontinuation of patient; 
• When the Investigator’s or nominee’s best professional judgment would indicate that it would 
be in the patient’s best interest to be withdrawn; 
• Violation of inclusion/exclusion requirements. 
 
The reasons for withdrawal or discontinuation of a patient will be recorded in the patient’s CRF as 
well as in the patient’s medical notes. If an AE is the reason for discontinuation, the event must be 
followed up and documented as described in 5.5.3.2 Safety variables of the protocol. If the patient 
discontinued for any reason after the enrolment into the study, during the treatment period, a study 
termination visit, as described in 5.5.1 Description of Study Days of the protocol, should be performed 
at the time of study discontinuation, or as soon as possible after discontinuation. This visit will be 
documented in the patient’s CRF as well as in the patient’s medical notes. 
 
Any patient(s) withdrawn from the trial prior to their completion, for any reason, will not be replaced. 
Data compiled to the point of discontinuation will be used for ‘intent to treat’ analysis. Participants 
deviating any of the inclusion and exclusion criteria will be described as protocol deviators. The way 
in which protocol deviators will be handled in the statistical analysis is described in the present 
protocol. 


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5.3 
Study Medication 
5.3.1 Description of Study Medication 
 
 afamelanotide. 
 
  
5.3.2 Treatment Group 
There is only one treatment group in this study. As such, all patients who satisfy the 
inclusion/exclusion criteria will be allocated a study subject number and receive afamelanotide. Study 
subject number allocation will be detailed in the CUV040 SOM.  
5.3.3 Dosage and Administration of Study Medication 
Afamelanotide 
 will be administered 
 
 on the designated study days. 
 
 
  
5.3.4 Packaging and Labeling of Study Medication 
The implant 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 implant 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. 
 
 
 
 
 


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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 will be instructed to report to the Investigator any kind of 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 until the end of the study and these will be fully documented in the 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 whether the medication may interfere with the 
objectives of the study. These include medications which cause photosensitivity or skin pigmentation.  
 
During the study, contraceptive therapy must not be changed. 
5.5 
Study Procedures 
 
This will be an outpatient study (see flowchart in Appendix 3). 
 
 
 
5.5.1 Description of Study Days 
5.5.1.1 Screening Period 
 
Screening 
 
 
The Screening Visit and related procedures will only occur after the informed consent process is 
performed and a signed and dated informed consent form has been obtained from the patient. The 
Investigator will assess eligibility for the study after the following procedures are performed: 
 
 


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Visit 2 
  
 
 
 After patient’s eligibility has been confirmed by 
the Investigator, the following procedures will be performed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.2 Study Procedures Flowchart 
Please refer to Appendix 3 for the full study flowchart. 
5.5.3 Methods of Assessment 
5.5.3.1 Efficacy variables 
 
The efficacy endpoints will be as follows: 
 
Primary Efficacy Endpoint 
• The change in severity 
 
as measured by the CGIC. 


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Secondary Efficacy Endpoints 
• The change in severity 
 
 as measured by: 
o The 5-point IGA 
o 11-point VAS IGA scale; 
o The Patient Global Impression of Change using PGIC 
o The Patient’s Global Assessment using a VAS. 
• The change in the number of new skin lesions 
 
 as 
counted by the Investigator.  
• The change in Quality of Life 
 
 
 
 
 
 
 
 
• Change in outdoors light exposure over time 
Trauma events will be tabulated. 
 
All the applied instruments will be analysed using appropriate methods to evaluate their suitability to 
assess changes in skin disease severity, 
 
 
The PRO instruments will be assessed based on the judgement of 
the patients on their suitability to document their skin disease. 
 
 
  
 
5.5.3.1.1 
Clinical Global Impression of Change (CGIC) 
A CGIC scale will be used to assess disease severity changes at Days 28, 56, 84, 112, 140, 168 and 
196, or Premature Termination Visit, if applicable. 
 
  


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5.5.3.1.2 
VAS IGA 
An 11-point Likert-type Visual Analogue Scale (VAS IGA) scale will be used to assess disease 
severity at Days -28, 0, 28, 56, 84, 112, 140, 168 and 196, or Premature Termination Visit, if 
applicable. 
 
 
5.5.3.1.3 
5-point IGA 
A 5-point Investigator’s Global Assessment (IGA) scale will be used to assess disease severity at 
Days -28, 0, 28, 56, 84, 112, 140, 168 and 196, or Premature Termination Visit, if applicable. 
 
 
 
5.5.3.1.4 
Patient Global Impression of Change (PGIC) 
A PGIC scale will be used to assess disease severity changes at Days  28, 56, 84, 112, 140, 168 and 
196, or Premature Termination Visit, if applicable. 
 
  
 
5.5.3.1.5 
Patient’s Global Assessment using a VAS 
A Patient’s Global Assessment scale of disease severity evaluating skin fragility using a VAS will be 
used at Days -28, 0, 28, 56, 84, 112, 140, 168 and 196, or Premature Termination Visit, if applicable. 
 
 
5.5.3.1.6 
Skin Mapping Photography 
A mapping of the skin will be performed at Days -28, 0, 28, 56, 84, 112, 140, 168 and 196, or 
Premature Termination Visit, 
 
  
 
  
 
 
 
 
5.5.3.1.7 
Skin Lesions Count 
The number of skin lesions 
 
will be assessed at Days -28, 0, 28, 56, 84 112, 140, 168 and 196, or Premature Termination 
Visit, if applicable. 
 


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5.5.3.1.8 
Quality of Life 
The patient’s Quality of Life, 
will be 
assessed at Days -28, 0, 28, 56, 84, 112, 140, 168 and 196, or Premature Termination Visit, if 
applicable. 
 
 
 
 
 
 
 
5.5.3.2 
Safety variables 
 
The number of participants with TEAEs will be summarised by MedDRA preferred term and body 
system. TEAEs will be further summarised by intensity, seriousness, outcome and relationship to 
study drug. Participants who prematurely terminate treatment due to AEs related to study medication 
will be summarised. 
 
5.5.3.2.1 Clinical Laboratory Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The Investigator will sign and date all laboratory reports and review all laboratory test results. The 
Investigator will evaluate the clinical significance of all values outside the reference range and will 
document within the laboratory report as well as in the patient’s CRF. If a laboratory value is outside 
the reference range and felt to represent a clinically significant change from the baseline value, this 
will be reported as an AE in the patient’s medical notes and on the AE CRF page. Clinically 
significant is defined as a change in the patient’s clinical status that is regarded as important, whether 
or not it is due to the Investigational Medicinal Product. An assessment of this AE will be made by 
the Investigator, in particular regarding the relationship and seriousness of the event to the study drug. 
 
5.5.3.2.2 Physical Examination 
A general physical examination will be performed 
 
 
  
 


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5.5.3.2.3 Weight and Height 
Weight in kilograms (kg) will be recorded 
 
 
 
5.5.3.2.4 Vital Signs Measurements 
Vital signs (blood pressure, temperature and pulse rate) will be recorded 
 
 
 
 
 
5.5.3.2.5 Dermatology Examination and Full Body Photography 
Examination of the skin and oral mucosa and full body photography will be performed 
 
  
 
 
  
 
 
 
5.5.3.2.6 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. 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 event 
spontaneously reported by or elicited from the patient itself 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. 
 
 
 
 


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 It is the responsibility of any member of the study site staff to immediately report any 
suspected AE to the Investigator. 
 
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. 
 
An Adverse Drug Reaction is a noxious and unintended response to a medicinal product related to 
any dose.  
 
All AEs will be followed up. 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, preventing the patient’s usual 
activities. 
 
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. 


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• Not Assessable - Report suggesting an adverse reaction BUT cannot be judged because 
information is insufficient or contradictory OR cannot be supplemented or verified. Non-
assessable cases by the site will be assessed by CLINUVEL and reported if deemed related to 
study drug. 
Serious Adverse Events 
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 inpatient hospitalisation or a prolongation of an existing hospitalisation; 
• 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 
hospitalisation but may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardise 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. 
In the event that the investigator becomes aware of an SAE which is thought to be related to the IMP, 
even months or years after the end of the clinical trial, it should be reported to the sponsor. 
A SAE report form will be completed and sent to CLINUVEL Safety Team at 
 or fax to the number provided in the CUV040 SOM 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 case), 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 
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Certain AEs and/or SAEs, including suspected unexpected serious adverse reactions (SUSARs), may 
warrant expediting to IECs, 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 CUV040 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 the start of the pregnancy is less than three 
months after the last afamelanotide implant was administered; 
• 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 implant was administered to 
the male patient; 
• Female patient breastfeeding when the start of breastfeeding is less than three months after 
the last afamelanotide implant 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 implant 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 implant was administered to the male 
patient. 
 
 Report Form and/or a Pregnancy Outcome/Breastfeeding Report form will be completed 
and sent to CLINUVEL Safety Team at 
or fax to the number provided in the 
CUV040 SOM 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 and breastfeeding 
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Female patients who become pregnant, give birth or begin breastfeeding during the treatment period 
will be withdrawn from treatment and complete the Premature Termination and Follow-Up Visits.  
 
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. 
Documentation and submission: 
The sponsor ensures to keep detailed records of all AEs which are reported to him by the investigators. 
Submission of SUSARs to the ethics committee (EC) and regulatory authorities will follow pertinent 
national legislation. 
These events are in particular: 
•  single cases of expected SADRs with an unexpected outcome, 
•  an increased incidence of expected SADRs considered clinically significant, 
•  SUSARs occurring after a concerned person has completed the trial, 
•  events related to the conduct of the trial or the development of the investigational medicinal product 
possibly affecting the safety of the concerned persons. 
All additional measures deemed necessary through new findings and taken by the Sponsor or the 
investigator to protect the safety of the persons concerned and their triggering circumstances will be 
reported as soon as possible to the concerned regulatory authorities and the ECs, if applicable. 
Periodic safety reporting to regulatory authorities and the IECs will follow pertinent national 
legislation. 
 
Follow Up: 
All SAEs judged to be related to the investigational medicinal product must be followed by the 
investigator until their conclusion or until the investigator determines that the patient’s condition is 
stable. All other ADRs must be followed by the investigator until the conditions mentioned above are 
met or until Day 196±5 or 28±5 Days after End of Treatment Visit, whichever comes first, and until 
all ADR-related queries for the subject have been resolved.  The investigator will take all appropriate 
and necessary therapeutic measures required for resolution of the ADRs, if applicable. All efforts to 
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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 a Data Management Plan. 
5.7 
Statistical Methods and Determination of Sample Size 
5.7.1 Statistical and Analytical Plans 
A formal statistical analysis plan will be prepared prior to completion of the study and before data 
analysis is undertaken.  
5.7.2 Efficacy Assessment 
 
5.7.2.1 
Specification of Efficacy Endpoints 
 
Efficacy of the treatment will be assessed by: 
• CGIC  
• IGA of disease severity using an 11-point VAS (VAS IGA); 
• Static IGA of disease severity on a 5-point scale (5-point IGA);  
• Patient’s Global Assessment of disease severity evaluating skin fragility using a VAS; 
• PGIC  
• Number of new skin lesions 
 
 as counted by the Investigator 
 
 
• Quality of Life, 
 
 
 
 
 
 
 


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• Patient records 
of outdoors light exposure and trauma. 
 
All the applied instruments will be analysed using appropriate methods to evaluate their suitability to 
assess changes in skin disease severity, 
 
 
The PRO instruments will be assessed based on the judgement of 
the patients on their suitability to document their skin disease. The methodology for analysis of the 
applied instruments, as well as for assessment of the PRO instruments, will be described in a separate 
document.  
5.7.3 Safety Assessment 
5.7.3.1 
Specification of Safety Endpoint 
 
The safety endpoint will be the incidence of TEAEs occurring during the study period, including 
clinically significant changes in laboratory parameters, which will be listed by intensity, seriousness, 
outcome, and relationship to study drug. 
5.7.4 Sample Size 
 
 A total of six (6) patients are planned to be enrolled in this study, 
 
 The data collected from these six patients will 
inform whether further trials will be needed. 
5.7.5 Analysis Plan 
5.7.5.1 
Safety Population 
 
The safety population will include all subjects who participate in the study and receive at least one 
study treatment. Participants screened but not enrolled will be shown in separate listings. 
 
5.7.5.2 
Intention To Treat (ITT) Population 
 
The ITT population will include all treated participants, who provide at least one post dose efficacy 
assessment. This will be the main population for all efficacy analyses.  


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5.7.5.3 
Handling of Missing and Incomplete Data 
 
 
 
 
  
 
5.7.5.4 
Per Protocol Analysis (PPA) Population 
 
 
 
  
 
5.7.5.5 
Demographic and Initial Characteristics 
 
Demographic and baseline characteristics will be summarised 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. 
 
 
 
 
  
 
 
 
 
  
 


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Since this study is in a rare disease, the clinical relevance of changes in the study endpoints has not 
yet been established, and so a minimal clinically importance change is not defined apriori. 
Further details will be included in the statistical analysis plan. 
 
5.7.5.7 
Safety 


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Descriptive methods will be used to summarise 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. 
• 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 dictionary (Version 23.0) will be used to map verbatim AE terms to preferred terms 
and body systems. The number of participants with TEAEs will be summarised by preferred term and 
body system. TEAEs will be further summarised by intensity, seriousness and relationship to study 
medication. The number of participants 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 and SUSARs will be listed individually. Any SAE that occurs after 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 
 
 
 


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5.7.5.11 
Interim Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.8 
Early 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 participants, failure of the Investigator to enrol 
participants at an acceptable rate, insufficient adherence to the protocol requirements, completion of 
study objectives or at the discretion of the Sponsor. 


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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 
25 years following study close-out. 
 
The Investigator will ensure to make all study data accessible to the Clinical Monitor, Sponsor, or 
other authorised 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. 
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 Principal Investigator and/or his/her agents, 
designees, sub-investigators, or other individuals involved in the running, administration, or 
collection/handling of participants/data for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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9.0 
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. 


 
 
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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 
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. 


 
 
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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. 
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. 
No amendment to the protocol may be made without consideration and approval by the committee. 


 
 
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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 
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. 


 
 
CLINUVEL                                                                -Confidential-                                                           
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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 
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 


 
 
CLINUVEL                                                                -Confidential-                                                           
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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-                                                           
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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-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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CLINUVEL                                                                -Confidential-                                                           
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