Phase III Confirmatory Study in Erythropoietic Protoporphyria

Study Overview
=================
Brief Summary
-----------------
This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Between 75 and 100 eligible patients will be enrolled. Patients will receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: Group A will be administered afamelanotide implants on Days 0, 60 and 120 Group B will be administered placebo implants on Days 0, 60 and 120 The number and severity of phototoxic reactions, the type and duration of sun exposure, treatment-emergent adverse events and the use of concomitant medication will be recorded by patients in study diaries between Days 0 and 180. Quality of life will be measured using the DLQI and EPP-QoL at Days 0, 60, 120 and 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events. A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) will be determined on Days 0, 30, 60, 90 and 120.

Detailed Description
-----------------
Afamelanotide is a man-made drug being studied for use as a preventative medication for Erythropoietic Protoporphyria (EPP) sufferers. It is a synthetically produced analogue of human alpha melanocyte stimulating hormone (alpha-MSH) and is available in Europe. The purpose of this study is to look at the type and duration of sun exposure when patients are exposed to light. This study will also look at how the drug is tolerated when taken by people with EPP. The study will involve the use of an implant, which comes in the form of a small rod to be administered under the skin. The implant may contain the study drug afamelanotide or a placebo (inactive medication). Over 620 subjects have been treated with afamelanotide to date with no serious safety concerns identified. For this study, afamelanotide has been formulated as a controlled release depot injection (implant). This means that the afamelanotide will be released slowly into the body over a few days. This study aims to confirm the photoprotective properties if afamelanotide demonstrated in the earlier Phase II and phase III studies.

Official Title
-----------------
A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients With Erythropoietic Protoporphyria (EPP)

Conditions
-----------------
Erythropoietic Protoporphyria

Intervention / Treatment
-----------------
* Drug: Afamelanotide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects with characteristic symptoms of EPP phototoxicity and a biochemically-confirmed diagnosis of EPP. Aged 18 years old and above (inclusive). Able to understand and sign the written Informed Consent Form. Willing to take precautions to prevent pregnancy until completion of the study (Day 180). Exclusion Criteria: Any allergy to afamelanotide or the polymer contained in the implant or to lidocaine or other local anesthetic to be used during the administration of the study medication EPP patients with significant hepatic involvement Personal history of melanoma or dysplastic nevus syndrome. Current Bowen's disease, basal cell carcinoma, squamous cell carcinoma, or other malignant or premalignant skin lesions. Any other photodermatosis such as polymorphic light eruption, actinic prurigo, discoid lupus erythematosus, chronic actinic dermatitis or solar urticaria. Any evidence of clinically significant organ dysfunction or any clinically significant deviation from normal in the clinical or laboratory determinations. Acute history of drug or alcohol abuse (in the last 6 months). Patient assessed as not suitable for the study in the opinion of the Investigator (e.g. noncompliance history, allergic to local anesthetics, faints when given injections or giving blood). Participation in a clinical trial for an investigational agent within 30 days prior to the screening visit. Prior and concomitant therapy with medications which may interfere with the objectives of the study, including drugs that cause photosensitivity or skin pigmentation. Female who is pregnant (confirmed by positive serum β-HCG pregnancy test prior to baseline) or lactating. Females of child-bearing potential (pre-menopausal, not surgically sterile) not using adequate contraceptive measures (i.e. oral contraceptives, diaphragm plus spermicide, intrauterine device).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afamelanotide<br>One 16mg subcutaneous implant every 2 months for 6 months. | Drug: Afamelanotide<br>* One 16mg subcutaneous implant every 2 months for 6 months.<br>|
| Placebo Comparator: Placebo<br>One placebo subcutaneous implant every 2 months for 6 months. | Drug: Placebo<br>* One placebo subcutaneous implant every 2 months for 6 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Direct Sunlight Exposure Between 10:00 and 18:00 Hours on Days When no Pain Was Experienced (Pain Score of 0). | The amount of direct sunlight exposure between 10:00 and 18:00 hours on days when no pain was experienced (e.g.11-point Likert pain score of 0). Time was recorded in a patient diary using 15 minute time blocks. The pain score is measured by the 11-point Likert Pain scale with minimum of 0 and maximum of 10. Likert Pain scale of 0 represents no pain and 10 represents worst imaginable pain. | Daily for 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined Sun Exposure and Phototoxic Pain | Time in direct sunlight exposure between 10:00 and 18:00 hours on days when no or mild pain was experienced (Likert scores of 0 to 3). The pain score is measured by the 11-point Likert Pain scale with minimum of 0 and maximum of 10. Likert Pain scale of 0 represents no pain and 10 represents worst imaginable pain. | Daily for 6 months | 
| Sun Exposure | Duration of direct sunlight exposure between 10:00 and 18:00 hours during the study. | Daily for 6 months | 
| Quality of Life Score | The Quality of life of participant is measured using DLQI and EPP QoL. The Dermatology Life Quality Index (DLQI) is a simple practical measure for routine clinical use. The DLQI ranges from 0 (no impact on life) to 30 (significant impact on life) . The Erthropoietic protoporphyria quality of life measure (EPP-QoL) scores range from 0 (worst imaginable QoL) to 100 (best possible QoL). | Day 60, Day 120, and Day 180 or early termination. | 
| Photoprovocation | A subset of subjects was photoprovoked on the dorsal surface of the hand (predilection place) and lower back and the minimum symptom dose (MSD) determined on Days 0, 30, 60, 90 and 120. The amount of radiation required to provoke the first clinical symptom was recorded. | Day 0, Day 30, Day 60, Day 90 and Day 120. | 
| Maximum Severity of Phototoxic Reaction Experienced by Participants | The phototoxicity - phototoxic pain secondary endpoint has been divided into two secondary outcome measures. The days on which the participant experienced pain as a result of phototoxic reactions (caused by exposure to natural light) was recorded in a study diary. On each day such a reaction occurred, the participant scored the level of pain using an 11-point Likert pain scale, with minimum of 0 and maximum of 10. The 11-point Likert pain scale with a value of 0 represents no pain and 10 represents worst imaginable pain. The maximum severity of a phototoxic reaction was determined by the highest daily 11-point Likert scale score that occurred during that phototoxic reaction. | Daily for 6 months | 
| Total Number Phototoxic Reactions Experienced by Participants | The phototoxicity - phototoxic pain secondary endpoint has been divided into two secondary outcome measures. The number of episodes was the endpoint. The days on which the participant experienced pain as a result of phototoxic reactions (caused by exposure to natural light) was recorded in a study diary. On each day such a reaction occurred, the participant scored the level of pain using an 11-point Likert pain scale, with minimum of 0 and maximum of 10. The 11-point Likert Pain scale with a value of 0 represents no pain and 10 represents worst imaginable pain. The number of phototoxic reactions was determined by counting the number of episodes on which participants report a 11-point Likert scale score of 4 or more for one or more consecutive days. | Daily for 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EPP, Erythropoietic Protoporphyria, Afamelanotide