Clinical trial NCT00979745: Phase III Confirmatory Study in Erythropoietic Protoporphyria (EPP)
Official title: A Phase III, Multicentre, Double-Blind, Randomised, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients With Erythropoietic Protoporphyria (EPP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Erythropoietic Protoporphyria
Keywords: Erythropoietic Protoporphyria
EPP
Afamelanotide
Lead sponsor: Clinuvel Pharmaceuticals Limited
Sponsor class: INDUSTRY
First posted: 2009-09-18
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Afamelanotide is a man-made drug being studied for use as a preventative medication for EPP sufferers. It is a synthetically produced analogue of human alpha melanocyte stimulating hormone (alpha-MSH) and is not yet available on the market.

The purpose of this study is to look at whether afamelanotide can reduce the number and severity of EPP symptoms 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 (approximately 2 cm x 0.15 cm) to be administered under the skin. The implant may contain the study drug afamelanotide or a placebo (inactive medication).

Over 450 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. Once inserted, the implant will remain in the body after afamelanotide has been released and will slowly dissolve.

This study will help to provide more information about afamelanotide. This information will be used to determine the safety and efficacy (the ability of the drug to produce an effect) of this drug in EPP sufferers.

Up to 70 people will participate in this study from study sites across Europe.

Detailed description: PURPOSE:

To determine whether afamelanotide can reduce the severity of phototoxic reactions in patients with EPP.

THEORETICAL FRAMEWORK:

EPP is a genetic photosensitivity disorder where the mainstays of management are covering up from sunlight, systemic beta carotene and the use of controlled courses of UVR treatment. One of the mechanisms for the protective effects of UVR treatment is the increase in melanin content of the skin. UVR treatment causes DNA damage to skin cells and increases the risk for skin cancers, hence it is unwise for this to be used on a recurring basis. Afamelanotide, through its ability to stimulate melanin production without causing the DNA damage associated with UVR treatment, appears to be a promising agent to combat this distressing disorder.

STUDY DESIGN:

This is a phase III, randomised, placebo controlled study to evaluate the safety and efficacy of subcutaneous implants of afamelanotide in patients suffering from EPP. The study will be performed in compliance with Good Clinical Practice (GCP) including the archiving of essential documents.

METHODOLOGY:

The target population consists of male and female participants. Up to 70 patients with diagnosed EPP (from past case history) and fulfilling the necessary inclusion/exclusion criteria will be enrolled. Potential study patients will be identified from each centre's records of patients with well characterised history (or documented diagnosis) of EPP.

Patients will be enrolled and will receive afamelanotide (16 mg implants) or placebo according to the following dosing regime:

* Group A will be administered active implants on Days 0, 60, 120, 180 and 240.
* Group B will be administered placebo implants on Days 0, 60, 120, 180 and 240.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects with a diagnosis of EPP (confirmed by elevated free protoporphyrin in peripheral erythrocytes) of sufficient severity that they have requested treatment to alleviate their symptoms.
* Aged 18 - 70 years (inclusive)
* Written informed consent prior to the performance of any study-specific procedures.

Exclusion Criteria:

* Any allergy to afamelanotide or the polymer contained in the implant or to lignocaine or other local anaesthetic to be used during the administration of 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 PLE, DLE 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 12 months).
* Patient assessed as not suitable for the study in the opinion of the Investigator (e.g. noncompliance history, allergic to local anaesthetics, faints when given injections or giving blood).
* 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).
* Sexually active men with partners of child bearing potential not using barrier contraception during the trial and for a period of three months thereafter.
* Participation in a clinical trial of 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.

Primary outcomes:
measure: The Duration of Direct Sunlight Exposure Between 10:00 and 15:00 Hours on Days When Patients Did Not Report Phototoxicity-related Pain (Likert Pain Scale Score of 0)
timeFrame: From baseline to Day 270
Secondary outcomes:
measure: Number of Phototoxic Reactions
timeFrame: 9 months
measure: Quality of Life Measured by Patient Completed Questionnaire
timeFrame: 9 months
measure: Free Protoporphyrin IX Level
timeFrame: 9 months
measure: Treatment Emergent Adverse Events
timeFrame: 9 months
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: HUS:n Iho-ja allergiasairaala (Skin and Allergy Hospital)
city: Colombes
country: France
facility: Centre Français des Porphyries, Hôpital Louis Mourier
state: Cedex
city: Duesseldorf
country: Germany
facility: Department of Dermatology , Heinrich-Heine-University Duesseldorf
city: Dublin
country: Ireland
facility: Beaumont Hospital, Department of Dermatology
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Newport
country: United Kingdom
facility: St Woolos Hospital
state: Wales
city: Manchester
country: United Kingdom
facility: Photobiology Unit - Hope Hospital, University of Manchester
Study officials:
affiliation: St Woolos Hospital, Newport
name: Alex Anstey, MBBS, FRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Academisch Ziekenhuis Maastricht
name: Jorge Frank, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Central Hospital of Helsinki
name: Raili Kauppinen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Eric JG Sijbrands, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Francais des Porphyries, Hopital Louis Mourier, Colombes, France
name: Jean-Charles Deybach, MD. PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Heinrich-Heine Universität, Düsseldorf, Germany
name: Sandra Hanneken, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beaumont Hospital, Dublin, Ireland
name: Gillian M Murphy, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hope Hospital, University of Manchester, UK
name: Lesley E Rhodes, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, Bloomer J, Edwards C, Neumann NJ, Parker C, Phillips JD, Lim HW, Hamzavi I, Deybach JC, Kauppinen R, Rhodes LE, Frank J, Murphy GM, Karstens FPJ, Sijbrands EJG, de Rooij FWM, Lebwohl M, Naik H, Goding CR, Wilson JHP, Desnick RJ. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. 2015 Jul 2;373(1):48-59. doi: 10.1056/NEJMoa1411481.