Multicentre Phase III Erythropoietic Protoporphyria Study

Phase 3

Completed

• Conditions: Erythropoietic Protoporphyria
• Interventions: Drug: Afamelanotide; Drug: Placebo

• Registration Number: NCT04053270
• Lead Sponsor: Clinuvel Pharmaceuticals Limited

Brief Summary

This was a phase III, multicentre, randomised, double-blind, placebo-controlled study, to evaluate the safety and efficacy of subcutaneous bioresorbable afamelanotide implants in patients with Erythropoietic Protoporphyria (EPP).

The study was conducted with two parallel study arms with crossover between treatments every 60 days.

Eligible patients were randomised to a treatment group, and received implants of active treatment (afamelanotide 16mg) or placebo, in an alternating crossover fashion according to the following dosing regime:

* Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300

* Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300

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).

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).

This study aims to provide insight into the effectiveness of afamelanotide under normal conditions of use in EPP patients.

Study Timeline

• Study Start: 2007-05
• Primary Completion: 2009-12-09
• Study Completion: 2009-12-09
• Study First Submitted: 2019-08-08
• Study First Submitted QC: 2019-08-08
• Results First Submitted: 2019-08-10
• Study First Posted: 2019-08-12
• Status Verified: 2019-10
• Results First Submitted QC: 2019-10-08
• Last Update Submitted: 2019-10-08
• Results First Posted: 2019-10-10
• Last Update Posted: 2019-10-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Male or female patients 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.
• Written informed consent prior to the performance of any study-specific procedure.

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Exclusion Criteria

• Any allergy to afamelanotide or the polymer contained in the implant or to lignocaine or other local anaesthetic 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.
• Diagnosed with HIV/AIDS or hepatitis.
• 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).
• History of disorders of the gastrointestinal, hepatic, renal, cardiovascular, respiratory, endocrine (including diabetes, Cushing's syndrome, Addison's disease, Peutz-Jeagher syndrome), neurological (including seizures), haematological (especially anaemia of less than 10 g/100 mL) or systemic disease judged to be clinically significant by the Investigator.
• Major medical or psychiatric illness
• 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 was 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).
• Participation in a clinical trial of an investigational agent within 30 days prior to the screening visit.
• Use of regular medications as specified in protocol Section 5.4 Prior and Concomitant Therapy.
• Any factors that may affect skin reflectance measurements.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Group A	Placebo	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300
Group B	Afamelanotide	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300
Group B	Placebo	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300
Group A	Afamelanotide	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300

Primary Outcome Measures

Name	Time	Method
The Mean Number of Phototoxic Reactions (Study Efficacy Population)	0-360 days or Early Termination	The mean number of phototoxic reactions that occurred whilst patients were on active compared with placebo implants.; 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 primary analysis population for efficacy was revised, to analyze only participants who reported a cumulative total Likert pain score of at least 26 during the study (0-360 days). This population, which was comprised of 60 patients, is identified as the Efficacy population.; Participants with less than 26 Likert pain scores were not included in the analysis.
Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)	0-360 days or Early Termination	The cumulative number of days where a phototoxic reaction occurred was recorded in the patient diary. The reported data represent a cumulative total for days of phototoxic reactions.; 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 primary analysis population for efficacy was revised, to analyze only participants who reported cumulative total Likert pain scores of at least 26 during the study (0-360 days). This population, which was comprised of 60 patients, is identified as the Efficacy population. Participants with less than 26 Likert pain scores were not included in the analysis.

Secondary Outcome Measures

Name	Time	Method
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population	Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination	The Summary of SF36 change from Baseline of Mental Component Score (MCS) to the scores during treatment on Days 60, 120, 180, 240, 300 and 360 using the SF36 questionnaire.; The SF-36 (The Short Form 36 Health Survey) consists of eight scaled scores, which are the weighted sums of the questions in each section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight.; The higher scores represent better health-related quality-of-life.
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)	0-360 days or Early Termination	The number of days with sunlight exposure was recorded in the patient diary. The sunlight exposures were divided into the following categories: none, \< 1 hour, 1 to 3 hours, 3 to 6 hours and \> 6 hours per day.
Skin Melanin Density (Study Completers Population)	Day0, Day14, Day30, Day60, Day74, Day90, Day120, Day150, Day180, Day210, Day240, Day270, Day300, Day330, Day360 or Early Termination	Changes in melanin density (MD) (measured by spectrophotometry) at each visit by group.; Participants had their skin pigmentation measured by a non-invasive quantitative skin chromaticity (reflectance) reading. Reflectance by the skin of light measured at the wavelengths of 400 nm and 420 nm was recorded using a Minolta cm-2500d spectrophotometer at the following skin sites: forehead, left cheek, right inside upper arm, left medial forearm, right side of abdomen (avoiding implant insertion site), left side of sacral region/buttock.; Melanin density was determined for each skin site using the method of Dwyer et al 1998.
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population	Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination	The Summary of SF36 change from Baseline of Physical Component Score (PCS) to the scores during treatment on Days 60, 120, 180, 240, 300 and 360 using the SF36 questionnaire.; The SF-36 (The Short Form 36 Health Survey) consists of eight scaled scores, which are the weighted sums of the questions in each section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight.; The higher scores represent better health-related quality-of-life.