Phase III Confirmatory Study in Erythropoietic Protoporphyria

• Sponsor: Clinuvel Pharmaceuticals Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01605136
• Collaborator: (none)
• Enrollment: 93
• Locations: 7
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 13.3
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Erythropoietic Protoporphyria	Drug: Afamelanotide; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afamelanotide One 16mg subcutaneous implant every 2 months for 6 months.	Drug: Afamelanotide; One 16mg subcutaneous implant every 2 months for 6 months.
Placebo Comparator: Placebo One placebo subcutaneous implant every 2 months for 6 months.	Drug: Placebo; One placebo subcutaneous implant every 2 months for 6 months

Outcome Measures

Primary Outcome Measures

1. Duration of Direct Sunlight Exposure Between 10:00 and 18:00 Hours on Days When no Pain Was Experienced (Pain Score of 0). [Daily for 6 months]

   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.

Secondary Outcome Measures

1. Combined Sun Exposure and Phototoxic Pain [Daily for 6 months]

   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.

2. Sun Exposure [Daily for 6 months]

   Duration of direct sunlight exposure between 10:00 and 18:00 hours during the study.

3. Quality of Life Score [Day 60, Day 120, and Day 180 or early termination.]

   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).

4. Photoprovocation [Day 0, Day 30, Day 60, Day 90 and Day 120.]

   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.

5. Maximum Severity of Phototoxic Reaction Experienced by Participants [Daily for 6 months]

   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.

6. Total Number Phototoxic Reactions Experienced by Participants [Daily for 6 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	University of California, San Francisco	San Francisco	California	United States	94143
3	Henry Ford Medical Center	Detroit	Michigan	United States	48202
4	Mt. Sinai	New York	New York	United States	10029
5	Carolina's Medical Center Cannon Research	Charlotte	North Carolina	United States	29203
6	University of Texas	Galveston	Texas	United States	77555
7	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• Clinuvel Pharmaceuticals Limited

Investigators

• Principal Investigator: Robert Desnick, MD, Mt. Sinai Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Clinuvel Pharmaceuticals Limited
• ClinicalTrials.gov Identifier: NCT01605136
• Other Study ID Numbers: CUV039
• First Posted: May 24, 2012
• Last Update Posted: Sep 19, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by Clinuvel Pharmaceuticals Limited: Erythropoietic Protoporphyria; EPP; Afamelanotide
• Additional relevant MeSH terms: Protoporphyria, Erythropoietic; Afamelanotide

Study Results

Participant Flow

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	One 16mg subcutaneous implant every 2 months for 6 months. Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	One placebo subcutaneous implant every 2 months for 6 months. Placebo: One placebo subcutaneous implant every 2 months for 6 months
Period Title: Study Period
STARTED	48	45
COMPLETED	45	42
NOT COMPLETED	3	3
Period Title: Study Period
STARTED	45	42
COMPLETED	44	40
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Afamelanotide	Placebo	Total
Arm/Group Description	One 16mg subcutaneous implant every 2 months for 6 months. Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	One placebo subcutaneous implant every 2 months for 6 months. Placebo: One placebo subcutaneous implant every 2 months for 6 months	Total of all reporting groups
Overall Participants	48	45	93
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	38.5	35	37
Sex: Female, Male (Count of Participants)
Female	20 41.7%	24 53.3%	44 47.3%
Male	28 58.3%	21 46.7%	49 52.7%

Outcome Measures

1. Primary Outcome

Title	Duration of Direct Sunlight Exposure Between 10:00 and 18:00 Hours on Days When no Pain Was Experienced (Pain Score of 0).
Description	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.
Time Frame	Daily for 6 months

Outcome Measure Data

Analysis Population Description

Number of subjects (ITT population, from Patient Diary Card)

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	46	43
Median (Full Range) [hours]	69.4	40.8

2. Secondary Outcome

Title	Combined Sun Exposure and Phototoxic Pain
Description	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.
Time Frame	Daily for 6 months

Outcome Measure Data

Analysis Population Description

Number of subjects (ITT population, from Patient Diary Card)

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	46	43
Median (Full Range) [hours]	80.0	51.0

3. Secondary Outcome

Title	Sun Exposure
Description	Duration of direct sunlight exposure between 10:00 and 18:00 hours during the study.
Time Frame	Daily for 6 months

Outcome Measure Data

Analysis Population Description

Number of subjects (ITT population, from Patient Diary Card)

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	46	43
Median (Full Range) [hours]	83.50	65.25

4. Secondary Outcome

Title	Quality of Life Score
Description	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).
Time Frame	Day 60, Day 120, and Day 180 or early termination.

Outcome Measure Data

Analysis Population Description

The number of participants analyzed differs from the overall number of participants analyzed because the data was either incomplete and/or missing. Only data from those who completed the Quality of Life assessments are included at each time point.

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	47	43
DLQI - Day 0 (baseline)	10.0	11.0
DLQI - Day 60	2.0	4.0
DLQI - Day 120	0.5	2.5
DLQI - Day 180/Early Termination	1.0	1.0
EPP QOL - Day 0 (baseline)	19.4	22.2
EPP QOL - Day 60	77.8	55.6
EPP QOL - Day 120	81.9	61.1
EPP QOL - Day 180/Early Termination	86.1	69.4

5. Secondary Outcome

Title	Photoprovocation
Description	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.
Time Frame	Day 0, Day 30, Day 60, Day 90 and Day 120.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	10	10
Day 0: dorsal surface of the hand	48.9	21.0
Change at Day 30: dorsal surface of the hand	197.5	75.6
Change at Day 60: dorsal surface of the hand	128.3	36.3
Change at Day 90: dorsal surface of the hand	208.3	13.9
Change at Day 120: dorsal surface of the hand	162.1	1.9
Day 0: lower back	32.0	24.1
Change at Day 30: lower back	237.1	44.8
Change at Day 60: lower back	50.7	4.3
Change at Day 90: lower back	227.5	-2.4
Change at Day 120: lower back	82.5	12.1

6. Secondary Outcome

Title	Maximum Severity of Phototoxic Reaction Experienced by Participants
Description	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.
Time Frame	Daily for 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	46	43
Median (Full Range) [score on a scale]	4.0	5.0

7. Secondary Outcome

Title	Total Number Phototoxic Reactions Experienced by Participants
Description	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.
Time Frame	Daily for 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.	Placebo: One placebo subcutaneous implant every 2 months for 6 months
Measure Participants	46	43
Median (Full Range) [episodes]	4	6

Adverse Events

Time Frame	Visit 1 (Day 0) - Visit 4 (Day 180)
Arm/Group Title	Afamelanotide		Placebo
Arm/Group Description	One 16mg subcutaneous implant every 2 months for 6 months. Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months.		One placebo subcutaneous implant every 2 months for 6 months. Placebo: One placebo subcutaneous implant every 2 months for 6 months
All Cause Mortality
	Afamelanotide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Afamelanotide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/48 (6.3%)		2/45 (4.4%)
Gastrointestinal disorders
Abdominal pain	1/48 (2.1%)		0/45 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/48 (2.1%)		0/45 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ	0/48 (0%)		1/45 (2.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/48 (0%)		1/45 (2.2%)
Skin and subcutaneous tissue disorders
Melanocytic naevus	1/48 (2.1%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Afamelanotide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/48 (93.8%)		39/45 (86.7%)
Gastrointestinal disorders
Nausea	9/48 (18.8%)		8/45 (17.8%)
Abdominal pain	1/48 (2.1%)		3/45 (6.7%)
Abdominal pain upper	1/48 (2.1%)		3/45 (6.7%)
Diarrhoea	2/48 (4.2%)		3/45 (6.7%)
Dyspepsia	3/48 (6.3%)		3/45 (6.7%)
General disorders
Pain	4/48 (8.3%)		4/45 (8.9%)
Implant site discolouration	9/48 (18.8%)		0/45 (0%)
Fatigue	3/48 (6.3%)		0/45 (0%)
Infections and infestations
Nasopharyngitis	6/48 (12.5%)		10/45 (22.2%)
Gastroenteritis viral	0/48 (0%)		3/45 (6.7%)
Influenza	2/48 (4.2%)		7/45 (15.6%)
Sinusitis	3/48 (6.3%)		3/45 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/48 (10.4%)		2/45 (4.4%)
Back Pain	6/48 (12.5%)		6/45 (13.3%)
Musculoskeletal pain	3/48 (6.3%)		1/45 (2.2%)
Myalgia	3/48 (6.3%)		1/45 (2.2%)
Nervous system disorders
Headache	19/48 (39.6%)		13/45 (28.9%)
Migraine	3/48 (6.3%)		3/45 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.