Multicentre Phase III Erythropoietic Protoporphyria Study

• Sponsor: Clinuvel Pharmaceuticals Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04053270
• Collaborator: (none)
• Enrollment: 100
• Arms: 2
• Actual Duration (Months): 31.3

Study Details

Study Description

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

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).

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 Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicentre, Randomised, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutanenous Bioresorbable CUV1647 Implants in Patients With Erythropoietic Protoporphyria (EPP)
• Actual Study Start Date: May 1, 2007
• Actual Primary Completion Date: Dec 9, 2009
• Actual Study Completion Date: Dec 9, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300	Drug: Afamelanotide; 16mg subcutaneous implant; Drug: Placebo; Placebo subcutaneous implant
Placebo Comparator: Group B Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300	Drug: Afamelanotide; 16mg subcutaneous implant; Drug: Placebo; Placebo subcutaneous implant

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Clinuvel Pharmaceuticals Limited

Investigators

• Study Director: Head of Clinical Development, CLINUVEL PHARMACEUTICALS LTD

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Clinuvel Pharmaceuticals Limited
• ClinicalTrials.gov Identifier: NCT04053270
• Other Study ID Numbers: CUV017
• First Posted: Aug 12, 2019
• Last Update Posted: Oct 10, 2019
• Last Verified: Oct 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	Group A	Group B
Arm/Group Description	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant. Placebo: Placebo subcutaneous implant.
Period Title: Overall Study
STARTED	49	51
COMPLETED	47	46
NOT COMPLETED	2	5

Baseline Characteristics

Arm/Group Title	Group A	Group B	Total
Arm/Group Description	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300 Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300 Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Total of all reporting groups
Overall Participants	49	51	100
Age, Customized (years) [Mean (Standard Deviation) ]
Age	38.5 (13.3)	39.2 (12.4)	38.9 (12.8)
Sex: Female, Male (Count of Participants)
Female	30 61.2%	23 45.1%	53 53%
Male	19 38.8%	28 54.9%	47 47%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	49 100%	50 98%	99 99%
Other	0 0%	1 2%	1 1%

Outcome Measures

1. Primary Outcome

Title	Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)
Description	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.
Time Frame	0-360 days or Early Termination

Outcome Measure Data

Analysis Population Description

Participants who reported a cumulative total Likert pain score of at least 26 during the study (0-360 days), which was comprised of 60 patients, is identified as the Efficacy population.

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: 16mg subcutaneous implant	Placebo: Placebo subcutaneous implant.
Measure Participants	60	60
Severe Pain	39	45
Moderate Pain	129	179
Mild Pain	1126	1237
No Pain	8650	8484

2. Primary Outcome

Title	The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Description	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.
Time Frame	0-360 days or Early Termination

Outcome Measure Data

Analysis Population Description

The result is reported in a "per sequence" format with the different time points at which the interventions were switched. Total of 60 Participants: 32 participants in Group A and 28 participants in Group B.

Arm/Group Title	Group A	Group B
Arm/Group Description	Afamelanotide: 16mg subcutaneous implant Of the 60 participants, 32 were in treatment Group A (active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300) and 28 in treatment Group B (placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300).	Placebo: Placebo subcutaneous implant. Of the 60 participants, 32 were in treatment Group A (active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300) and 28 in treatment Group B (placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300).
Measure Participants	32	28
Day 0	1.44 (3.25)	2.64 (5.33)
Day 60	0.56 (1.87)	0.11 (0.31)
Day 120	1.09 (2.08)	0.79 (2.25)
Day 180	0.32 (2.07)	0.78 (0.61)
Day 240	0.63 (1.52)	2.21 (3.57)
Day 300	0.72 (1.42)	1.96 (4.53)

3. Secondary Outcome

Title	Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
Description	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.
Time Frame	0-360 days or Early Termination

Outcome Measure Data

Analysis Population Description

The primary analysis population for efficacy was revised, with an additional criterion of a total cumulative pain score of at least 26, and omitting patients who did not complete the study. This population, which was comprised of 60 patients, is identified as the Efficacy population.

Arm/Group Title	Afamelanotide	Placebo
Arm/Group Description	Afamelanotide: 16mg subcutaneous implant	Placebo: Placebo subcutaneous implant.
Measure Participants	60	60
> 6 hrs per day	339	250
3 - 6 hrs per day	969	854
1 - 3 hrs per day	2810	2695
< 1 hr per day	1468	1564
None per day	4358	4582

4. Secondary Outcome

Title	Skin Melanin Density (Study Completers Population)
Description	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.
Time Frame	Day0, Day14, Day30, Day60, Day74, Day90, Day120, Day150, Day180, Day210, Day240, Day270, Day300, Day330, Day360 or Early Termination

Outcome Measure Data

Analysis Population Description

The secondary analysis population for efficacy included those subjects who received all required doses of investigational product. This population is identified as the study completers population. Calculated MD <0 or >6 were omitted.

Arm/Group Title	Group A	Group B
Arm/Group Description	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant. Placebo: Placebo subcutaneous implant.
Measure Participants	49	51
Day 0	3.42 (0.83)	3.22 (1.01)
Day 14	3.75 (0.77)	3.39 (0.95)
Day 30	3.86 (0.72)	3.40 (1.01)
Day 60	3.80 (0.77)	3.34 (1.00)
Day 74	3.70 (0.85)	3.71 (0.89)
Day 90	3.67 (0.80)	3.75 (0.87)
Day 120	3.52 (0.79)	3.71 (0.83)
Day 150	3.79 (0.82)	3.57 (0.89)
Day 180	3.84 (0.74)	3.50 (0.89)
Day 210	3.76 (0.76)	3.93 (0.75)
Day 240	3.68 (0.81)	3.89 (0.73)
Day 270	3.97 (0.72)	3.81 (0.72)
Day 300	3.89 (0.72)	3.76 (0.72)
Day 330	3.82 (0.73)	4.08 (0.63)
Day 360	3.73 (0.69)	3.97 (0.69)

5. Secondary Outcome

Title	Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Description	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.
Time Frame	Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination

Outcome Measure Data

Analysis Population Description

The secondary analysis population for efficacy included those subjects who received all required doses of investigational product. This population, which was comprised of 93 patients, is identified as the study completers population.

Arm/Group Title	Group A	Group B
Arm/Group Description	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant. Placebo: Placebo subcutaneous implant.
Measure Participants	47	46
Day 0	51.90 (7.05)	54.22 (5.48)
Day 60	54.20 (5.99)	54.85 (5.59)
Day 120	54.26 (5.53)	54.68 (5.78)
Day 180	53.39 (5.88)	53.72 (5.59)
Day 240	53.19 (7.09)	54.25 (5.22)
Day 300	53.48 (5.71)	53.88 (4.93)
Day 360	52.30 (6.03)	54.88 (5.01)

6. Secondary Outcome

Title	Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Description	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.
Time Frame	Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination

Outcome Measure Data

Analysis Population Description

The secondary analysis population for efficacy included those subjects who received all required doses of investigational product. This population, which was comprised of 93 patients, is identified as the study completers population.

Arm/Group Title	Group A	Group B
Arm/Group Description	Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant Placebo: Placebo subcutaneous implant	Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300. Afamelanotide: 16mg subcutaneous implant. Placebo: Placebo subcutaneous implant.
Measure Participants	47	46
Day 0	51.41 (6.61)	53.03 (6.75)
Day 60	52.31 (9.58)	52.26 (7.46)
Day 120	53.16 (7.34)	52.71 (7.39)
Day 180	53.84 (7.12)	52.06 (7.50)
Day 240	51.96 (8.48)	52.34 (8.07)
Day 300	52.99 (9.21)	52.76 (7.61)
Day 360	52.44 (8.13)	52.23 (8.00)

Adverse Events

Time Frame	Day 1 - Day 360 or Early Termination
Arm/Group Title	Afamelanotide		Placebo
Arm/Group Description	Afamelanotide: 16mg subcutaneous implant.		Placebo: Placebo subcutaneous implant.
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	3/100 (3%)		3/100 (3%)
Blood and lymphatic system disorders
Thrombocytopenia	1/100 (1%)		0/100 (0%)
Hepatobiliary disorders
Cholelithiasis	1/100 (1%)		0/100 (0%)
Infections and infestations
Diverticulitis	0/100 (0%)		1/100 (1%)
Tonsillitis	0/100 (0%)		1/100 (1%)
Injury, poisoning and procedural complications
Joint injury	0/100 (0%)		1/100 (1%)
Post procedural complication	0/100 (0%)		1/100 (1%)
Spinal fracture	1/100 (1%)		0/100 (0%)
Nervous system disorders
Dyskinesia	0/100 (0%)		1/100 (1%)
Other (Not Including Serious) Adverse Events
	Afamelanotide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	94/100 (94%)		88/100 (88%)
Gastrointestinal disorders
Abdominal pain	9/100 (9%)		6/100 (6%)
Abdominal pain upper	7/100 (7%)		5/100 (5%)
Diarrhoea	13/100 (13%)		13/100 (13%)
Nausea	34/100 (34%)		19/100 (19%)
Toothache	4/100 (4%)		7/100 (7%)
Vomiting	8/100 (8%)		6/100 (6%)
General disorders
Fatigue	12/100 (12%)		11/100 (11%)
Implant site haematoma	8/100 (8%)		8/100 (8%)
Implant site pain	8/100 (8%)		6/100 (6%)
Oedema peripheral	5/100 (5%)		2/100 (2%)
Pyrexia	7/100 (7%)		4/100 (4%)
Infections and infestations
Influenza	13/100 (13%)		4/100 (4%)
Nasopharyngitis	17/100 (17%)		16/100 (16%)
Upper respiratory tract infection	7/100 (7%)		6/100 (6%)
Musculoskeletal and connective tissue disorders
Back pain	11/100 (11%)		6/100 (6%)
Nervous system disorders
Dizziness	12/100 (12%)		5/100 (5%)
Headache	45/100 (45%)		38/100 (38%)
Migraine	7/100 (7%)		8/100 (8%)
Reproductive system and breast disorders
Dysmenorrhoea	1/100 (1%)		5/100 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	5/100 (5%)		9/100 (9%)
Oropharyngeal pain	4/100 (4%)		11/100 (11%)
Vascular disorders
Flushing	8/100 (8%)		0/100 (0%)
Haematoma	7/100 (7%)		9/100 (9%)

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.