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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A | Experimental | Group A was administered active implants on Days 0, 120, 240 and placebo implants on Days 60, 180, 300 |
|
| Group B | Placebo Comparator | Group B was administered placebo implants on Days 0, 120, 240 and active implants on Days 60, 180, 300 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Afamelanotide | Drug | 16mg subcutaneous implant |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population) | 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. | 0-360 days or Early Termination |
| The Mean Number of Phototoxic Reactions (Study Efficacy Population) | 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. | 0-360 days or Early Termination |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population) | 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. | 0-360 days or Early Termination |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Head of Clinical Development | CLINUVEL PHARMACEUTICALS LTD | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9521433 | Result | Dwyer T, Muller HK, Blizzard L, Ashbolt R, Phillips G. The use of spectrophotometry to estimate melanin density in Caucasians. Cancer Epidemiol Biomarkers Prev. 1998 Mar;7(3):203-6. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group A | 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 |
| FG001 | Group B | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A | 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 |
| BG001 | Group B |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Between 18-70 years. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population) | 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. | 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. | Posted | Number | Days | 0-360 days or Early Termination |
|
Day 1 - Day 360 or Early Termination
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Afamelanotide | Afamelanotide: 16mg subcutaneous implant. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version 12.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Dennis Wright | CLINUVEL PHARMACEUTICAL LIMITED | + 61 3 9660 4900 | mail@clinuvel.com |
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| ID | Term |
|---|---|
| D046351 | Protoporphyria, Erythropoietic |
| ID | Term |
|---|---|
| D017094 | Porphyrias, Hepatic |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D012873 | Skin Diseases, Genetic |
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| ID | Term |
|---|---|
| C534526 | afamelanotide |
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| Placebo |
| Drug |
Placebo subcutaneous implant |
|
| Skin Melanin Density (Study Completers Population) |
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. |
| Day0, Day14, Day30, Day60, Day74, Day90, Day120, Day150, Day180, Day210, Day240, Day270, Day300, Day330, Day360 or Early Termination |
| Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population | 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. | Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination |
| Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population | 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. | Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination |
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
| BG002 | Total | Total of all reporting groups |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| OG000 | Afamelanotide | Afamelanotide: 16mg subcutaneous implant |
| OG001 | Placebo | Placebo: Placebo subcutaneous implant. |
|
|
| Primary | The Mean Number of Phototoxic Reactions (Study Efficacy Population) | 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. | 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. | Posted | Mean | Standard Deviation | counts of episodes | 0-360 days or Early Termination |
|
|
|
| Secondary | Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population) | 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. | 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. | Posted | Number | Days | 0-360 days or Early Termination |
|
|
|
| Secondary | Skin Melanin Density (Study Completers Population) | 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. | 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. | Posted | Mean | Standard Deviation | unitless | Day0, Day14, Day30, Day60, Day74, Day90, Day120, Day150, Day180, Day210, Day240, Day270, Day300, Day330, Day360 or Early Termination |
|
|
|
| Secondary | Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population | 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination |
|
|
|
| Secondary | Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population | 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early Termination |
|
|
|
| 3 |
| 100 |
| 94 |
| 100 |
| EG001 | Placebo | Placebo: Placebo subcutaneous implant. | 3 | 100 | 88 | 100 |
| Cholelithiasis | Hepatobiliary disorders | MedDRA version 12.0 | Non-systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA version 12.0 | Non-systematic Assessment |
|
| Tonsillitis | Infections and infestations | MedDRA version 12.0 | Non-systematic Assessment |
|
| Joint injury | Injury, poisoning and procedural complications | MedDRA version 12.0 | Non-systematic Assessment |
|
| Post procedural complication | Injury, poisoning and procedural complications | MedDRA version 12.0 | Non-systematic Assessment |
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| Spinal fracture | Injury, poisoning and procedural complications | MedDRA version 12.0 | Non-systematic Assessment |
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| Dyskinesia | Nervous system disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Toothache | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Implant site haematoma | General disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Implant site pain | General disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Influenza | Infections and infestations | MedDRA version 12.0 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA version 12.0 | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA version 12.0 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Migraine | Nervous system disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA version 12.0 | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA version 12.0 | Non-systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA version 12.0 | Non-systematic Assessment |
|
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| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D011164 | Porphyrias |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Day 120 |
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| Day 180 |
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| Day 240 |
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| Day 300 |
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| 1 - 3 hrs per day |
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| < 1 hr per day |
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| None per day |
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| Day 14 |
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| Day 30 |
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| Day 60 |
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| Day 74 |
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| Day 90 |
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| Day 120 |
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| Day 150 |
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| Day 180 |
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| Day 210 |
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| Day 240 |
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| Day 270 |
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| Day 300 |
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| Day 330 |
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| Day 360 |
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| Day 60 |
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| Day 120 |
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| Day 180 |
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| Day 240 |
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| Day 300 |
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| Day 360 |
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| Day 60 |
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| Day 120 |
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| Day 180 |
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| Day 240 |
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| Day 300 |
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| Day 360 |
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