Trial Outcomes & Findings for Multicentre Phase III Erythropoietic Protoporphyria Study (NCT NCT04053270)
NCT ID: NCT04053270
Last Updated: 2019-10-10
Results Overview
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.
COMPLETED
PHASE3
100 participants
0-360 days or Early Termination
2019-10-10
Participant Flow
Participant milestones
| Measure |
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
|
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.
|
|---|---|---|
|
Overall Study
STARTED
|
49
|
51
|
|
Overall Study
COMPLETED
|
47
|
46
|
|
Overall Study
NOT COMPLETED
|
2
|
5
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Multicentre Phase III Erythropoietic Protoporphyria Study
Baseline characteristics by cohort
| Measure |
Group A
n=49 Participants
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
n=51 Participants
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
n=100 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
Age
|
38.5 years
STANDARD_DEVIATION 13.3 • n=5 Participants
|
39.2 years
STANDARD_DEVIATION 12.4 • n=7 Participants
|
38.9 years
STANDARD_DEVIATION 12.8 • n=5 Participants
|
|
Sex: Female, Male
Female
|
30 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
53 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
19 Participants
n=5 Participants
|
28 Participants
n=7 Participants
|
47 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Caucasian
|
49 Participants
n=5 Participants
|
50 Participants
n=7 Participants
|
99 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Other
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 0-360 days or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=60 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=60 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)
Moderate Pain
|
129 Days
|
179 Days
|
|
Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)
Severe Pain
|
39 Days
|
45 Days
|
|
Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)
Mild Pain
|
1126 Days
|
1237 Days
|
|
Cumulative Number of Days of Phototoxic Reactions (Study Efficacy Population)
No Pain
|
8650 Days
|
8484 Days
|
PRIMARY outcome
Timeframe: 0-360 days or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=32 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=28 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 60
|
0.56 counts of episodes
Standard Deviation 1.87
|
0.11 counts of episodes
Standard Deviation 0.31
|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 180
|
0.32 counts of episodes
Standard Deviation 2.07
|
0.78 counts of episodes
Standard Deviation 0.61
|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 300
|
0.72 counts of episodes
Standard Deviation 1.42
|
1.96 counts of episodes
Standard Deviation 4.53
|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 0
|
1.44 counts of episodes
Standard Deviation 3.25
|
2.64 counts of episodes
Standard Deviation 5.33
|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 120
|
1.09 counts of episodes
Standard Deviation 2.08
|
0.79 counts of episodes
Standard Deviation 2.25
|
|
The Mean Number of Phototoxic Reactions (Study Efficacy Population)
Day 240
|
0.63 counts of episodes
Standard Deviation 1.52
|
2.21 counts of episodes
Standard Deviation 3.57
|
SECONDARY outcome
Timeframe: 0-360 days or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=60 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=60 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
> 6 hrs per day
|
339 Days
|
250 Days
|
|
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
3 - 6 hrs per day
|
969 Days
|
854 Days
|
|
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
1 - 3 hrs per day
|
2810 Days
|
2695 Days
|
|
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
< 1 hr per day
|
1468 Days
|
1564 Days
|
|
Cumulative Number of Days With Sunlight Exposure (Study Efficacy Population)
None per day
|
4358 Days
|
4582 Days
|
SECONDARY outcome
Timeframe: Day0, Day14, Day30, Day60, Day74, Day90, Day120, Day150, Day180, Day210, Day240, Day270, Day300, Day330, Day360 or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=49 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=51 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Skin Melanin Density (Study Completers Population)
Day 0
|
3.42 unitless
Standard Deviation 0.83
|
3.22 unitless
Standard Deviation 1.01
|
|
Skin Melanin Density (Study Completers Population)
Day 14
|
3.75 unitless
Standard Deviation 0.77
|
3.39 unitless
Standard Deviation 0.95
|
|
Skin Melanin Density (Study Completers Population)
Day 60
|
3.80 unitless
Standard Deviation 0.77
|
3.34 unitless
Standard Deviation 1.00
|
|
Skin Melanin Density (Study Completers Population)
Day 240
|
3.68 unitless
Standard Deviation 0.81
|
3.89 unitless
Standard Deviation 0.73
|
|
Skin Melanin Density (Study Completers Population)
Day 300
|
3.89 unitless
Standard Deviation 0.72
|
3.76 unitless
Standard Deviation 0.72
|
|
Skin Melanin Density (Study Completers Population)
Day 330
|
3.82 unitless
Standard Deviation 0.73
|
4.08 unitless
Standard Deviation 0.63
|
|
Skin Melanin Density (Study Completers Population)
Day 360
|
3.73 unitless
Standard Deviation 0.69
|
3.97 unitless
Standard Deviation 0.69
|
|
Skin Melanin Density (Study Completers Population)
Day 74
|
3.70 unitless
Standard Deviation 0.85
|
3.71 unitless
Standard Deviation 0.89
|
|
Skin Melanin Density (Study Completers Population)
Day 90
|
3.67 unitless
Standard Deviation 0.80
|
3.75 unitless
Standard Deviation 0.87
|
|
Skin Melanin Density (Study Completers Population)
Day 120
|
3.52 unitless
Standard Deviation 0.79
|
3.71 unitless
Standard Deviation 0.83
|
|
Skin Melanin Density (Study Completers Population)
Day 30
|
3.86 unitless
Standard Deviation 0.72
|
3.40 unitless
Standard Deviation 1.01
|
|
Skin Melanin Density (Study Completers Population)
Day 150
|
3.79 unitless
Standard Deviation 0.82
|
3.57 unitless
Standard Deviation 0.89
|
|
Skin Melanin Density (Study Completers Population)
Day 180
|
3.84 unitless
Standard Deviation 0.74
|
3.50 unitless
Standard Deviation 0.89
|
|
Skin Melanin Density (Study Completers Population)
Day 210
|
3.76 unitless
Standard Deviation 0.76
|
3.93 unitless
Standard Deviation 0.75
|
|
Skin Melanin Density (Study Completers Population)
Day 270
|
3.97 unitless
Standard Deviation 0.72
|
3.81 unitless
Standard Deviation 0.72
|
SECONDARY outcome
Timeframe: Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=47 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=46 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 60
|
54.20 score on a scale
Standard Deviation 5.99
|
54.85 score on a scale
Standard Deviation 5.59
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 120
|
54.26 score on a scale
Standard Deviation 5.53
|
54.68 score on a scale
Standard Deviation 5.78
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 180
|
53.39 score on a scale
Standard Deviation 5.88
|
53.72 score on a scale
Standard Deviation 5.59
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 240
|
53.19 score on a scale
Standard Deviation 7.09
|
54.25 score on a scale
Standard Deviation 5.22
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 300
|
53.48 score on a scale
Standard Deviation 5.71
|
53.88 score on a scale
Standard Deviation 4.93
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 360
|
52.30 score on a scale
Standard Deviation 6.03
|
54.88 score on a scale
Standard Deviation 5.01
|
|
Change in Quality of Life Using SF36 Questionnaire (Physical Component Score) for Study Completers Population
Day 0
|
51.90 score on a scale
Standard Deviation 7.05
|
54.22 score on a scale
Standard Deviation 5.48
|
SECONDARY outcome
Timeframe: Day0, Day60, Day120, Day180, Day240, Day300, Day360 or Early TerminationPopulation: 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.
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.
Outcome measures
| Measure |
Afamelanotide
n=47 Participants
Afamelanotide: 16mg subcutaneous implant
|
Placebo
n=46 Participants
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 0
|
51.41 score on a scale
Standard Deviation 6.61
|
53.03 score on a scale
Standard Deviation 6.75
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 60
|
52.31 score on a scale
Standard Deviation 9.58
|
52.26 score on a scale
Standard Deviation 7.46
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 120
|
53.16 score on a scale
Standard Deviation 7.34
|
52.71 score on a scale
Standard Deviation 7.39
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 180
|
53.84 score on a scale
Standard Deviation 7.12
|
52.06 score on a scale
Standard Deviation 7.50
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 240
|
51.96 score on a scale
Standard Deviation 8.48
|
52.34 score on a scale
Standard Deviation 8.07
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 300
|
52.99 score on a scale
Standard Deviation 9.21
|
52.76 score on a scale
Standard Deviation 7.61
|
|
Change in Quality of Life Using SF36 Questionnaire (Mental Component Score) for Study Completers Population
Day 360
|
52.44 score on a scale
Standard Deviation 8.13
|
52.23 score on a scale
Standard Deviation 8.00
|
Adverse Events
Afamelanotide
Placebo
Serious adverse events
| Measure |
Afamelanotide
n=100 participants at risk
Afamelanotide: 16mg subcutaneous implant.
|
Placebo
n=100 participants at risk
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
|
Hepatobiliary disorders
Cholelithiasis
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
|
Infections and infestations
Diverticulitis
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
|
Infections and infestations
Tonsillitis
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
|
Injury, poisoning and procedural complications
Joint injury
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
|
Injury, poisoning and procedural complications
Post procedural complication
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
|
Injury, poisoning and procedural complications
Spinal fracture
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
|
Nervous system disorders
Dyskinesia
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
Other adverse events
| Measure |
Afamelanotide
n=100 participants at risk
Afamelanotide: 16mg subcutaneous implant.
|
Placebo
n=100 participants at risk
Placebo: Placebo subcutaneous implant.
|
|---|---|---|
|
Gastrointestinal disorders
Abdominal pain
|
9.0%
9/100 • Day 1 - Day 360 or Early Termination
|
6.0%
6/100 • Day 1 - Day 360 or Early Termination
|
|
Gastrointestinal disorders
Abdominal pain upper
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
5.0%
5/100 • Day 1 - Day 360 or Early Termination
|
|
Gastrointestinal disorders
Diarrhoea
|
13.0%
13/100 • Day 1 - Day 360 or Early Termination
|
13.0%
13/100 • Day 1 - Day 360 or Early Termination
|
|
Gastrointestinal disorders
Nausea
|
34.0%
34/100 • Day 1 - Day 360 or Early Termination
|
19.0%
19/100 • Day 1 - Day 360 or Early Termination
|
|
Gastrointestinal disorders
Toothache
|
4.0%
4/100 • Day 1 - Day 360 or Early Termination
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
|
Gastrointestinal disorders
Vomiting
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
6.0%
6/100 • Day 1 - Day 360 or Early Termination
|
|
General disorders
Fatigue
|
12.0%
12/100 • Day 1 - Day 360 or Early Termination
|
11.0%
11/100 • Day 1 - Day 360 or Early Termination
|
|
General disorders
Implant site haematoma
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
|
General disorders
Implant site pain
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
6.0%
6/100 • Day 1 - Day 360 or Early Termination
|
|
General disorders
Oedema peripheral
|
5.0%
5/100 • Day 1 - Day 360 or Early Termination
|
2.0%
2/100 • Day 1 - Day 360 or Early Termination
|
|
General disorders
Pyrexia
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
4.0%
4/100 • Day 1 - Day 360 or Early Termination
|
|
Infections and infestations
Influenza
|
13.0%
13/100 • Day 1 - Day 360 or Early Termination
|
4.0%
4/100 • Day 1 - Day 360 or Early Termination
|
|
Infections and infestations
Nasopharyngitis
|
17.0%
17/100 • Day 1 - Day 360 or Early Termination
|
16.0%
16/100 • Day 1 - Day 360 or Early Termination
|
|
Infections and infestations
Upper respiratory tract infection
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
6.0%
6/100 • Day 1 - Day 360 or Early Termination
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
11.0%
11/100 • Day 1 - Day 360 or Early Termination
|
6.0%
6/100 • Day 1 - Day 360 or Early Termination
|
|
Nervous system disorders
Dizziness
|
12.0%
12/100 • Day 1 - Day 360 or Early Termination
|
5.0%
5/100 • Day 1 - Day 360 or Early Termination
|
|
Nervous system disorders
Headache
|
45.0%
45/100 • Day 1 - Day 360 or Early Termination
|
38.0%
38/100 • Day 1 - Day 360 or Early Termination
|
|
Nervous system disorders
Migraine
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
|
Reproductive system and breast disorders
Dysmenorrhoea
|
1.0%
1/100 • Day 1 - Day 360 or Early Termination
|
5.0%
5/100 • Day 1 - Day 360 or Early Termination
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
5.0%
5/100 • Day 1 - Day 360 or Early Termination
|
9.0%
9/100 • Day 1 - Day 360 or Early Termination
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
4.0%
4/100 • Day 1 - Day 360 or Early Termination
|
11.0%
11/100 • Day 1 - Day 360 or Early Termination
|
|
Vascular disorders
Flushing
|
8.0%
8/100 • Day 1 - Day 360 or Early Termination
|
0.00%
0/100 • Day 1 - Day 360 or Early Termination
|
|
Vascular disorders
Haematoma
|
7.0%
7/100 • Day 1 - Day 360 or Early Termination
|
9.0%
9/100 • Day 1 - Day 360 or Early Termination
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place