Erythropoietic Protoporphyria
Conditions
Keywords
Erythropoietic Protoporphyria, EPP, Afamelanotide
Brief summary
This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Approximately 10 eligible patients per center will be enrolled and 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 To determine eligibility for study inclusion, patients will undergo a screening evaluation 7 to 14 days prior to the administration of the first dose. The number and severity of phototoxic reactions will be determined Days 60, 120, and 180. Quality of life will be measured using the EPP specific questionnaire (EPP-QoL) every 60 days and the DLQI questionnaire every 7 days, beginning at Day 0 until Day 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events.
Detailed description
Afamelanotide is a man-made drug being studied for use as a preventative medication for EPP sufferers. It is a synthetically produced analogue of human alpha melanocyte stimulating hormone (alpha-MSH) and is not yet available on the market. The purpose of this study is to look at whether afamelanotide can reduce the number and severity of EPP symptoms when patients are exposed to light between 10:00 and 20:00 hours. 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 450 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. Once inserted, the implant will remain in the body after afamelanotide has been released and will slowly dissolve. This study will help to provide more information about afamelanotide. This information will be used to determine the safety and efficacy (the ability of the drug to produce an effect) of this drug in EPP sufferers.
Interventions
DRUGAfamelanotide
One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total)
DRUGPlacebo
One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total)
Sponsors
Clinuvel Pharmaceuticals Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects with characteristic photosensitivity of EPP symptoms and positive diagnosis of EPP confirmed by laboratory result of elevated total protoporphyrin IX. * 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 PLE, DLE 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 within 60 days prior to the screening visit. * 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time in Direct Sunlight Between 10:00-15:00 on Pain-free Days | Daily for 6 months | The amount of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (e.g. 11-point Likert pain score of 0). Time was recorded in a patient dairy 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
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Measured by Participant Completed Questionnaire | Day 0, Day 60, Day 120, Day 180 | Erythropoietic Protoporphyria Quality of Life Measure (EPP-QoL) is used to measure the quality of life of participants. The total EPP-QoL score ranges from 0 to 100, with a score of 0 as the worst quality of life and score of 100 as the best quality of life. |
| Change of Total Protoporphyrin IX Level in Participants | Baseline, Day 60, Day 120, Day 180 | This was an exploratory assessment only to analyze whether afamelanotide-induced change in sun exposure would result in a reduction of protoporphyrin IX. The changes of the Total Protoporphyrin IX Level (μg/dL) from Screening Visit (ITT Population) were measured between the two groups. The Protoporphyrin IX level is a laboratory parameter that is measured in specialist labs. |
| Maximum Severity of Phototoxic Reaction Experienced by Participants | Daily for 6 months | 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. |
| Number of Phototoxic Reactions Experienced by Participants | Daily for 6 months | 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. |
| Total Severity of Phototoxic Reactions Experienced by Participants Over the Entire Study | Daily for 6 months. | 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 total severity of phototoxic reactions was determined by the sum of daily 11-point Likert scale scores that occurred during phototoxic reactions. The overall sum of the severity per participant over the entire study was analyzed. The theoretical minimum score is 0 and the maximum possible score is 1800. |
| Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 | Daily for 6 months | The number of participants who experienced phototoxic reactions with Likert severity scores ≥ 4 and severity scores ≥7 were recorded. A derived endpoint was used. The number of participants who reported at least one phototoxic reaction with a Likert severity score of ≥ 4 was recorded. For severity scores ≥ 7, the number of patients who reported at least one phototoxic reaction with a Likert severity score of ≥ 7 was recorded. The 11-point Likert pain scale ranges from minimum of 0 to maximum of 10. The 11-point Likert pain scale with a value of 0 represents no pain and 10 represents worst imaginable pain. |
Countries
United States
Participant flow
Recruitment details
Study Recruitment period: April2010 - July2010 Study site location: Mt. Sinai, New York Carolinas Medical Center, North Carolina University of Alabama at Birmingham, Alabama University of Utah, Utah University of Texas Medical Branch, Texas University of California, San Francisco, California
Participants by arm
| Arm | Count |
|---|---|
| Afamelanotide Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | 39 |
| Placebo Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) | 38 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Afamelanotide | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 36 Participants | 71 Participants |
| Age, Continuous | 38.1 years STANDARD_DEVIATION 14.5 | 42.6 years STANDARD_DEVIATION 15.7 | 40.3 years STANDARD_DEVIATION 15.2 |
| Region of Enrollment United States | 39 participants | 38 participants | 77 participants |
| Sex: Female, Male Female | 16 Participants | 18 Participants | 34 Participants |
| Sex: Female, Male Male | 23 Participants | 20 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 39 | 29 / 38 |
| serious Total, serious adverse events | 2 / 39 | 2 / 38 |
Outcome results
Primary
Time in Direct Sunlight Between 10:00-15:00 on Pain-free Days
The amount of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (e.g. 11-point Likert pain score of 0). Time was recorded in a patient dairy 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
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afamelanotide | Time in Direct Sunlight Between 10:00-15:00 on Pain-free Days | 8.25 Hours |
| Placebo | Time in Direct Sunlight Between 10:00-15:00 on Pain-free Days | 0.75 Hours |
Secondary
Change of Total Protoporphyrin IX Level in Participants
This was an exploratory assessment only to analyze whether afamelanotide-induced change in sun exposure would result in a reduction of protoporphyrin IX. The changes of the Total Protoporphyrin IX Level (μg/dL) from Screening Visit (ITT Population) were measured between the two groups. The Protoporphyrin IX level is a laboratory parameter that is measured in specialist labs.
Time frame: Baseline, Day 60, Day 120, Day 180
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afamelanotide | Change of Total Protoporphyrin IX Level in Participants | Day 60 | -471.3 mcg/dL | Standard Deviation 505.4 |
| Afamelanotide | Change of Total Protoporphyrin IX Level in Participants | Day 120 | -511.8 mcg/dL | Standard Deviation 595.3 |
| Afamelanotide | Change of Total Protoporphyrin IX Level in Participants | Day 180 | -92.7 mcg/dL | Standard Deviation 549.1 |
| Placebo | Change of Total Protoporphyrin IX Level in Participants | Day 60 | -628.5 mcg/dL | Standard Deviation 837.5 |
| Placebo | Change of Total Protoporphyrin IX Level in Participants | Day 120 | -619.9 mcg/dL | Standard Deviation 1022.3 |
| Placebo | Change of Total Protoporphyrin IX Level in Participants | Day 180 | -369.2 mcg/dL | Standard Deviation 1265.6 |
Secondary
Maximum Severity of Phototoxic Reaction Experienced by Participants
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
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afamelanotide | Maximum Severity of Phototoxic Reaction Experienced by Participants | 5.0 score on a scale |
| Placebo | Maximum Severity of Phototoxic Reaction Experienced by Participants | 5.0 score on a scale |
Secondary
Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7
The number of participants who experienced phototoxic reactions with Likert severity scores ≥ 4 and severity scores ≥7 were recorded. A derived endpoint was used. The number of participants who reported at least one phototoxic reaction with a Likert severity score of ≥ 4 was recorded. For severity scores ≥ 7, the number of patients who reported at least one phototoxic reaction with a Likert severity score of ≥ 7 was recorded. The 11-point Likert pain scale ranges from minimum of 0 to maximum of 10. The 11-point Likert pain scale with a value of 0 represents no pain and 10 represents worst imaginable pain.
Time frame: Daily for 6 months
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afamelanotide | Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 | Severity Likert score of ≥ 4 | 26 Count of Participants |
| Afamelanotide | Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 | Severity Likert score of ≥ 7 | 7 Count of Participants |
| Placebo | Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 | Severity Likert score of ≥ 4 | 24 Count of Participants |
| Placebo | Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 | Severity Likert score of ≥ 7 | 14 Count of Participants |
Secondary
Number of Phototoxic Reactions Experienced by Participants
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
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afamelanotide | Number of Phototoxic Reactions Experienced by Participants | 2.0 Episodes |
| Placebo | Number of Phototoxic Reactions Experienced by Participants | 1.0 Episodes |
Secondary
Quality of Life Measured by Participant Completed Questionnaire
Erythropoietic Protoporphyria Quality of Life Measure (EPP-QoL) is used to measure the quality of life of participants. The total EPP-QoL score ranges from 0 to 100, with a score of 0 as the worst quality of life and score of 100 as the best quality of life.
Time frame: Day 0, Day 60, Day 120, Day 180
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Afamelanotide | Quality of Life Measured by Participant Completed Questionnaire | Day 60 | 73.6 units on a scale |
| Afamelanotide | Quality of Life Measured by Participant Completed Questionnaire | Day 0 | 34.7 units on a scale |
| Afamelanotide | Quality of Life Measured by Participant Completed Questionnaire | Day 120 | 84.7 units on a scale |
| Afamelanotide | Quality of Life Measured by Participant Completed Questionnaire | Day 180 | 88.9 units on a scale |
| Placebo | Quality of Life Measured by Participant Completed Questionnaire | Day 180 | 63.9 units on a scale |
| Placebo | Quality of Life Measured by Participant Completed Questionnaire | Day 120 | 55.6 units on a scale |
| Placebo | Quality of Life Measured by Participant Completed Questionnaire | Day 0 | 22.2 units on a scale |
| Placebo | Quality of Life Measured by Participant Completed Questionnaire | Day 60 | 44.4 units on a scale |
Secondary
Total Severity of Phototoxic Reactions Experienced by Participants Over the Entire Study
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 total severity of phototoxic reactions was determined by the sum of daily 11-point Likert scale scores that occurred during phototoxic reactions. The overall sum of the severity per participant over the entire study was analyzed. The theoretical minimum score is 0 and the maximum possible score is 1800.
Time frame: Daily for 6 months.
Population: One active participant and one placebo participant withdrew after Baseline assessment and no data was provided for the analysis of this endpoint.~The overall number of participants analyzed differs from the total number of study participants because the data was either incomplete and/or missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afamelanotide | Total Severity of Phototoxic Reactions Experienced by Participants Over the Entire Study | 27.9 units on a scale | Standard Deviation 43.1 |
| Placebo | Total Severity of Phototoxic Reactions Experienced by Participants Over the Entire Study | 37.2 units on a scale | Standard Deviation 102.6 |