Phase II Confirmatory Study in Erythropoietic Protoporphyria (EPP)
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). 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Afamelanotide Dose: 16 mg implant; release of 16 mg over 7 to 10 days Mode of administration: Subcutaneous implantation Frequency: Every 60 days (on Days 0, 60 and 120) |
Drug: Afamelanotide
One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total)
|
| Placebo Comparator: Placebo Dose: 16 mg implant; Mode of administration: Subcutaneous implantation Frequency: Every 60 days (on Days 0, 60 and 120) |
Drug: Placebo
One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total)
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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.
- 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.
- 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.
Eligibility Criteria
Criteria
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).
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 | Mt. Sinai | New York | New York | United States | 10029 |
| 4 | Carolina's Medical Center Cannon Research | Charlotte | North Carolina | United States | 29203 |
| 5 | University of Texas | Galveston | Texas | United States | 77555 |
| 6 | University of Utah | Salt Lake City | Utah | United States | 84132 |
Sponsors and Collaborators
- Clinuvel Pharmaceuticals Limited
Investigators
- Principal Investigator: Robert Desnick, MD, Mt. Sinai
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CUV030
Study Results
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 |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Period Title: Overall Study | ||
| STARTED | 39 | 38 |
| COMPLETED | 34 | 33 |
| NOT COMPLETED | 5 | 5 |
Baseline Characteristics
| Arm/Group Title | Afamelanotide | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) | Total of all reporting groups |
| Overall Participants | 39 | 38 | 77 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
38.1
(14.5)
|
42.6
(15.7)
|
40.3
(15.2)
|
| Age (Count of Participants) | |||
| <=18 years |
3
7.7%
|
0
0%
|
3
3.9%
|
| Between 18 and 65 years |
35
89.7%
|
36
94.7%
|
71
92.2%
|
| >=65 years |
1
2.6%
|
2
5.3%
|
3
3.9%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
16
41%
|
18
47.4%
|
34
44.2%
|
| Male |
23
59%
|
20
52.6%
|
43
55.8%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
39
100%
|
38
100%
|
77
100%
|
Outcome Measures
| Title | Time in Direct Sunlight Between 10:00-15:00 on Pain-free Days |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Median (Full Range) [Hours] |
8.25
|
0.75
|
| Title | Maximum Severity of Phototoxic Reaction Experienced by Participants |
|---|---|
| Description | 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 |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Median (Full Range) [score on a scale] |
5.0
|
5.0
|
| Title | Quality of Life Measured by Participant Completed Questionnaire |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Day 0 |
34.7
|
22.2
|
| Day 60 |
73.6
|
44.4
|
| Day 120 |
84.7
|
55.6
|
| Day 180 |
88.9
|
63.9
|
| Title | Change of Total Protoporphyrin IX Level in Participants |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Day 60 |
-471.3
(505.4)
|
-628.5
(837.5)
|
| Day 120 |
-511.8
(595.3)
|
-619.9
(1022.3)
|
| Day 180 |
-92.7
(549.1)
|
-369.2
(1265.6)
|
| Title | Number of Participants With Phototoxic Reactions With Likert Severity Scores ≥ 4 and ≥ 7 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Severity Likert score of ≥ 4 |
26
66.7%
|
24
63.2%
|
| Severity Likert score of ≥ 7 |
7
17.9%
|
14
36.8%
|
| Title | Number of Phototoxic Reactions Experienced by Participants |
|---|---|
| Description | 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 |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Median (Full Range) [Episodes] |
2.0
|
1.0
|
| Title | Total Severity of Phototoxic Reactions Experienced by Participants Over the Entire Study |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Afamelanotide | Placebo |
|---|---|---|
| Arm/Group Description | Dose: 16 mg implant; release of 16 mg over 7 to 10 days Mode of administration: Subcutaneous implantation Frequency: Every 60 days (on Days 0, 60 and 120) Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Dose: 16 mg implant; Mode of administration: Subcutaneous implantation Frequency: Every 60 days (on Days 0, 60 and 120) Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) |
| Measure Participants | 38 | 37 |
| Mean (Standard Deviation) [units on a scale] |
27.9
(43.1)
|
37.2
(102.6)
|
Adverse Events
| Time Frame | 6 months (180 days) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Afamelanotide | Placebo | ||
| Arm/Group Description | Afamelanotide: One 16mg subcutaneous implant every 2 months for 6 months. (3 implants in total) | Placebo: One placebo subcutaneous implant every 2 months for 6 months. (3 implants in total) | ||
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 | 2/39 (5.1%) | 2/38 (5.3%) | ||
| Cardiac disorders | ||||
| Low Pulse Rate | 0/39 (0%) | 1/38 (2.6%) | ||
| Gastrointestinal disorders | ||||
| CRAMPY ABDOMINAL PAIN | 1/39 (2.6%) | 0/38 (0%) | ||
| RECURRENT RECTAL BLEEDING | 1/39 (2.6%) | 0/38 (0%) | ||
| Nervous system disorders | ||||
| DIZZINESS | 0/39 (0%) | 1/38 (2.6%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Afamelanotide | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 31/39 (79.5%) | 29/38 (76.3%) | ||
| Gastrointestinal disorders | ||||
| Nausea | 8/39 (20.5%) | 2/38 (5.3%) | ||
| Abdominal discomfort | 3/39 (7.7%) | 2/38 (5.3%) | ||
| General disorders | ||||
| Fatigue | 3/39 (7.7%) | 1/38 (2.6%) | ||
| Implant Site Pain | 1/39 (2.6%) | 5/38 (13.2%) | ||
| Pyrexia | 3/39 (7.7%) | 1/38 (2.6%) | ||
| Infections and infestations | ||||
| Nasopharyngitis | 7/39 (17.9%) | 2/38 (5.3%) | ||
| Sinusitis | 1/39 (2.6%) | 3/38 (7.9%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 3/39 (7.7%) | 4/38 (10.5%) | ||
| Back pain | 3/39 (7.7%) | 5/38 (13.2%) | ||
| Nervous system disorders | ||||
| Headache | 5/39 (12.8%) | 10/38 (26.3%) | ||
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Dr. Dennis Wright, Acting Chief Scientific Officer |
|---|---|
| Organization | Clinuvel Pharmaceuticals Limited |
| Phone | 646 527 7310 |
| Dennis.Wright@clinuvel.com |
- CUV030