EPP, XLP
Conditions
Brief summary
The primary objective of this study is to investigate the efficacy of MT-7117 on time to onset and severity of first prodromal symptoms (burning, tingling, itching, or stinging) associated with sunlight exposure in adults and adolescents with EPP or XLP aged 12-75.
Interventions
Sponsors
Tanabe Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Additional screening criteria check may apply for qualification. Inclusion Criteria: 1. Subjects provided written informed consent to participate. For minor subjects, both minor assent and parental consent will be provided. 2. Male and female subjects with a confirmed diagnosis of EPP or XLP based on medical history, aged 12 years to 75 years, inclusive, at Screening. 3. Subjects have a body weight of ≥30 kg. 4. Subjects are willing and able to travel to the study sites for all scheduled visits. 5. In the Investigator's opinion, subject is able to understand the nature of the study and any risks involved in participation, and willing to cooperate and comply with the protocol restrictions and requirements (including travel). 6. Female subjects who are non-lactating and have a negative urine pregnancy test at baseline visit prior to receiving the first dose of study drug. 7. Female subjects of childbearing potential and male subjects with partner of child-bearing potential currently using/willing to use 2 effective methods of contraception including barrier method as described in the protocol.
Exclusion criteria
1. History or presence of photodermatoses other than EPP or XLP. 2. Subjects who are unwilling or unable to go outside during daylight hours most days (e.g., between 1 hour post sunrise and 1 hour pre-sunset) during the study. 3. Presence of clinically significant hepatobiliary disease based on LFT values at Screening. 4. Subjects with AST, ALT, ALP ≥3.0 × upper limit of normal (ULN) or total bilirubin \>1.5 × ULN at Screening. 5. Subjects with or having a history (in the last 2 years) of excessive alcohol intake in the opinion of the Investigator. 6. History of melanoma. 7. Presence of melanoma and/or lesions suspicious for melanoma at Screening. 8. History of familial melanoma (defined as having 2 or more first-degree relatives, such as parents, sibling and/or child). 9. Presence of squamous cell carcinoma, basal cell carcinoma, or other malignant skin lesions. Any suspicious lesions or nevi will be evaluated. If the suspicious lesion or nevi cannot be resolved through biopsy or excision, the subject will be excluded from the study. 10. History or presence of psychiatric disease judged to be clinically significant by the Investigator and which may interfere with the study evaluation and/or safety of the subjects. 11. Presence of clinically significant acute or chronic renal disease based upon the subject's medical records including hemodialysis; an estimated glomerular filtration rate (eGFR) \<60 mL/min as calculated by the Chronic Kidney Disease-Epidemiology Collaboration (CKDEPI) creatinine equation (2009) for adults and by the Schwartz creatinine equation for adolescents (2009). Modification of Diet in Renal Disease (MDRD) can be used for adults per local recommendations. 12. Presence of any clinically significant disease or laboratory abnormality which, in the opinion of the Investigator, can interfere with the study objectives and/or safety of the subjects. 13. Female subjects who are pregnant, lactating, or intending to become pregnant during the study. 14. Treatment with phototherapy within 3 months before Randomization (Visit 2). 15. Treatment with afamelanotide within 3 months before Randomization (Visit 2). 16. Treatment with cimetidine within 4 weeks before Randomization (Visit 2). 17. Treatment with antioxidant agents within 4 weeks before Randomization (Visit 2), at doses which, in the opinion of the Investigator, may affect study endpoints (including but not limited to beta-carotene, cysteine, pyridoxine). 18. Chronic treatment with any scheduled analgesic agents including, but not limited to, opioids and opioid derivatives such as morphine, hydrocodone, oxycodone, fentanyl, or their combination with other unscheduled analgesics or non-steroidal anti-inflammatory drug (Percocet and Vicodin-like prescription drugs) within 4 weeks before Randomization (Visit 2). Acute use of scheduled narcotics greater than 3 months prior to randomization, OTCs, such as NSAIDs or aspirin for analgesia, or prior temporary use of scheduled agents within 3 months of screening are not excluded. 19. Treatment with any drugs or supplements which, in the opinion of the Investigator, can interfere with the objectives of the study or safety of the subjects. 20. Previous exposure to MT-7117 (this does not include placebo treated subjects). 21. Previous treatment with any investigational agent within 12 weeks before Screening OR 5 half-lives of the investigational product (whichever is longer).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Average Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post Sunrise and 1 Hour Pre-sunset at Week 26 (Visit 7) | From 1 hour post-sunrise to 1 hour pre-sunset at Week 26 (Visit 7) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Global Impression of Change (PGIC) at Week 26 | Week 26 | PGIC: Scale from 1 to 7, where 7 is worse. |
| Total Number of Sunlight-induced Pain Events Defined as Prodrome Symptoms (Burning, Tingling, Itching, or Stinging) With Pain Rating of 1-10 on the Likert Scale During the 26-week Double-blind Treatment Period. | During the 26-week double-blind treatment period | The Likert scale used ranges from 0 to 10, where 0 indicates the lowest pain rating and 10 indicates the highest pain rating. Likewise, 0 indicates to best outcome and 10 indicates the worst outcome. The sum of the number of pain events with pain rating of 1 to 10 for the day is used as the number of sunlight-induced pain events in the day. The sum of the number of the pain events with pain rating of 1 to 10 in each day during the 26-week Double-blind Treatment Period is calculated as this endpoint. |
| Change From Baseline for Total Score in the Domain of Pain Intensity in the PROMIS-57 at Week 26 | Baseline (Week 0) and Week 26 | Pain intensity: 0 to 10, where 10 is worst pain imaginable. |
| The Percentage of Subjects Who Are Responders | Week 26 | The percentage of subjects who are responders based on average daily sunlight exposure time to first prodromal symptom associated with sunlight exposure between 1 hour post-sunrise and 1 hour presunset defined by within-subject meaningful change of 66 minutes increase from baseline to Week 26 |
| Change From Baseline for Total Score in the Domain of Physical Function in the PROMIS-57 at Week 26 | Baseline (Week 0) and Week 26 | Physical function: 1-5, where 5 is without any difficulty. |
Countries
Australia, Canada, Germany, Italy, Japan, Norway, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects who were randomized to receive matching oral tablet of placebo once a day in Double-Blind treatment | 61 |
| MT-7117 Low Dose Subjects who were randomized to receive oral tablet of MT-7117 Low Dose once a day in Double-Blind Treatment and Double-Blind Extension | 63 |
| MT-7117 High Dose Subjects who were randomized to receive oral tablet of MT-7117 High Dose once a day in Double-Blind Treatment and Double-Blind Extension | 60 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 26 Weeks Double-Blind Extension (DBE) | Adverse Event | 0 | 0 | 1 | 0 | 0 |
| 26 Weeks Double-Blind Extension (DBE) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| 26 Weeks Double-Blind Extension (DBE) | Withdrawal by Subject | 0 | 1 | 2 | 0 | 0 |
| 26 Weeks Double-Blind Treatment (DBT) | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| 26 Weeks Double-Blind Treatment (DBT) | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| 26 Weeks Double-Blind Treatment (DBT) | Withdrawal by Subject | 3 | 2 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | MT-7117 Low Dose | MT-7117 High Dose | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 13 Participants | 12 Participants | 37 Participants |
| Age, Categorical >=65 years | 2 Participants | 5 Participants | 2 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants | 45 Participants | 46 Participants | 138 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 2 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 52 Participants | 58 Participants | 163 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 1 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 52 Participants | 60 Participants | 55 Participants | 167 Participants |
| Sex: Female, Male Female | 30 Participants | 30 Participants | 33 Participants | 93 Participants |
| Sex: Female, Male Male | 31 Participants | 33 Participants | 27 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 63 | 1 / 60 | 0 / 28 | 0 / 28 | 0 / 56 | 0 / 54 |
| other Total, other adverse events | 30 / 61 | 35 / 63 | 40 / 60 | 19 / 28 | 18 / 28 | 24 / 56 | 21 / 54 |
| serious Total, serious adverse events | 0 / 61 | 2 / 63 | 2 / 60 | 2 / 28 | 1 / 28 | 1 / 56 | 2 / 54 |
Outcome results
Primary
Change From Baseline in Average Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post Sunrise and 1 Hour Pre-sunset at Week 26 (Visit 7)
Time frame: From 1 hour post-sunrise to 1 hour pre-sunset at Week 26 (Visit 7)
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DBT ITT1 Placebo | Change From Baseline in Average Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post Sunrise and 1 Hour Pre-sunset at Week 26 (Visit 7) | 20.59 minute | Standard Error 10.29 |
| DBT ITT1 MT- 7117 Low Dose | Change From Baseline in Average Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post Sunrise and 1 Hour Pre-sunset at Week 26 (Visit 7) | 30.39 minute | Standard Error 10.04 |
| DBT ITT1 MT- 7117 High Dose | Change From Baseline in Average Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post Sunrise and 1 Hour Pre-sunset at Week 26 (Visit 7) | 43.29 minute | Standard Error 10.13 |
Comparison: Change from BL at Week 26 (DBT EOT) - lower dosep-value: 0.49695% CI: [-18.52, 38.12]Mixed-effect model for repeated measures
Comparison: Change from BL at Week 26 (DBT EOT) - higher dosep-value: 0.11695% CI: [-5.68, 51.09]Mixed-effect model for repeated measures
Secondary
Change From Baseline for Total Score in the Domain of Pain Intensity in the PROMIS-57 at Week 26
Pain intensity: 0 to 10, where 10 is worst pain imaginable.
Time frame: Baseline (Week 0) and Week 26
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DBT ITT1 Placebo | Change From Baseline for Total Score in the Domain of Pain Intensity in the PROMIS-57 at Week 26 | -1.42 total score | Standard Error 0.18 |
| DBT ITT1 MT- 7117 Low Dose | Change From Baseline for Total Score in the Domain of Pain Intensity in the PROMIS-57 at Week 26 | -1.56 total score | Standard Error 0.16 |
| DBT ITT1 MT- 7117 High Dose | Change From Baseline for Total Score in the Domain of Pain Intensity in the PROMIS-57 at Week 26 | -1.65 total score | Standard Error 0.17 |
p-value: 0.5595% CI: [-0.62, 0.33]mixed-effect model for repeated measures
p-value: 0.34395% CI: [-0.72, 0.25]mixed-effect model for repeated measures
Secondary
Change From Baseline for Total Score in the Domain of Physical Function in the PROMIS-57 at Week 26
Physical function: 1-5, where 5 is without any difficulty.
Time frame: Baseline (Week 0) and Week 26
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DBT ITT1 Placebo | Change From Baseline for Total Score in the Domain of Physical Function in the PROMIS-57 at Week 26 | 0.67 total score | Standard Error 0.36 |
| DBT ITT1 MT- 7117 Low Dose | Change From Baseline for Total Score in the Domain of Physical Function in the PROMIS-57 at Week 26 | 1.54 total score | Standard Error 0.32 |
| DBT ITT1 MT- 7117 High Dose | Change From Baseline for Total Score in the Domain of Physical Function in the PROMIS-57 at Week 26 | 1.22 total score | Standard Error 0.33 |
p-value: 0.07295% CI: [-0.08, 1.82]mixed-effect model for repeated measures
p-value: 0.25295% CI: [-0.4, 1.51]mixed-effect model for repeated measures
Secondary
Patient Global Impression of Change (PGIC) at Week 26
PGIC: Scale from 1 to 7, where 7 is worse.
Time frame: Week 26
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DBT ITT1 Placebo | Patient Global Impression of Change (PGIC) at Week 26 | 3.25 point | Standard Error 1.14 |
| DBT ITT1 MT- 7117 Low Dose | Patient Global Impression of Change (PGIC) at Week 26 | 2.41 point | Standard Error 0.14 |
| DBT ITT1 MT- 7117 High Dose | Patient Global Impression of Change (PGIC) at Week 26 | 1.82 point | Standard Error 0.14 |
p-value: <0.00195% CI: [-1.23, -0.44]Mixed-effect model for repeated measures
p-value: <0.00195% CI: [-1.83, -1.03]Mixed-effect model for repeated measures
Secondary
The Percentage of Subjects Who Are Responders
The percentage of subjects who are responders based on average daily sunlight exposure time to first prodromal symptom associated with sunlight exposure between 1 hour post-sunrise and 1 hour presunset defined by within-subject meaningful change of 66 minutes increase from baseline to Week 26
Time frame: Week 26
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DBT ITT1 Placebo | The Percentage of Subjects Who Are Responders | 12 percentage of participants |
| DBT ITT1 MT- 7117 Low Dose | The Percentage of Subjects Who Are Responders | 11 percentage of participants |
| DBT ITT1 MT- 7117 High Dose | The Percentage of Subjects Who Are Responders | 16 percentage of participants |
p-value: 0.64295% CI: [0.323, 2.007]Regression, Logistic
p-value: 0.43195% CI: [0.598, 3.336]Regression, Logistic
Secondary
Total Number of Sunlight-induced Pain Events Defined as Prodrome Symptoms (Burning, Tingling, Itching, or Stinging) With Pain Rating of 1-10 on the Likert Scale During the 26-week Double-blind Treatment Period.
The Likert scale used ranges from 0 to 10, where 0 indicates the lowest pain rating and 10 indicates the highest pain rating. Likewise, 0 indicates to best outcome and 10 indicates the worst outcome. The sum of the number of pain events with pain rating of 1 to 10 for the day is used as the number of sunlight-induced pain events in the day. The sum of the number of the pain events with pain rating of 1 to 10 in each day during the 26-week Double-blind Treatment Period is calculated as this endpoint.
Time frame: During the 26-week double-blind treatment period
Population: Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DBT ITT1 Placebo | Total Number of Sunlight-induced Pain Events Defined as Prodrome Symptoms (Burning, Tingling, Itching, or Stinging) With Pain Rating of 1-10 on the Likert Scale During the 26-week Double-blind Treatment Period. | 23.9 events | Standard Deviation 30.93 |
| DBT ITT1 MT- 7117 Low Dose | Total Number of Sunlight-induced Pain Events Defined as Prodrome Symptoms (Burning, Tingling, Itching, or Stinging) With Pain Rating of 1-10 on the Likert Scale During the 26-week Double-blind Treatment Period. | 15.87 events | Standard Deviation 22.05 |
| DBT ITT1 MT- 7117 High Dose | Total Number of Sunlight-induced Pain Events Defined as Prodrome Symptoms (Burning, Tingling, Itching, or Stinging) With Pain Rating of 1-10 on the Likert Scale During the 26-week Double-blind Treatment Period. | 13.78 events | Standard Deviation 18.7 |
p-value: 0.19995% CI: [0.49, 1.16]Refer to comments below:
p-value: 0.00695% CI: [0.36, 0.84]Refer to comments below: