Fabry Disease
Conditions
Brief summary
This study aimed to determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease.
Detailed description
The primary objective of this prospective, multicenter, double-blind, randomized, placebo-controlled, parallel group, Phase 3 study is to determine the effect of oral lucerastat monotherapy on neuropathic pain in subjects with Fabry disease (FD) through daily collection of patient-reported outcomes with an electronic diary.
Interventions
DRUGLucerastat
Hard gelatin capsules containing 250 mg of lucerastat and inactive excipients; 1000 mg (4 capsules) twice daily (b.i.d.); dose adjusted for renal function.
DRUGPlacebo
Placebo capsules are identical in appearance to the lucerastat capsules, and contain inactive excipients; 4 capsules b.i.d.; dose adjusted for renal function.
Sponsors
Idorsia Pharmaceuticals Ltd.
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
1. Signed and dated ICF prior to any study-mandated procedure; 2. Male or female adult subjects; 3. FD diagnosis confirmed with local genetic test results; 4. Fabry-associated neuropathic pain, as defined by the subject, in the last 3 months prior to screening; 5. Enzyme replacement therapy (ERT) status: 1. Subject never treated with ERT; or 2. Subject has not received ERT for at least 6 months prior to screening; or 3. Subject treated with ERT since at least 12 months at the time of the screening visit, and agreeing to stop ERT for approximately 8 months. 6. A woman of childbearing potential is eligible only under certain conditions, e.g. taking contraceptive measures. 7. Subjects with moderate or severe neuropathic pain during the screening period.
Exclusion criteria
1. Pregnant, planning to be become pregnant, or lactating subject. 2. Severe renal insufficiency (eGFR \< 30 mL/min/1.73 m2) at screening. 3. Subject on regular dialysis for the treatment of chronic kidney disease. 4. Known and documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within 6 months prior to screening. 5. Clinically significant unstable cardiac disease (e.g. uncontrolled symptomatic arrhythmia, congestive heart failure NYHA class III or IV). 6. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neuropathic Pain Monthly Score: Change From Baseline to Month 6 | From baseline to Month 6 (duration: 6 months) | Neuropathic pain on the modified BPI-SF3: subjects rated their neuropathic pain intensity (neuropathic pain at its worst in the last 24 hours) on an 11-point scale, from 0 (no neuropathic pain) to 10 (worst imaginable neuropathic pain). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Globotriaosylceramide (Gb3; in ng/ml): Change From Baseline to Month 6 | From baseline to Month 6 (duration: 6 months) | — |
| Abdominal Pain Monthly Score: Change From Baseline to Month 6 | From baseline to Month 6 (duration: 6 months) | Abdominal pain on the 11-point Numerical Rating Scale (NRS-11): subjects rated their abdominal pain intensity (abdominal pain at its worst in the last 24 hours) on an 11-point scale, from 0 (no pain) to 10 (worst imaginable pain). |
| Number of Days With Diarrhea: Change From Baseline to Month 6 | From baseline to Month 6 (duration: 6 months) | A subject was considered to have diarrhea on a specific day if at least one stool of a Bristol Stool Scale (BSS) consistency Type 6 or 7 was reported. The number of days with diarrhea at baseline and Month 6 was the number of days with diarrhea over the 4 weeks prior to the randomization visit or the Month 6 visit, respectively, adjusted for the number of days with data available. |
Countries
Australia, Austria, Belgium, Canada, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 49 sites in 14 countries, including North America (USA, CAN), Europe (Austria, Belgium, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, UK), and Australia.
Participants by arm
| Arm | Count |
|---|---|
| Lucerastat Lucerastat (ACT-434964) was provided as hard-gelatin capsules containing 250 mg of lucerastat.
Capsules were administered orally b.i.d. to provide a lucerastat dose of 250, 500, 750, or 1000 mg b.i.d. based on the subject's eGFR. | 80 |
| Placebo Matching placebo capsules were administered orally b.i.d., with the number of capsules administered based on the subject's eGFR. | 38 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Randomized but not treated | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Lucerastat | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 38 years | 39 years | 39 years |
| Neuropathic pain monthly score at baseline | 6.26 units on a scale STANDARD_DEVIATION 1.54 | 6.21 units on a scale STANDARD_DEVIATION 1.49 | 6.11 units on a scale STANDARD_DEVIATION 1.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 76 Participants | 113 Participants | 37 Participants |
| Region of Enrollment Australia | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Austria | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Belgium | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Canada | 10 participants | 15 participants | 5 participants |
| Region of Enrollment Germany | 10 participants | 14 participants | 4 participants |
| Region of Enrollment Netherlands | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Norway | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Poland | 9 participants | 13 participants | 4 participants |
| Region of Enrollment Spain | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Switzerland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 8 participants | 11 participants | 3 participants |
| Region of Enrollment United States | 26 participants | 32 participants | 6 participants |
| Sex: Female, Male Female | 43 Participants | 63 Participants | 20 Participants |
| Sex: Female, Male Male | 37 Participants | 55 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 0 / 37 |
| other Total, other adverse events | 46 / 80 | 21 / 37 |
| serious Total, serious adverse events | 5 / 80 | 1 / 37 |
Outcome results
Primary
Neuropathic Pain Monthly Score: Change From Baseline to Month 6
Neuropathic pain on the modified BPI-SF3: subjects rated their neuropathic pain intensity (neuropathic pain at its worst in the last 24 hours) on an 11-point scale, from 0 (no neuropathic pain) to 10 (worst imaginable neuropathic pain).
Time frame: From baseline to Month 6 (duration: 6 months)
Population: The analysis included all subjects who were randomized and took at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lucerastat | Neuropathic Pain Monthly Score: Change From Baseline to Month 6 | -1.64 score on a scale |
| Placebo | Neuropathic Pain Monthly Score: Change From Baseline to Month 6 | -2.05 score on a scale |
p-value: 0.318995% CI: [-0.4, 1.23]ANCOVA
Secondary
Abdominal Pain Monthly Score: Change From Baseline to Month 6
Abdominal pain on the 11-point Numerical Rating Scale (NRS-11): subjects rated their abdominal pain intensity (abdominal pain at its worst in the last 24 hours) on an 11-point scale, from 0 (no pain) to 10 (worst imaginable pain).
Time frame: From baseline to Month 6 (duration: 6 months)
Population: The analysis included randomized and treated subjects with gastrointestinal symptoms at baseline (diarrhea on at least 8 days and/or moderate or severe abdominal pain in the 4 weeks prior to randomization).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lucerastat | Abdominal Pain Monthly Score: Change From Baseline to Month 6 | -1.37 score on a scale |
| Placebo | Abdominal Pain Monthly Score: Change From Baseline to Month 6 | -1.68 score on a scale |
p-value: 0.467695% CI: [-0.53, 1.16]ANCOVA
Secondary
Number of Days With Diarrhea: Change From Baseline to Month 6
A subject was considered to have diarrhea on a specific day if at least one stool of a Bristol Stool Scale (BSS) consistency Type 6 or 7 was reported. The number of days with diarrhea at baseline and Month 6 was the number of days with diarrhea over the 4 weeks prior to the randomization visit or the Month 6 visit, respectively, adjusted for the number of days with data available.
Time frame: From baseline to Month 6 (duration: 6 months)
Population: The analysis included randomized and treated subjects with gastrointestinal symptoms at baseline (diarrhea on at least 8 days and/or moderate or severe abdominal pain in the 4 weeks prior to randomization) and a non-missing change from baseline to Month 6 value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lucerastat | Number of Days With Diarrhea: Change From Baseline to Month 6 | -3.45 Number of days within 4 weeks | Standard Deviation 4.96 |
| Placebo | Number of Days With Diarrhea: Change From Baseline to Month 6 | -3.95 Number of days within 4 weeks | Standard Deviation 9.29 |
Comparison: The p-value was derived from a rank ANCOVA adjusted for the baseline value and stratified by sex and ERT treatment status.p-value: 0.898695% CI: [0.57, 1.89]ANCOVA
Secondary
Plasma Globotriaosylceramide (Gb3; in ng/ml): Change From Baseline to Month 6
Time frame: From baseline to Month 6 (duration: 6 months)
Population: The analysis included all subjects who were randomized and took at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lucerastat | Plasma Globotriaosylceramide (Gb3; in ng/ml): Change From Baseline to Month 6 | -672.68 ng/ml |
| Placebo | Plasma Globotriaosylceramide (Gb3; in ng/ml): Change From Baseline to Month 6 | 200.84 ng/ml |
p-value: <0.000195% CI: [-1097.53, -649.53]ANCOVA