Leber's Hereditary Optic Neuropathy (LHON)
Conditions
Brief summary
LEROS is an open-label interventional Phase IV study, designed to further assess the efficacy and safety of Raxone® in the long-term treatment of LHON patients.
Interventions
DRUGIdebenone
Sponsors
Santhera Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Impaired visual acuity in affected eyes due to LHON 2. No explanation for visual loss besides LHON 3. Age more or equal 12 years 4. Onset of symptoms ≤5 years of Baseline 5. Confirmation of either G11778A, G3460A or T14484C LHON mtDNA (for the Intent-to Treat (ITT) population, not required for enrolment) 6. Written informed consent obtained from the patient 7. Ability and willingness to comply with study procedures and visits 8. Women of Childbearing Potential (WCBP) who have a negative urine or serum pregnancy test at Baseline visit and who are willing to use a highly effective contraceptive measure and maintain it until treatment discontinuation.
Exclusion criteria
1. Patient has provided natural history data to the Case Record Survey (SNT-CRS-002) 2. Any previous use of idebenone 3. Any other cause of visual impairment (e.g. glaucoma, diabetic retinopathy, AIDS related visual impairment, cataract, macular degeneration, etc.) or any active ocular disorder (uveitis, infections, inflammatory retinal disease, thyroid eye disease, etc.) 4. Known history of clinically significant elevations (greater than 3 times the upper limit of normal) of aspartate aminotransferase (AST), alanine transaminase (ALT) or creatinine 5. Patient has a condition or is in a situation which, in an investigator's opinion may put the patient at significant risk, may confound study results or may interfere significantly with the patient's participation in the study 6. Participation in another clinical trial of any investigational drug within 3 months prior to Baseline 7. Hypersensitivity to the active substance or to any of the following excipients (as listed in section 6.1 of Raxone SmPC): Lactose monohydrate, Microcrystalline cellulose, Croscarmellose sodium, Povidone K25, Magnesium stearate, Colloidal silica, Macrogol 3350, Poly(vinyl alcohol), Talc, Titanium dioxide, Sunset yellow FCF (E110). 8. Women who are pregnant or have a positive pregnancy test at Baseline visit 9. Women who are breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion (Number) of Eyes With Clinically Relevant Recovery of Visual Acuity From Baseline | 12 months | Proportion (number) of eyes with clinically relevant recovery of visual acuity (VA) from Baseline or in which Baseline VA better than 1.0 logMAR was maintained at Month 12 in patients treated with Raxone® ≤1 year after the onset of symptoms, compared to matching external natural history control group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Components of the Primary Endpoint: Proportion of Eyes With Clinically Relevant Recovery (CRR) of VA From Baseline at Month 12 Compared to Matching External National History (NH) Control Group | 12 months | CRR is defined as: * Improvement from off-chart (the equivalent of Counting fingers, Hand motion, Light perception or No light perception) Visual Acuity to at least 1.6 logMAR value, OR * Improvement of at least 0.2 logMAR value within on-chart Visual Acuity A patient had a CRR if at least one eye had CRR. logMAR = Logarithm of the minimum angle of resolution |
| Components of the Primary Endpoint: Proportion of Eyes in Which Baseline Visual Acuity (VA) Better Than 1.0 logMAR Was Maintained at Month 12 (Clinically Relevant Stabilization) Compared to Matching External NH Control Group | 12 months | For proportion of eyes in which baseline VA better than 1.0 logMAR was maintained at Month 12 (CRS) compared to matching external NH control group only patients having VA \< 1.0 at baseline are taking into account. Clinically relevant stabilization (CRS) was defined as maintenance of VA \<1.0 logMAR in eyes with VA \<1.0 logMAR at Baseline. A patient had a CRS if at least one eye had CRS. logMAR = Logarithm of the minimum angle of resolution |
Countries
Austria, Belgium, Bulgaria, Germany, Italy, Poland, Portugal, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raxone Raxone® (idebenone) 150 mg film-coated tablets. 900 mg/day (2 x 150 mg taken orally 3 times daily with meals) | 199 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | another study | 1 |
| Overall Study | cardiologist imposed travel restriction | 1 |
| Overall Study | Death | 1 |
| Overall Study | Due to Covid-19 lockdown V9 was not completed | 1 |
| Overall Study | Genetic diagnosis reveals that a patient does not harbour a LHON-specific mtDNA mutation | 12 |
| Overall Study | Lack of compliance with study medication | 4 |
| Overall Study | Lost to Follow-up | 7 |
| Overall Study | Patient unable to return for visits. Sent medication back to site | 1 |
| Overall Study | Pt not willing to perform onsite V9,did not withdraw consent,not triggered by Covid19 situation | 1 |
| Overall Study | subject is enrolling in a different LHON study that excludes use of idebenone | 1 |
| Overall Study | Withdrawal by Subject | 23 |
Baseline characteristics
| Characteristic | Raxone |
|---|---|
| Age, Categorical <=18 years | 29 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 164 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 131 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Region of Enrollment Austria | 9 participants |
| Region of Enrollment Belgium | 15 participants |
| Region of Enrollment Bulgaria | 5 participants |
| Region of Enrollment Germany | 4 participants |
| Region of Enrollment Italy | 12 participants |
| Region of Enrollment Poland | 39 participants |
| Region of Enrollment Portugal | 4 participants |
| Region of Enrollment Spain | 12 participants |
| Region of Enrollment United Kingdom | 29 participants |
| Region of Enrollment United States | 70 participants |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 198 |
| other Total, other adverse events | 148 / 198 |
| serious Total, serious adverse events | 27 / 198 |
Outcome results
Primary
Proportion (Number) of Eyes With Clinically Relevant Recovery of Visual Acuity From Baseline
Proportion (number) of eyes with clinically relevant recovery of visual acuity (VA) from Baseline or in which Baseline VA better than 1.0 logMAR was maintained at Month 12 in patients treated with Raxone® ≤1 year after the onset of symptoms, compared to matching external natural history control group
Time frame: 12 months
Population: In the Month 12 dataset with eyes ≤ 1 year after the onset of symptoms at Baseline, used in the evaluation of the primary endpoint, there were 80 patients in the LEROS mITT who contributed 142 eyes for the evaluation.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Raxone | Proportion (Number) of Eyes With Clinically Relevant Recovery of Visual Acuity From Baseline | 60 eyes |
p-value: 0.002195% CI: [1.352, 3.884]Wald Chi-square
Secondary
Components of the Primary Endpoint: Proportion of Eyes in Which Baseline Visual Acuity (VA) Better Than 1.0 logMAR Was Maintained at Month 12 (Clinically Relevant Stabilization) Compared to Matching External NH Control Group
For proportion of eyes in which baseline VA better than 1.0 logMAR was maintained at Month 12 (CRS) compared to matching external NH control group only patients having VA \< 1.0 at baseline are taking into account. Clinically relevant stabilization (CRS) was defined as maintenance of VA \<1.0 logMAR in eyes with VA \<1.0 logMAR at Baseline. A patient had a CRS if at least one eye had CRS. logMAR = Logarithm of the minimum angle of resolution
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Raxone | Components of the Primary Endpoint: Proportion of Eyes in Which Baseline Visual Acuity (VA) Better Than 1.0 logMAR Was Maintained at Month 12 (Clinically Relevant Stabilization) Compared to Matching External NH Control Group | 20 eyes |
p-value: 0.000595% CI: [2.339, 25.912]Waldi-Chi-Square
Secondary
Components of the Primary Endpoint: Proportion of Eyes With Clinically Relevant Recovery (CRR) of VA From Baseline at Month 12 Compared to Matching External National History (NH) Control Group
CRR is defined as: * Improvement from off-chart (the equivalent of Counting fingers, Hand motion, Light perception or No light perception) Visual Acuity to at least 1.6 logMAR value, OR * Improvement of at least 0.2 logMAR value within on-chart Visual Acuity A patient had a CRR if at least one eye had CRR. logMAR = Logarithm of the minimum angle of resolution
Time frame: 12 months
Population: In the Month 12 dataset with eyes ≤ 1 year after the onset of symptoms at Baseline, used in the evaluation of the primary endpoint, there were 80 patients in the LEROS mITT who contributed 142 eyes for the evaluation.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Raxone | Components of the Primary Endpoint: Proportion of Eyes With Clinically Relevant Recovery (CRR) of VA From Baseline at Month 12 Compared to Matching External National History (NH) Control Group | 47 eyes |
p-value: 0.087395% CI: [0.929, 2.918]Waldi-Chi-Square