A Multi-Site, Open-Label Extension Trial of Oral RPC1063 in Relapsing Multiple Sclerosis

An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of medicinal product, whether or not considered related to the investigational medicinal product.

A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization.

An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of medicinal product, whether or not considered related to the investigational medicinal product.

An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of medicinal product, whether or not considered related to the investigational medicinal product.

An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of medicinal product, whether or not considered related to the investigational medicinal product.

An absolute lymphocyte count (ALC) is a part of a blood test that measures the number of lymphocytes, a type of white blood cell, in the blood. Lymphocytes help fight infections and diseases. Reductions in ALC levels for participants in this study is expected and is a primary pharmacodynamic effect of RPC1063.

LLN = Lower limit of normal

A white blood cell count is a part of a blood test that measures the number of white blood cells in the blood. White blood cells help fight infections and diseases.

LLN = Lower limit of normal

An absolute neutrophil count is a part of a blood test that measures the number of neutrophils, a type of white blood cell, in the blood. Neutrophils help fight infections and diseases.

The number of participants with laboratory abnormalities in specific liver tests above ULN by category. ULN = Upper Limit of Normal

An electrocardiogram (ECG) measures electrical activity of the heart to detect cardiac problems.

Vital signs included body temperature, sitting heart rate/pulse (HR), sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP).

Baseline refers to assessments made on or before the first day participants received study treatment.

The number of participants with abnormal physical examination results. The assessments included abdominal, extremity, head, heart, lungs, neck, neurological non-MS, other and skin assessments.

Baseline refers to assessments made on or before the first day participants received study treatment.

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a unique suicide risk assessment tool that supports suicide risk assessment through a series of simple, plain-language questions. The answers help users identify whether someone is at risk for suicide, assess the severity and immediacy of that risk, and gauge the level of support that the person needs.

Results are displayed as the number of participants who answered "Yes" to at least one of the 10 questions in the suicidal ideation or suicidal behavior section.

Ideation from 1 (wishing to be dead) - 5 (Active suicidal ideation with specific plan and intent) Behavior from 6 (Preparatory acts or behavior) - 10 (Completed suicide). Baseline refers to assessments made on or before the first day participants received study treatment.

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a unique suicide risk assessment tool that supports suicide risk assessment through a series of simple, plain-language questions. The answers help users identify whether someone is at risk for suicide, assess the severity and immediacy of that risk, and gauge the level of support that the person needs.

Results are displayed as the number of participants who answered "Yes" to at least one of the 10 questions in the suicidal ideation or suicidal behavior section.

Ideation from 1 (wishing to be dead) - 5 (Active suicidal ideation with specific plan and intent) Behavior from 6 (Preparatory acts or behavior) - 10 (Completed suicide).

The PWC-20 is a rater-administered 20-item scale to assess signs and symptoms of withdrawal. Twenty items are rated on a 4-point scale as not present (0 points), mild (1 point), moderate (2 points), or severe (3 points). The points from all items are calculated as a total score. Higher scores indicate more severe withdrawal symptoms.

The HADS is a validated patient reported outcome for assessing anxiety and depression. It consists of 14 items in total, 7 items related to anxiety and 7 items related to depression. For each item patients select a statement (valued at 0 to 3 points) that closest matches their own feeling over the past week. Separate total scores for anxiety and depression are derived by adding up points. Total scores can range from 0 to 21 points. Higher scores indicate more severe anxiety and depression and scores of 8 to 10 are generally considered indicative of borderline anxiety/depression disorders and scores of 11 and higher are generally considered indicative of anxiety/depression disorders.

The ESS is a validated self administered questionnaire with 8 questions. Respondents rate on a 4-point scale (0 to 3) their chances of dozing off or falling asleep while engaged in 8 different activities. The ESS score is the sum of 8 item scores and can range from 0 to 24 points. Higher scores indicate more daytime sleepiness.

Vital signs included sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP).

The Annualized Relapse Rate (ARR) is the average number of relapses per study arm in one year. A relapse is defined as the occurrence of new or worsening neurological symptoms attributable to multiple sclerosis (MS) and immediately preceded by a relatively stable or improving neurological state of at least 30 days. The adjusted ARR was based on the negative binomial regression model with parent treatment group, adjusted for region (Eastern Europe vs Rest of World), age at parent baseline, and the parent baseline number of gadolinium-enhanced (GdE) lesions. The natural log transformation of time on treatment was used as an offset term to adjust for participants having different exposure times.

The time between first dose of study treatment and first relapse if experienced by a participant. A participant was censored if follow-up ended before a relapse occurred, whether due to the participant completing study, withdrawing from the study, or due to the cutoff of data collection for the analysis. The censor date was the date of the end of study or the date of the data cutoff for participant who were ongoing. Participants who withdrew from the study after the baseline visit were censored at the last known date while on study. Based on Kaplan-Meier product limit estimates.

The number of participants who did not experience relapse. A relapse is defined as the occurrence of new or worsening neurological symptoms attributable to multiple sclerosis (MS) and immediately preceded by a relatively stable or improving neurological state of at least 30 days.

Adjusted Mean of new enlarging T2 lesions per scan at each visit. Based on a negative binomial regression model, adjusted for parent study, region (Eastern Europe vs. Rest of the World), age at Baseline, and baseline number of GdE lesions.

T2 Magnetic Resonance Imaging (MRI) sequences are used to highlight areas of demyelination in brain neurons, which happens when the outer layer of the neurons is damaged due to multiple sclerosis (MS) activity. T2 sequences can be used to count the total number of MS lesions, which look like bright white spots on T2 sequences, and can be called "hyperintense".

Number of gadolinium-enhanced (GdE) (also called GdE enhanced T1) brain MRI lesions per scan at each visit.

Increased numbers of GdE lesions indicates an increase in the in the amount of active inflammation at the site and may be indicative of progressive disease.

Based on a negative binomial regression model, adjusted for parent study, region (Eastern Europe vs. Rest of the World), age at Baseline, and Baseline number of GdE lesions.

Baseline refers to assessments made on or before the first day participants received study treatment.

Multiple sclerosis (MS) disability progression is defined as a sustained worsening in EDSS of 1.0 points or more from baseline, confirmed after a 3-month and 6-month period. The EDSS is a standardized method, widely accepted, numerical scale used to evaluate disability in people with multiple sclerosis (MS). The EDSS is evaluated according to signs and symptoms observed during a standard neurological examination. These clinical observations are classified in 7 FS scales, each of them grading signs and symptoms for different neurological functions: pyramidal, cerebellar, brainstem, sensory, bowel or bladder, visual, and cerebral.

Derived using Kaplan-Meier estimates.

Number of participants without gadolinium enhanced (GdE) brain MRI lesions at each visit. Increased numbers of GdE lesions indicates an increase in the in the amount of active inflammation at the site and may be indicative of progressive disease.

Based on cumulative number of GdE lesions at a participant level.

Number of participants without new or enlarging T2 brain MRI lesions at each visit. Some multiple Sclerosis (MS) lesions appear as bright spots in a T2-weighted MRI scan - these are called T2 lesions. The presence of new or larger T2 lesions may mean the participant is at higher risk of disability and may have a less favorable long-term outcome.

Based on cumulative number of new or enlarging T2 lesions at a participant level.

Baseline refers to assessments made on or before the first day participants received study treatment.

Percent change in normalized brain volume (Atrophy) on brain MRI scans from baseline at each visit. Brain atrophy can be seen in the earliest stages of multiple sclerosis (MS) and is a reliable predictor of future physical and cognitive disability.

Baseline refers to assessments made on or before the first day participants received study treatment.

The Multiple Sclerosis Functional Composite (MSFC) is a 3-part tool to measure disability progression in those with multiple sclerosis (MS). It assesses leg, arm, hand, and cognitive function using 3 individual scales: - The Timed 25-Foot Walk: To measure leg function - The 9-Hole Peg Test: To measure arm and hand function - The Symbol Digit Modalities Test (SDMT): To measure cognitive processing speed, flexibility, and calculation ability. Scores from each of the three are converted into Z-scores and averaged to create an overall composite score. The Low-Contrast Letter Acuity Test (LCLA) is performed with the MSFC using a set of charts to assess low contrast visual acuity. Each chart corresponds to a different contrast level, and charts are scored based on the number of letters identified correctly. A Z-score of 0 represents the population mean. Standard deviations above the mean represent a better outcome. Baseline refers to assessments on or before receiving study treatment.

The Multiple Sclerosis Quality of Life 54 (MSQOL-54) questionnaire is a health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). This 54-item instrument generates 12 subscales along with two summary scores (physical health and mental health - derived from a weighted combination of scale scores), and two additional single-item measures. The subscales are: physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual function. The MSQOL-54 items are transformed to 0-100 scores, and final scores are obtained by averaging items within the scales. The overall quality of life is assessed in question 54, which is scored on a scale of 0-100. Higher scores indicate better health-related quality of life. Baseline refers to assessments made on or before the first day participants received study treatment.

Change from baseline in volume of gadolinium enhanced T1 lesions. T1-lesions are permanently damaged areas of the brain that appear as dark spots or "black holes" on a type of MRI scan. The growth of T1 lesions may mean the participant's Multiple Sclerosis (MS) is progressing.

Baseline refers to assessments made on or before the first day participants received study treatment.

Some multiple Sclerosis (MS) lesions appear as bright spots in a T2-weighted MRI scan - these are called T2 lesions. Larger T2 lesions may mean the participant is at higher risk of disability and may have a less favorable long-term outcome.

Baseline refers to assessments made on or before the first day participants received study treatment.

Change from baseline in volume of unenhancing T1 lesions. T1-lesions are permanently damaged areas of the brain that appear as dark spots or "black holes" on a type of MRI scan. The growth of T1 lesions may mean the participant's Multiple Sclerosis (MS) is progressing.

Baseline refers to assessments made on or before the first day participants received study treatment.

Number of new unenhancing T1 lesions. T1-lesions are permanently damaged areas of the brain that appear as dark spots or "black holes" on a type of MRI scan. The appearance of new T1 lesions may mean the participant's MS is progressing.

Derived as the cumulative number of new or enlarging T1 lesions relative to baseline at a participant level.

Baseline refers to assessments made on or before the first day participants received study treatment.