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

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.

Time frame: 1, 4, 7, 14, 21, and 90 days post last dose.

Population: All treated participants who discontinued study treatment and had at least one on study and one post-dose assessment. Prespecified to be collected in combination for all three study arms.

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.

Time frame: 1, 4, 7, 14, 21, and 90 days post last dose.

Population: All treated participants who discontinued study treatment and had at least one on study and one post-dose assessment. Prespecified to be collected in combination for all three study arms.

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.

Time frame: 1, 4, 7, 14, 21, and 90 days post last dose.

Population: All treated participants who discontinued study treatment and had at least one on study and one post-dose assessment. Prespecified to be collected in combination for all three study arms.

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

Time frame: 1, 4, 7, 14, 21, 28, and 90 days post last dose.

Population: All treated participants who discontinued study treatment and had at least one on study and one post-dose assessment. Prespecified to be collected in combination for all three study arms.

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.

Time frame: From first dose to 90-days post last dose (an average of 65 months up to a max of 85 months)

Population: All treated participants

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.

Time frame: From first dose to 90-days post last dose (an average of 65 months up to a max of 85 months)

Population: All treated participants

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.

Time frame: From first dose to 90-days post last dose (an average of 65 months up to a max of 85 months)

Population: All treated participants

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.

Time frame: From first dose to 90-days post last dose (an average of 65 months up to a max of 85 months)

Population: All treated participants

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.

Time frame: From first dose to 90-days post last dose (an average of 65 months up to a max of 85 months)

Population: All treated participants

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.

Time frame: At baseline and every 3 months thereafter up until 78 months post first dose.

Population: All treated participants with an assessment

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

Time frame: From first dose up until last dose of study treatment (up to approximately 82 months)

Population: All treated participants with at least one on treatment ALC assessment

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.

Time frame: From first dose up until last dose of study treatment (up to approximately 82 months)

Population: All treated participants with at least one on treatment ANC assessment

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

Time frame: From first dose up until last dose of study treatment (up to approximately 82 months)

Population: All treated participants with at least one on treatment liver function test

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

Time frame: From first dose up until last dose of study treatment (up to approximately 82 months)

Population: All treated participants with at least one on treatment WBC assessment

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).

Time frame: 1, 4, 7, 14, 21, 28, and 90 days post last dose.

Population: All treated participants who discontinued study treatment and had at least one on study and one post-dose assessment. Prespecified to be collected in combination for all three study arms.

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.

Time frame: At baseline and 60 months after first dose of study therapy

Population: All treated participants with baseline and on study assessment for that vital sign at 60 months post first dose

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

Time frame: From first dose to 28-days post last dose (an average of 63 months up to a max of 83 months)

Population: All treated participants with baseline and at least one post baseline ECG assessment

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.

Time frame: At baseline and every 12 months thereafter up until 84 months post first dose.

Population: All treated participants with baseline and at least one on treatment physical assessment.

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.

Time frame: From first dose up until last dose of study treatment or data-cutoff date, whichever occurred first (up to approximately 87 months)

Population: All treated participants

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment showing the presence of GdE brain MRI lesions.

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.

Time frame: At 12 months post first dose and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with at least one on treatment MRI assessment showing new or enlarging lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment showing the presence of brain MRI lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment showing the presence of brain MRI lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment showing the presence of brain MRI lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 84 months post first dose.

Population: All treated participants with baseline and non-baseline MSFC Z-score assessments for the respective visit

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.

Time frame: At baseline and every 12 months thereafter up until 84 months post first dose.

Population: All treated participants with baseline and non-baseline MSQOL-54 scores for the respective visit

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment showing new or enlarging lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All participants in the intent to treat (ITT) population with baseline and at least one on treatment MRI assessment showing the absence of GdE brain lesions.

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.

Time frame: At baseline and every 12 months thereafter up until 72 months post first dose.

Population: All participants in the intent to treat population with baseline and at least one on treatment MRI assessment for T2 hyperintense lesions.

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.

Time frame: From first dose to last dose of study treatment or data-cutoff date, whichever occurred first (up to approximately 87 months)

Population: All treated participants

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.

Time frame: At baseline and every 12 months thereafter up until approximately 87 months post first dose.

Population: All treated participants with baseline and at least one on treatment MRI assessment.

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.

Time frame: Overall: From first dose to first relapse, last dose, or data-cutoff date, whichever occurred first (up to approx 87 months); Visits: 2 weeks post first dose, 3 months post first dose, and every 3 months thereafter up until 81 months post first dose.

Population: All treated participants with confirmed relapse.

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.

Time frame: At 3 and 6 months post first dose.

Population: All treated participants with disability progression data