Relapsing-Remitting Multiple Sclerosis (RRMS)
Conditions
Keywords
RRMS, Multiple Sclerosis (MS)
Brief summary
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of 2 once-daily oral doses of IMU-838 (vidofludimus calcium), a small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), 30 mg/day and 45 mg/day in the main study, cohort 1 (and 10 mg/day for the patients in the cohort 2 substudy), in patients with RRMS and evidence of active disease. The trial consists of a screening period, a blinded 24-week main treatment period, and an optional initially blinded, then open-label extended treatment period of up to 9.5 years. About 40 centers are planned to participate in Romania, Bulgaria, Ukraine, and Poland; potential additional centers in Hungary and Croatia were not used. The study started with 195 patients in the main group (cohort 1) planned to be randomized 1:1:1 to treatment with 30 mg/day or 45 mg/day IMU-838, or placebo (65 patients each) in the main treatment period. During the extended treatment period, patients were initially re-randomized so that patients previously on placebo were re-randomized 1:1 to treatment with 30 g/day or 45 mg/day IMU-838, all other patients were re-randomized to the same treatment they previously received. With approval of Protocol Version 3.0, a sub-study patient group (cohort 2) has been added with up to 60 patients, randomized to placebo or 10 mg IMU-838 for 24 weeks after which the option is available to continue into the extended treatment period and the recommended dose of 30 mg/day. However, based on discussion between investigator and patient 45 mg/day IMU-838/day may also be used.
Interventions
DRUGIMU-838 (30 mg/day)
* Main treatment period: All patients will receive half the assigned dose during the first 7 days of the main treatment period (one 15 mg tablet IMU-838 daily) and then start taking the full assigned dose from Day 7 onwards (two 15 mg tablets IMU-838 once daily). * Optional extended treatment period (optional): Participants who were re-randomized to a 30 mg/day dose will take the full assigned dose which consists of two 15 mg tablets IMU-838 once daily.
DRUGIMU-838 (45 mg/day)
* Main treatment period: All patients will receive half the assigned dose during the first 7 days of the main treatment period (one 22.5 mg tablet per day) and then start taking the full assigned dose from Day 7 onwards (two 22.5 mg tablets once daily). * Optional extended treatment period (optional): Participants who were re-randomized to a 45 mg/day dose will take the full assigned dose of two 22.5 mg tablets IMU-838 once daily.
DRUGPlacebo
* Main treatment period (Cohort 1 and Cohort 2): All patients will receive 1 tablet per day during the first 7 days of the main treatment period and then start taking 2 tablets once daily from Day 7 onwards. * Optional extended treatment period: Placebo not applicable as participants were re-randomized to a 30 mg/day dose or a 45 mg/day dose.
DRUGIMU-838 (10 mg/day)
* Main treatment period for Cohort 2: All patients will receive half the assigned dose during the first 7 days of the main treatment period (one 5 mg tablet per day) and then start taking the full assigned dose from Day 7 onwards (two 5 mg tablets once daily). * Optional extended treatment period (not applicable to Cohort 2): IMU-838 10 mg/day not applicable.
Sponsors
Immunic AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Trial participants, treating and evaluating physicians, central MRI readers and all other personnel directly involved in the conduct of the trial will be blinded to treatment assignments during the main treatment period and for the initial time of the extended treatment period. The evaluating physician will also be blinded to any clinical outcome or treatment change. Once the results of the main treatment period are available, treating physicians, participants, and other involved personnel, except for the evaluating physician, will be unblinded. The evaluating physician will remain blinded to patients' clinical characteristics and treatment assignment during the entire clinical trial.
Intervention model description
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of 2 once-daily oral doses of IMU-838 (30 mg/day and 45 mg/day) in the main study (10 mg/day for the patients in the substudy) in patients with RRMS and evidence of active disease. The trial consists of a screening period, a blinded 24-week main treatment period, and an optional initially blinded, then open-label extended treatment period of up to 9.5 years. The trial includes 2 patient cohorts: * Cohort 1 main trial: main Phase 2 trial with assessment of primary and key secondary endpoints. * Cohort 2 sub-trial: additional sub-trial with a small double-blind, placebo-controlled, randomized, parallel-group assessment of 10 mg/day IMU-838 dose to provide additional data for pharmacodynamic modelling.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
for the main treatment period 1. Male or female patient (age ≥18 to 55 years, inclusive) 2. Diagnosis of RRMS according to the revised McDonald criteria (2017) Note: The diagnosis of MS (including dissemination in time) must have been established before the patient is screened for the trial. 3. Disease activity evidenced * by either at least 2 relapses in the last 24 months, or at least 1 relapse in the last 12 months before randomization (relapses must have been assessed and documented by a physician in the patient files), AND * ≥1 documented Gd+ MS-related brain lesion, in the last 6 months before informed consent (date of MRI examination as well as copy of MRI report or representative image has to be available and accessible as patient source data at the study site) 4. Expanded Disability Status Scale (EDSS) score between 0 and 4.0 (inclusive) at Screening Visit 1 5. Female patients * must be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening Visit 1) or post menopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or * if of child-bearing potential, must have a negative pregnancy test at Screening Visit 1 (blood test) and before the first IMP intake (Day 0 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method (see below) together with a barrier method between trial consent and 30 days after the last intake of the of the IMP. Highly effective forms of birth control are those with a failure rate less than 1% per year and include: * oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation * oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation * intrauterine device or intrauterine hormone-releasing system * bilateral tubal occlusion * vasectomized partner (i.e. the patient's male partner underwent effective surgical sterilization before the female patient entered the clinical trial and is the sole sexual partner of the female patient during the clinical trial) * sexual abstinence (acceptable only if it is the patient's usual form of birth control/lifestyle choice; periodic abstinence \[e.g. calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are no acceptable methods of contraception) Barrier methods of contraception include: * Condom * Occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository 6. Male patients must agree not to father a child or to donate sperm starting at Screening Visit 1, throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients must also * abstain from sexual intercourse with a female partner (acceptable only if it is the patient's usual form of birth control/lifestyle choice), or * use adequate barrier contraception during treatment with the IMP and until at least 30 days after the last intake of the IMP, and * if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 5 * if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP 7. Willingness and ability to comply with the protocol 8. Written informed consent given prior to any trial-related procedure Inclusion criteria for optional extended treatment period 1. Completed 24 weeks of main treatment 2. Baseline MRI and Week 24 MRI, as well as 2 additional post-dose MRIs Continuation criteria for optional extended treatment period 1. In case the initial Week 24 MRI was not evaluated at least partially assessable, availability of a repeated Week 24 MRI 2. Week 24 MRI (initial or repeated one, if applicable) evaluated at least partially assessable
Exclusion criteria
MS-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | Up to Week 24 | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of gadolinium enhancing (Gd+) lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference Between 45 mg/Day IMU-838 and 30 mg/Day IMU-838 in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | At Week 24 | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838). |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0,≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Throughout the main treatment period (Day 0 - Week 18) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Volume Changes of T2 Lesions at Weeks 6, 12, 18 and 24 Compared to Baseline | Throughout the main treatment period (Day 0 - Week 24) | The endpoint was removed in the statistical analysis plan \[SAP\], since the content was considered the same as the endpoint T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T2 lesion load was calculated. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T1 lesion load was calculated. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. |
| Rate of Treatment Discontinuations up to Week 24 | at Week 24 | The discontinuation rate during the main treatment period was assessed. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New Gd+ Lesions Over 24 Weeks | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients who did not develop new Gd+ lesions over the 24-week main treatment period was assessed. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New or Enlarging T2-weighted Lesions Over 24 Weeks | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients who did not develop new or enlarging T2 lesions over the 24-week main treatment period was assessed. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With CUA Lesions at Week 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with CUA lesions at Week 24 was assessed. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With Gd+ Lesions at Week 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with Gd+ lesions at Week 24 was assessed. |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With T2 Lesions at Week 24 | Throughout the main treatment period (Day 0 - Week 24) | MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with T2 lesions at Week 24 was assessed. |
| Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | Throughout the main treatment period (Day 0 - Week 24) | The adjusted mean annualized relapse rate during the main treatment period was calculated. Estimates were adjusted for baseline number of Gd+ lesions (0, ≥1) using a Poisson model with a logarithmic link function. Log transformation of real exposure time of main treatment period was used as offset term. All of the following criteria had to be met for a clinical event to qualify as a relapse: 1. Neurological deficit, either newly appearing or re-appearing, with abnormality specified by both neurological abnormality separated by at least 30 days from onset of a preceding relapse AND neurological abnormality lasting for at least 24 hours 2. Absence of fever or known infection (i.e. temperature \[axillary, oral, or intra-auricular\] ≤37.5ºC) 3. Neurological impairment, defined as either increase in at least one of the functional systems of the EDSS OR increase of the total EDSS score. In both cases, the increase in EDSS had to correlate with the patient's reported symptoms. |
| Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter | Throughout the main treatment period (Day 0 - Week 24) | The proportion of relapse-free patients up to Week 24 was assessed. Patients with no documented relapse and last assessment of relapse before Week 18 were not included. Patients with no documented relapse up to Week 18 and a missing assessment at Week 24 were regarded as relapse-free patients. |
| Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Time to Relapse at Time of Final Analysis of Main Part | Throughout the main treatment period (Day 0 - Week 24) | Since only a total of 39 of 209 patients had a relapse up to Week 24, the median time to relapse could not be calculated. |
| Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Baseline, Week 12, and Week 24 | The EDSS is a widely used and validated instrument evaluating the functional systems of the CNS to describe disease progression and the efficacy of MS therapy. The composite rating system ranges from 0 (normal neurological status) to 10 (death due to MS) in 0.5-unit increments. An increase in score indicates a worsening. |
| Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Week 12 and Week 24 | The EDSS is a widely used and validated instrument evaluating the functional systems of the CNS to describe disease progression and the efficacy of MS therapy. The composite rating system ranges from 0 (normal neurological status) to 10 (death due to MS) in 0.5-unit increments. EDSS progression was defined as an increase of the EDSS score compared to Baseline of at least 1.0 point for patients with a baseline EDSS score of 1 to 4.0 or of at least 1.5 points for patients with a baseline EDSS score of 0. |
| Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | At Week 24 | The cumulative number of CUA MRI lesions up to Week 24 was correlated with quartiles of IMU-838 trough levels at Week 24 of treatment groups IMU-838 30 mg and IMU-838 45 mg. |
| Number of Participants With AEs | Up to 24 weeks | The number of patients experiencing treatment-emergent adverse events during the main treatment period was assessed. |
| Number of Participants With Serious AEs | Up to 24 weeks | The number of patients experiencing serious adverse events during the main treatment period was assessed. |
| Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Up to 24 weeks | Abnormal results in laboratory assessments were assessed by the investigator and classified as clinically significant (yes/no). Clinically significantly abnormal values had to be reported as AE, if not already clinically significantly abnormal at Baseline. Treatment-emergent adverse events related to hematological abnormalities and clinical chemistry abnormalities are reported. |
| Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity | Up to 24 weeks | The number of patients diagnosed with red blood cell (RBC) urine positive of at least moderate intensity during the main treatment period were assessed. The evaluation of RBC in urine was to be solely based on findings from microscopic examinations of urinary sediment and not from dipstick reading only. Therefore, all conspicuous dipstick readings were to be followed up by a microscopic examination of urinary sediment. All findings of RBC in urine per high-powered field (HPF) were to be listed as urinalysis abnormalities but not as an AE, if assessed by the investigator as not clinically significant. The investigator was also to assess any increased RBC in urine as not clinically significant, if there were more likely alternatives to explain this finding. |
| Number of Participants With AEs of Special Interest: Hematuria | Up to 24 weeks | The number of patients diagnosed with hematuria during the main treatment period were assessed. |
| Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis | Up to 24 weeks | The number of patients diagnosed with retroperitoneal colicky pain with suspected or confirmed nephrolithiasis during the main treatment period were assessed. |
| Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Up to 24 weeks | * Neutropenia * Lymphopenia * Diarrhea * Alopecia * Hemorrhage * Abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and total bilirubin with both elevations ˃1.5 x ULN and ≥35% elevated compared to Baseline |
| 12-lead Electrocardiogram (ECG): Heart Rate | Up to 24 weeks | The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice. |
| 12-lead Electrocardiogram (ECG): PQ-interval | Up to 24 weeks | The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice. |
| 12-lead Electrocardiogram (ECG): QRS-interval | Up to 24 weeks | The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice. |
| 12-lead Electrocardiogram (ECG): QT-interval | Up to 24 weeks | The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice. |
| Population Pharmacokinetics: Minimum IMU-838 Plasma Concentration Over the Dosing Interval (Cmin) | At Week 6 (3-10 hours post-dose) | One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet. |
| 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Up to 24 weeks | The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice. |
| Physical Examination | Up to 24 weeks | Physical examinations covered the following body systems: general appearance, skin, neck (including thyroid), throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, neurological systems, and, if applicable, others. Any new clinically significant finding compared to Screening Visit 1 had to be documented as AE. Any clinically significant finding at Screening Visit 1 had to be documented in the medical history section of the eCRF. Patients with clinically significant findings in the physical examination post Day 0 are reported. |
| Vital Signs: Height | at Screening | Height in centimeters was recorded without shoes. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Vital Signs: Weight (Absolute Change From Baseline at Week 24) | Baseline and 24 weeks | Weight in kilograms was recorded without shoes. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24) | Baseline and 24 weeks | Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24) | Baseline and 24 weeks | Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24) | Baseline and 24 weeks | Pulse had to be measured with the patient in a seated position, after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Baseline and 24 weeks | Blood pressure (systolic and diastolic) had to be measured with the patient in a seated position, after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE. |
| Micro Ribonucleic Acid (miR)-122 Expression | Change from Baseline to 4 hours after first dose | The fold change in miR-122 from pre dose to 4 hours post dose was assessed. |
| Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | At Screening Visit 1, at Week 24, and at EoS visit (EoS visit 30 days (+14 days) after last IMP intake) | The presence of JCV-DNA in urine in patients with detectable JCV-DNA in urine at Screening Visit 1, at Week 24, and at end-of-study (EoS) was determined. |
| Time to Treatment Discontinuation for Any Reason | Up to 24 weeks | The time to treatment discontinuation up to Week 24 for any reason was determined. |
| Population Pharmacokinetics: Maximum IMU-838 Plasma Concentration Over the Dosing Interval (Cmax) | At Week 6 (3-10 hours post-dose) | One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet. |
| Population Pharmacokinetics: Area Under the IMU-838 Plasma Concentration-time Curve Over the Dosing Interval (AUC0-τ) | At Week 6 (3-10 hours post-dose) | One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet. |
| Population Pharmacokinetics: IMU-838 Apparent Clearance Following Oral Dosing (CL/F) | At Week 6 (3-10 hours post-dose) | One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet. |
| Population Pharmacokinetics: IMU-838 Apparent Volume of Distribution (V/F) | At Week 6 (3-10 hours post-dose) | One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet. |
| Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | Up to Week 24 | This was the key secondary endpoint (hierarchical testing to primary efficacy). MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838). |
| Changes From Baseline in Th1 Lymphocyte Subset as Measured by Flow Cytometry | At Weeks 6 and 24 (in selected Biomarker Centers only) | Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated. |
| Changes From Baseline in Th17 Lymphocyte Subset as Measured by Flow Cytometry | At Weeks 6 and 24 (in selected Biomarker Centers only) | Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated. |
| Changes From Baseline in Treg Lymphocyte Subset as Measured by Flow Cytometry | At Weeks 6 and 24 (in selected Biomarker Centers only) | Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated. |
| Changes From Baseline in Serum Neurofilament | At Week 6 and Week 24 | The percentage change from Baseline in serum neurofilament was calculated. |
| Treatment Satisfaction Questionnaire for Medication (TSQM) | assessed at 6 weeks, 24 weeks, and end of study visit (EoS visit 30 days [+14 days] after last IMP intake), reported at Week 6 and Week 24 | The TSQM is a reliable and valid instrument to assess patients' satisfaction with medication comprising 14 items across 4 domains: side effects, performance, convenience and global satisfaction. All items have 5 to 7 possible answers, except for item 4 (2 answers). Item scores for each domain are summed and transformed to a scale from 0 (extremely dissatisfied) to 100 (extremely satisfied). |
| Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for Brain Atrophy. | Baseline, Week 6, Week 12, Week 18, and Week 24 | This endpoint was added in statistical analysis plan Version 2.0. Results of the brain atrophy analysis included biologically implausible changes (including changes of more than 1% over 24 weeks) in all treatment groups. Hence, the brain volume changes were considered technically inadequate for any conclusions of a treatment effect of IMU-838 versus placebo. |
| Plasma Trough Levels of IMU-838 | At Day 7 and Weeks 6, 12, 18, and 24 | Plasma trough levels of IMU-838 were assessed at Day 7 and at Weeks 6, 12, 18, and 24. |
Countries
Bulgaria, Poland, Romania, Ukraine
Participant flow
Recruitment details
The trial consists of a main trial (Cohort 1) and a sub-trial (Cohort 2): Cohort 1 compares 30 mg IMU-838, 45 mg IMU-838 and placebo and assesses the primary and key secondary endpoints; Cohort 2 compares 10 mg/day IMU-838 with placebo. The main trial consists of a blinded 24-week main treatment period and an optional initially blinded, then open-label extended treatment period of up to 9.5 years (currently ongoing). Results of the Cohort 1 main treatment period are reported.
Pre-assignment details
Patients were randomized in a 1:1:1 ratio to once-daily oral treatment with 30 mg IMU-838, 45 mg IMU-838, or matching placebo for 24 weeks. At Week 24 (end-of-main treatment period), patients had the option to continue into the extended treatment period if they met respective eligibility criteria including an magnetic resonance imaging (MRI) scan.
Participants by arm
| Arm | Count |
|---|---|
| IMU-838 (30 mg/Day) During the main treatment period (24 weeks), patients received once-daily oral doses of 30 mg IMU-838 (consisting of 2 tablets of 15 mg vidofludimus calcium \[IM90838\]).
All patients received half the assigned dose during the first 7 days of the main treatment period (1 tablet per day) and then started taking the full assigned dose from Day 7 onwards (2 tablets once daily). | 72 |
| IMU-838 (45 mg/Day) During the main treatment period (24 weeks), patients received once-daily oral doses of 45 mg IMU-838 consisting of 2 tablets of 22.5 mg vidofludimus calcium \[IM90838\]).
All patients received half the assigned dose during the first 7 days of the main treatment period (1 tablet per day) and then started taking the full assigned dose from Day 7 onwards (2 tablets once daily). | 69 |
| Placebo During the main treatment period (24 weeks), patients received once-daily oral doses of 2 tablets of placebo.
All patients received 1 tablet per day during the first 7 days of the main treatment period and then started taking 2 tablets once daily from Day 7 onwards. | 69 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Fulfilled hepatoxicity-related stopping rules | 0 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 2 |
Baseline characteristics
| Characteristic | IMU-838 (30 mg/Day) | IMU-838 (45 mg/Day) | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 38.0 years | 36.0 years | 37.0 years | 36.0 years |
| Body mass index | 23.491 kg/m^2 STANDARD_DEVIATION 5.311 | 24.786 kg/m^2 STANDARD_DEVIATION 5.067 | 24.462 kg/m^2 STANDARD_DEVIATION 4.758 | 24.239 kg/m^2 STANDARD_DEVIATION 5.059 |
| Duration of disease <=4 years | 37 Participants | 37 Participants | 37 Participants | 111 Participants |
| Duration of disease >4 years | 34 Participants | 32 Participants | 32 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 69 Participants | 69 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Expanded Disability Status Scale | 2.65 units on a scale STANDARD_DEVIATION 0.83 | 2.56 units on a scale STANDARD_DEVIATION 0.96 | 2.73 units on a scale STANDARD_DEVIATION 0.9 | 2.65 units on a scale STANDARD_DEVIATION 0.9 |
| Gadolinium enhancing (Gd+) lesions | 1.4 lesions STANDARD_DEVIATION 2.4 | 0.9 lesions STANDARD_DEVIATION 1.3 | 1.2 lesions STANDARD_DEVIATION 2.1 | 1.2 lesions STANDARD_DEVIATION 2 |
| MRI field strength 1.5 Tesla | 65 Participants | 66 Participants | 67 Participants | 198 Participants |
| MRI field strength 3.0 Tesla | 6 Participants | 3 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 69 Participants | 69 Participants | 209 Participants |
| Region of Enrollment Bulgaria | 18 participants | 25 participants | 17 participants | 60 participants |
| Region of Enrollment Poland | 11 participants | 6 participants | 9 participants | 26 participants |
| Region of Enrollment Romania | 3 participants | 2 participants | 1 participants | 6 participants |
| Region of Enrollment Ukraine | 40 participants | 36 participants | 42 participants | 118 participants |
| Sex: Female, Male Female | 40 Participants | 50 Participants | 46 Participants | 136 Participants |
| Sex: Female, Male Male | 31 Participants | 19 Participants | 23 Participants | 73 Participants |
| T2 lesion load | 13.341 cm^3 STANDARD_DEVIATION 15.079 | 13.918 cm^3 STANDARD_DEVIATION 12.946 | 11.980 cm^3 STANDARD_DEVIATION 10.417 | 13.082 cm^3 STANDARD_DEVIATION 12.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 69 | 0 / 69 |
| other Total, other adverse events | 6 / 71 | 7 / 69 | 7 / 69 |
| serious Total, serious adverse events | 2 / 71 | 0 / 69 | 1 / 69 |
Outcome results
Primary
Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of gadolinium enhancing (Gd+) lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838).
Time frame: Up to Week 24
Population: FAS consisting of all randomized patients who received at least 1 dose of the investigational medicinal product (IMP).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 2.4 CUA MRI lesions |
| Placebo | Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 6.3 CUA MRI lesions |
Comparison: H0: cumulative number of CUA MRI lesions up to Week 24 with 45 mg IMU-838 equal to or higher than that with placebo. A generalized linear model with a negative binomial distribution and logarithmic link function was used. Log transformation of time from 1st IMP dose to date of last MRI assessment was used as offset term. 51 patients per group were necessary to have 80% power to detect a difference of 3.5 in mean event rate with a significance level 0.1, 1-sided.p-value: 0.000295% CI: [0.22, 0.64]generalized linear model
Secondary
12-lead Electrocardiogram (ECG): Heart Rate
The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): Heart Rate | Screening 1 | 67.0 beats per minute |
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): Heart Rate | Week 24 | 69.5 beats per minute |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate | Screening 1 | 68.0 beats per minute |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate | Week 24 | 69.0 beats per minute |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate | Screening 1 | 67.0 beats per minute |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate | Week 24 | 70.0 beats per minute |
Secondary
12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula)
The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Screening 1 | 407.0 msec |
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Week 24 | 407.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Screening 1 | 404.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Week 24 | 404.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Screening 1 | 410.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) | Week 24 | 409.0 msec |
Secondary
12-lead Electrocardiogram (ECG): PQ-interval
The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): PQ-interval | Screening 1 | 147.0 msec |
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): PQ-interval | Week 24 | 146.5 msec |
| Placebo | 12-lead Electrocardiogram (ECG): PQ-interval | Screening 1 | 140.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): PQ-interval | Week 24 | 146.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): PQ-interval | Screening 1 | 150.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): PQ-interval | Week 24 | 150.5 msec |
Secondary
12-lead Electrocardiogram (ECG): QRS-interval
The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): QRS-interval | Screening 1 | 90.0 msec |
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): QRS-interval | Week 24 | 90.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QRS-interval | Screening 1 | 86.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QRS-interval | Week 24 | 86.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QRS-interval | Screening 1 | 90.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QRS-interval | Week 24 | 91.0 msec |
Secondary
12-lead Electrocardiogram (ECG): QT-interval
The 12-lead ECG was recorded in supine position after at least 5 minutes at rest using the local standard ECG machine. The ECG was analyzed qualitatively (normal or abnormal, if abnormal clinically significant \[yes/no\]). The heart rate, PQ-, QRS-, and QT intervals, as well as the heart rate-corrected QTc interval (according to Bazett's formula) were determined. All procedures were done according to local practice.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): QT-interval | Screening 1 | 383.0 msec |
| IMU-838 (45 mg/Day) | 12-lead Electrocardiogram (ECG): QT-interval | Week 24 | 376.5 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QT-interval | Screening 1 | 380.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QT-interval | Week 24 | 374.5 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QT-interval | Screening 1 | 387.0 msec |
| Placebo | 12-lead Electrocardiogram (ECG): QT-interval | Week 24 | 385.0 msec |
Secondary
Changes From Baseline in Serum Neurofilament
The percentage change from Baseline in serum neurofilament was calculated.
Time frame: At Week 6 and Week 24
Population: Safety data set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Changes From Baseline in Serum Neurofilament | Week 6 | -4.0 percent change |
| IMU-838 (45 mg/Day) | Changes From Baseline in Serum Neurofilament | Week 24 | -17.0 percent change |
| Placebo | Changes From Baseline in Serum Neurofilament | Week 6 | -1.0 percent change |
| Placebo | Changes From Baseline in Serum Neurofilament | Week 24 | -20.5 percent change |
| Placebo | Changes From Baseline in Serum Neurofilament | Week 6 | 8.0 percent change |
| Placebo | Changes From Baseline in Serum Neurofilament | Week 24 | 6.5 percent change |
Secondary
Changes From Baseline in Th17 Lymphocyte Subset as Measured by Flow Cytometry
Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Time frame: At Weeks 6 and 24 (in selected Biomarker Centers only)
Population: Changes from Baseline in Th17 lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Secondary
Changes From Baseline in Th1 Lymphocyte Subset as Measured by Flow Cytometry
Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Time frame: At Weeks 6 and 24 (in selected Biomarker Centers only)
Population: Changes from Baseline in Th1 lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Secondary
Changes From Baseline in Treg Lymphocyte Subset as Measured by Flow Cytometry
Changes from Baseline in lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Time frame: At Weeks 6 and 24 (in selected Biomarker Centers only)
Population: Changes from Baseline in Treg lymphocyte subsets were listed only; no descriptive statistics by treatment arm were calculated.
Secondary
Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels
The cumulative number of CUA MRI lesions up to Week 24 was correlated with quartiles of IMU-838 trough levels at Week 24 of treatment groups IMU-838 30 mg and IMU-838 45 mg.
Time frame: At Week 24
Population: Patients with observations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IMU-838 (45 mg/Day) | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 1st quartile of IMU-838 trough level | 1.1 CUA MRI lesions | Standard Deviation 2 |
| IMU-838 (45 mg/Day) | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 2nd quartile of IMU-838 trough level | 2.2 CUA MRI lesions | Standard Deviation 4.9 |
| IMU-838 (45 mg/Day) | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 3rd quartile of IMU-838 trough level | 4.4 CUA MRI lesions | Standard Deviation 5.8 |
| IMU-838 (45 mg/Day) | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 4th quartile of IMU-838 trough level | 6.8 CUA MRI lesions | Standard Deviation 14.7 |
| Placebo | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 4th quartile of IMU-838 trough level | 5.3 CUA MRI lesions | Standard Deviation 9.8 |
| Placebo | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 1st quartile of IMU-838 trough level | 1.6 CUA MRI lesions | Standard Deviation 3.1 |
| Placebo | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 3rd quartile of IMU-838 trough level | 2.0 CUA MRI lesions | Standard Deviation 2.2 |
| Placebo | Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels | 2nd quartile of IMU-838 trough level | 1.8 CUA MRI lesions | Standard Deviation 2.8 |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for Brain Atrophy.
This endpoint was added in statistical analysis plan Version 2.0. Results of the brain atrophy analysis included biologically implausible changes (including changes of more than 1% over 24 weeks) in all treatment groups. Hence, the brain volume changes were considered technically inadequate for any conclusions of a treatment effect of IMU-838 versus placebo.
Time frame: Baseline, Week 6, Week 12, Week 18, and Week 24
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for Brain Atrophy. | NA Percent change |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for Brain Atrophy. | NA Percent change |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for Brain Atrophy. | NA Percent change |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term.
Time frame: Throughout the main treatment period (Day 0 - Week 18)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 12 | 1.7 CUA MRI lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 6 | 0.8 CUA MRI lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 18 | 2.7 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 12 | 1.6 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 6 | 0.6 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 18 | 2.5 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 6 | 2.5 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 18 | 8.0 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of CUA MRI Lesions up to Weeks 6, 12, and 18 | Week 12 | 5.3 CUA MRI lesions |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 1.0 Gd+ lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 2.1 Gd+ lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 3.1 Gd+ lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 4.5 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 1.7 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 2.4 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 0.8 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 4.0 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 9.1 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 6.2 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 13.0 Gd+ lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New Gd+ Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 2.8 Gd+ lesions |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 0.3 T1 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 0.6 T1 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 1.0 T1 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 1.4 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 1.5 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 0.2 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 1.0 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 0.6 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 4.7 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 2.5 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 3.9 T1 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T1 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 1.1 T1 lesions |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 2.8 T2 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 4.1 T2 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 1.8 T2 lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 0.8 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 2.7 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 1.8 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 4.2 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 0.7 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 24 | 11.9 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 6 | 2.6 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 12 | 6.0 T2 lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Cumulative Number of New T2 Lesions up to Weeks 6, 12, 18 and 24 | Week 18 | 8.8 T2 lesions |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for MRI field strength (1.5 or 3.0 Tesla) and baseline number of Gd+ lesions (0,≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 6 | 1.1 CUA MRI lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 12 | 1.3 CUA MRI lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 18 | 1.3 CUA MRI lesions |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 24 | 1.6 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 24 | 1.6 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 6 | 0.8 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 18 | 0.8 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 12 | 1.2 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 24 | 3.7 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 12 | 3.4 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 18 | 3.2 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Mean Number of CUA Lesions Per Patient Per Scan at Weeks 6, 12, 18 and 24 | Week 6 | 3.2 CUA MRI lesions |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With CUA Lesions at Week 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with CUA lesions at Week 24 was assessed.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Patients with observations at Week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With CUA Lesions at Week 24 | 15 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With CUA Lesions at Week 24 | 19 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With CUA Lesions at Week 24 | 25 Participants |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With Gd+ Lesions at Week 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with Gd+ lesions at Week 24 was assessed.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Patients with observations at Week 24.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With Gd+ Lesions at Week 24 | 10 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With Gd+ Lesions at Week 24 | 16 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With Gd+ Lesions at Week 24 | 25 Participants |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New Gd+ Lesions Over 24 Weeks
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients who did not develop new Gd+ lesions over the 24-week main treatment period was assessed.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New Gd+ Lesions Over 24 Weeks | 42 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New Gd+ Lesions Over 24 Weeks | 34 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New Gd+ Lesions Over 24 Weeks | 26 Participants |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New or Enlarging T2-weighted Lesions Over 24 Weeks
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients who did not develop new or enlarging T2 lesions over the 24-week main treatment period was assessed.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New or Enlarging T2-weighted Lesions Over 24 Weeks | 36 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New or Enlarging T2-weighted Lesions Over 24 Weeks | 29 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients Without New or Enlarging T2-weighted Lesions Over 24 Weeks | 22 Participants |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With T2 Lesions at Week 24
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with T2 lesions at Week 24 was assessed.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Patients with observations in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With T2 Lesions at Week 24 | 15 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With T2 Lesions at Week 24 | 18 Participants |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Number of Patients With T2 Lesions at Week 24 | 21 Participants |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T1 lesion load was calculated.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | -2.9 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | -4.0 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | -3.8 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | -5.7 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | -0.9 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | -0.4 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | -1.4 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | -1.6 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | -0.8 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | 0.0 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | -0.7 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T1-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | -4.2 % change from Baseline |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline
MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T2 lesion load was calculated.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | 2.2 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | 3.3 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | 4.9 % change from Baseline |
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | 6.6 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | 7.3 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | 1.7 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | 4.6 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | 3.4 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 24 | 9.0 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 12 | 4.7 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 18 | 7.1 % change from Baseline |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the T2-lesion Load at Weeks 6, 12, 18 and 24 Compared to Baseline | Week 6 | 2.4 % change from Baseline |
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo, 45 mg/Day IMU-838 and Placebo, and 30 mg/Day and 45 mg/Day IMU-838 for the Volume Changes of T2 Lesions at Weeks 6, 12, 18 and 24 Compared to Baseline
The endpoint was removed in the statistical analysis plan \[SAP\], since the content was considered the same as the endpoint T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: This measure was not analyzed because it was determined to be redundant with Outcome Measure 7. No data are available to be reported.
Secondary
Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions
This was the key secondary endpoint (hierarchical testing to primary efficacy). MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838).
Time frame: Up to Week 24
Population: FAS consisting of all randomized patients who received at least 1 dose of the IMP.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 4.0 CUA MRI lesions |
| Placebo | Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 13.2 CUA MRI lesions |
Comparison: A generalized linear model with a negative binomial distribution and logarithmic link function was used. Log transformation of time from 1st IMP dose to date of last MRI assessment was used as offset term.p-value: <0.000195% CI: [0.17, 0.53]Generalized linear model
Secondary
Difference Between 45 mg/Day IMU-838 and 30 mg/Day IMU-838 in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions
MRI scans were assessed centrally and adhered to a standardized MRI protocol. Estimates were adjusted for baseline volume of T2 lesions, MRI field strength (1.5 or 3.0 Tesla), and baseline number of Gd+ lesions (0, ≥1) using a generalized linear model with a negative binomial distribution and a logarithmic link function. Log transformation of time from first IMP dose to date of last MRI assessment was used as offset term. Mainly due to the differing number of patients with 3.0 Tesla MRI examinations in each treatment arm, the statistical adjustments (to ensure comparabiltiy) for each individual comparison differed and hence the adjusted mean cumulative number of CUA MRI lesions in each arm (e.g. placebo) differed depending on the comparison (45 mg IMU-838 vs placebo, 30 mg IMU-838 vs placebo, or 45 mg vs 30 mg IMU-838).
Time frame: At Week 24
Population: FAS consisting of all randomized patients who received at least 1 dose of the investigational medicinal product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Difference Between 45 mg/Day IMU-838 and 30 mg/Day IMU-838 in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 4.2 CUA MRI lesions |
| Placebo | Difference Between 45 mg/Day IMU-838 and 30 mg/Day IMU-838 in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions | 4.4 CUA MRI lesions |
Secondary
Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period)
The adjusted mean annualized relapse rate during the main treatment period was calculated. Estimates were adjusted for baseline number of Gd+ lesions (0, ≥1) using a Poisson model with a logarithmic link function. Log transformation of real exposure time of main treatment period was used as offset term. All of the following criteria had to be met for a clinical event to qualify as a relapse: 1. Neurological deficit, either newly appearing or re-appearing, with abnormality specified by both neurological abnormality separated by at least 30 days from onset of a preceding relapse AND neurological abnormality lasting for at least 24 hours 2. Absence of fever or known infection (i.e. temperature \[axillary, oral, or intra-auricular\] ≤37.5ºC) 3. Neurological impairment, defined as either increase in at least one of the functional systems of the EDSS OR increase of the total EDSS score. In both cases, the increase in EDSS had to correlate with the patient's reported symptoms.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | 0.39 relapses per person-years |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | 0.48 relapses per person-years |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | 0.53 relapses per person-years |
| IMU-838 Combined | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | 0.43 relapses per person-years |
| Placebo (Compared With IMU-838 Combined) | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Mean Annualized Relapse Rate (During Main and Extended Treatment Period) | 0.54 relapses per person-years |
Secondary
Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter
The proportion of relapse-free patients up to Week 24 was assessed. Patients with no documented relapse and last assessment of relapse before Week 18 were not included. Patients with no documented relapse up to Week 18 and a missing assessment at Week 24 were regarded as relapse-free patients.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Patients analyzed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter | 60 Participants |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter | 54 Participants |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter | 51 Participants |
| IMU-838 Combined | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Proportion of Relapse-free Patients up to Week 24 and at Extended Periods Thereafter | 114 Participants |
Secondary
Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Time to Relapse at Time of Final Analysis of Main Part
Since only a total of 39 of 209 patients had a relapse up to Week 24, the median time to relapse could not be calculated.
Time frame: Throughout the main treatment period (Day 0 - Week 24)
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Time to Relapse at Time of Final Analysis of Main Part | NA days |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Time to Relapse at Time of Final Analysis of Main Part | NA days |
| Placebo | Differences Between Individual Treatments and Between the Pooled 30 mg/Day and 45 mg/Day Groups and Placebo in the Relapse-related Clinical Endpoints: Time to Relapse at Time of Final Analysis of Main Part | NA days |
Secondary
Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12)
The EDSS is a widely used and validated instrument evaluating the functional systems of the CNS to describe disease progression and the efficacy of MS therapy. The composite rating system ranges from 0 (normal neurological status) to 10 (death due to MS) in 0.5-unit increments. An increase in score indicates a worsening.
Time frame: Baseline, Week 12, and Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IMU-838 (45 mg/Day) | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 12 | -0.01 score on a scale | Standard Deviation 0.28 |
| IMU-838 (45 mg/Day) | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 24 | 0.01 score on a scale | Standard Deviation 0.25 |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 24 | 0.00 score on a scale | Standard Deviation 0.39 |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 12 | 0.00 score on a scale | Standard Deviation 0.42 |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 12 | 0.03 score on a scale | Standard Deviation 0.38 |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Mean Change in the Expanded Disability Status Scale (EDSS) as Compared to Baseline During the Main and Extended Period (Every 12 Weeks Starting at Week 12) | Week 24 | 0.08 score on a scale | Standard Deviation 0.39 |
Secondary
Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively)
The EDSS is a widely used and validated instrument evaluating the functional systems of the CNS to describe disease progression and the efficacy of MS therapy. The composite rating system ranges from 0 (normal neurological status) to 10 (death due to MS) in 0.5-unit increments. EDSS progression was defined as an increase of the EDSS score compared to Baseline of at least 1.0 point for patients with a baseline EDSS score of 1 to 4.0 or of at least 1.5 points for patients with a baseline EDSS score of 0.
Time frame: Week 12 and Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 12 | 6 Participants |
| IMU-838 (45 mg/Day) | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 24 | 8 Participants |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 12 | 7 Participants |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 24 | 8 Participants |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 12 | 9 Participants |
| Placebo | Differences Between Treatments in Changes of Disease Activity as Measured by the Number of Patients With EDSS Progression During the Main and Extended Period (Every 12 Weeks Starting at Week 12, and Cumulatively) | Up to Week 24 | 15 Participants |
Secondary
Micro Ribonucleic Acid (miR)-122 Expression
The fold change in miR-122 from pre dose to 4 hours post dose was assessed.
Time frame: Change from Baseline to 4 hours after first dose
Population: Patients with observations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Micro Ribonucleic Acid (miR)-122 Expression | 0.727 fold change |
| Placebo | Micro Ribonucleic Acid (miR)-122 Expression | 0.991 fold change |
| Placebo | Micro Ribonucleic Acid (miR)-122 Expression | 0.946 fold change |
Secondary
Number of Participants With AEs
The number of patients experiencing treatment-emergent adverse events during the main treatment period was assessed.
Time frame: Up to 24 weeks
Population: Safety analysis set consisting of all randomized patients who received at least 1 dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With AEs | 32 Participants |
| Placebo | Number of Participants With AEs | 28 Participants |
| Placebo | Number of Participants With AEs | 30 Participants |
Secondary
Number of Participants With AEs of Special Interest: Hematuria
The number of patients diagnosed with hematuria during the main treatment period were assessed.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With AEs of Special Interest: Hematuria | 0 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Hematuria | 0 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Hematuria | 1 Participants |
Secondary
Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity
The number of patients diagnosed with red blood cell (RBC) urine positive of at least moderate intensity during the main treatment period were assessed. The evaluation of RBC in urine was to be solely based on findings from microscopic examinations of urinary sediment and not from dipstick reading only. Therefore, all conspicuous dipstick readings were to be followed up by a microscopic examination of urinary sediment. All findings of RBC in urine per high-powered field (HPF) were to be listed as urinalysis abnormalities but not as an AE, if assessed by the investigator as not clinically significant. The investigator was also to assess any increased RBC in urine as not clinically significant, if there were more likely alternatives to explain this finding.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity | 0 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity | 0 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity | 0 Participants |
Secondary
Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis
The number of patients diagnosed with retroperitoneal colicky pain with suspected or confirmed nephrolithiasis during the main treatment period were assessed.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis | 1 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis | 0 Participants |
| Placebo | Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis | 0 Participants |
Secondary
Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator)
Abnormal results in laboratory assessments were assessed by the investigator and classified as clinically significant (yes/no). Clinically significantly abnormal values had to be reported as AE, if not already clinically significantly abnormal at Baseline. Treatment-emergent adverse events related to hematological abnormalities and clinical chemistry abnormalities are reported.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Anemia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | C-reactive protein increased | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Aspartate aminotransferase increased | 1 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatinine increased | 1 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood bilirubin increased | 1 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Transaminases increased | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatine phosphokinase increased | 2 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Leukopenia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hypertriglyceridemia | 1 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Lipase increased | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Neutropenia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Iron deficiency anemia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hepatic enzyme increased | 1 Participants |
| IMU-838 (45 mg/Day) | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Alanine aminotransferase increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hepatic enzyme increased | 2 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Anemia | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Iron deficiency anemia | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Leukopenia | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Neutropenia | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Alanine aminotransferase increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood bilirubin increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatine phosphokinase increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatinine increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | C-reactive protein increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Aspartate aminotransferase increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Lipase increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Transaminases increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hypertriglyceridemia | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hypertriglyceridemia | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | C-reactive protein increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Neutropenia | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Transaminases increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Hepatic enzyme increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Leukopenia | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Anemia | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood bilirubin increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Lipase increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatine phosphokinase increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Aspartate aminotransferase increased | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Iron deficiency anemia | 2 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Blood creatinine increased | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) | Alanine aminotransferase increased | 2 Participants |
Secondary
Number of Participants With Serious AEs
The number of patients experiencing serious adverse events during the main treatment period was assessed.
Time frame: Up to 24 weeks
Population: Safety data set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Number of Participants With Serious AEs | 2 Participants |
| Placebo | Number of Participants With Serious AEs | 0 Participants |
| Placebo | Number of Participants With Serious AEs | 1 Participants |
Secondary
Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs:
* Neutropenia * Lymphopenia * Diarrhea * Alopecia * Hemorrhage * Abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and total bilirubin with both elevations ˃1.5 x ULN and ≥35% elevated compared to Baseline
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Alopecia | 3 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Total bilirubin >1.5 x ULN AND representing a % change from Baseline ≥35% | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | ALT >1.5 x ULN AND representing a % change from Baseline ≥35% | 2 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Hemorrhage | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Neutropenia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | GGT >1.5 x ULN AND representing a % change from Baseline ≥35% | 3 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Diarrhea | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Lymphopenia | 0 Participants |
| IMU-838 (45 mg/Day) | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | AST >1.5 x ULN AND representing a % change from Baseline ≥35% | 1 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Hemorrhage | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Neutropenia | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Lymphopenia | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Diarrhea | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Alopecia | 1 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | ALT >1.5 x ULN AND representing a % change from Baseline ≥35% | 4 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | AST >1.5 x ULN AND representing a % change from Baseline ≥35% | 3 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | GGT >1.5 x ULN AND representing a % change from Baseline ≥35% | 2 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Total bilirubin >1.5 x ULN AND representing a % change from Baseline ≥35% | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Diarrhea | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Neutropenia | 1 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | AST >1.5 x ULN AND representing a % change from Baseline ≥35% | 4 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Lymphopenia | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Total bilirubin >1.5 x ULN AND representing a % change from Baseline ≥35% | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Hemorrhage | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | Alopecia | 0 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | GGT >1.5 x ULN AND representing a % change from Baseline ≥35% | 1 Participants |
| Placebo | Number of Patients Treated With 30 mg/Day or 45 mg/Day IMU-838 as Compared to Placebo Who Experienced at Least One of the Following AEs: | ALT >1.5 x ULN AND representing a % change from Baseline ≥35% | 5 Participants |
Secondary
Physical Examination
Physical examinations covered the following body systems: general appearance, skin, neck (including thyroid), throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, neurological systems, and, if applicable, others. Any new clinically significant finding compared to Screening Visit 1 had to be documented as AE. Any clinically significant finding at Screening Visit 1 had to be documented in the medical history section of the eCRF. Patients with clinically significant findings in the physical examination post Day 0 are reported.
Time frame: Up to 24 weeks
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Physical Examination | 0 Participants |
| Placebo | Physical Examination | 1 Participants |
| Placebo | Physical Examination | 3 Participants |
Secondary
Plasma Trough Levels of IMU-838
Plasma trough levels of IMU-838 were assessed at Day 7 and at Weeks 6, 12, 18, and 24.
Time frame: At Day 7 and Weeks 6, 12, 18, and 24
Population: Safety set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Plasma Trough Levels of IMU-838 | Week 6 | 4.320 μg/mL |
| IMU-838 (45 mg/Day) | Plasma Trough Levels of IMU-838 | Week 18 | 4.165 μg/mL |
| IMU-838 (45 mg/Day) | Plasma Trough Levels of IMU-838 | Week 12 | 4.160 μg/mL |
| IMU-838 (45 mg/Day) | Plasma Trough Levels of IMU-838 | Week 24 | 4.010 μg/mL |
| IMU-838 (45 mg/Day) | Plasma Trough Levels of IMU-838 | Day 7 | 2.155 μg/mL |
| Placebo | Plasma Trough Levels of IMU-838 | Week 24 | 5.700 μg/mL |
| Placebo | Plasma Trough Levels of IMU-838 | Day 7 | 3.100 μg/mL |
| Placebo | Plasma Trough Levels of IMU-838 | Week 6 | 6.240 μg/mL |
| Placebo | Plasma Trough Levels of IMU-838 | Week 12 | 5.420 μg/mL |
| Placebo | Plasma Trough Levels of IMU-838 | Week 18 | 5.990 μg/mL |
Secondary
Population Pharmacokinetics: Area Under the IMU-838 Plasma Concentration-time Curve Over the Dosing Interval (AUC0-τ)
One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.
Time frame: At Week 6 (3-10 hours post-dose)
Population: Data have not yet been analyzed.
Secondary
Population Pharmacokinetics: IMU-838 Apparent Clearance Following Oral Dosing (CL/F)
One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.
Time frame: At Week 6 (3-10 hours post-dose)
Population: Data have not yet been analyzed.
Secondary
Population Pharmacokinetics: IMU-838 Apparent Volume of Distribution (V/F)
One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.
Time frame: At Week 6 (3-10 hours post-dose)
Population: Data have not yet been analyzed.
Secondary
Population Pharmacokinetics: Maximum IMU-838 Plasma Concentration Over the Dosing Interval (Cmax)
One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.
Time frame: At Week 6 (3-10 hours post-dose)
Population: Data have not yet been analyzed.
Secondary
Population Pharmacokinetics: Minimum IMU-838 Plasma Concentration Over the Dosing Interval (Cmin)
One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.
Time frame: At Week 6 (3-10 hours post-dose)
Population: Data have not yet been analyzed.
Secondary
Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine
The presence of JCV-DNA in urine in patients with detectable JCV-DNA in urine at Screening Visit 1, at Week 24, and at end-of-study (EoS) was determined.
Time frame: At Screening Visit 1, at Week 24, and at EoS visit (EoS visit 30 days (+14 days) after last IMP intake)
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Week 24 | 27 Participants |
| IMU-838 (45 mg/Day) | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Screening 1 | 32 Participants |
| IMU-838 (45 mg/Day) | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | End-of-study | 0 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Week 24 | 16 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Screening 1 | 27 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | End-of-study | 1 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Screening 1 | 29 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | End-of-study | 1 Participants |
| Placebo | Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine | Week 24 | 18 Participants |
Secondary
Rate of Treatment Discontinuations up to Week 24
The discontinuation rate during the main treatment period was assessed.
Time frame: at Week 24
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMU-838 (45 mg/Day) | Rate of Treatment Discontinuations up to Week 24 | 2 Participants |
| Placebo | Rate of Treatment Discontinuations up to Week 24 | 4 Participants |
| Placebo | Rate of Treatment Discontinuations up to Week 24 | 5 Participants |
Secondary
Time to Treatment Discontinuation for Any Reason
The time to treatment discontinuation up to Week 24 for any reason was determined.
Time frame: Up to 24 weeks
Population: Patients with observations
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Time to Treatment Discontinuation for Any Reason | 106.5 days |
| Placebo | Time to Treatment Discontinuation for Any Reason | 66.5 days |
| Placebo | Time to Treatment Discontinuation for Any Reason | 98.0 days |
Secondary
Treatment Satisfaction Questionnaire for Medication (TSQM)
The TSQM is a reliable and valid instrument to assess patients' satisfaction with medication comprising 14 items across 4 domains: side effects, performance, convenience and global satisfaction. All items have 5 to 7 possible answers, except for item 4 (2 answers). Item scores for each domain are summed and transformed to a scale from 0 (extremely dissatisfied) to 100 (extremely satisfied).
Time frame: assessed at 6 weeks, 24 weeks, and end of study visit (EoS visit 30 days [+14 days] after last IMP intake), reported at Week 6 and Week 24
Population: Safety analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 6 | 62.45 score | Standard Deviation 16.73 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 24 | 66.43 score | Standard Deviation 14.61 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 6 | 92.70 score | Standard Deviation 16.53 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 24 | 97.10 score | Standard Deviation 9.37 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 6 | 82.62 score | Standard Deviation 13.03 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 24 | 82.12 score | Standard Deviation 12.55 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 6 | 67.30 score | Standard Deviation 18.34 |
| IMU-838 (45 mg/Day) | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 24 | 70.07 score | Standard Deviation 16.13 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 6 | 96.02 score | Standard Deviation 12.21 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 6 | 70.29 score | Standard Deviation 15.34 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 24 | 97.41 score | Standard Deviation 11.25 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 6 | 81.48 score | Standard Deviation 15.4 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 24 | 84.18 score | Standard Deviation 14.66 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 6 | 67.16 score | Standard Deviation 15.44 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 24 | 71.28 score | Standard Deviation 17.58 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 24 | 75.05 score | Standard Deviation 17.87 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 6 | 95.29 score | Standard Deviation 13.65 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 24 | 61.72 score | Standard Deviation 15.27 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Effectiveness at Week 6 | 60.55 score | Standard Deviation 15.66 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Side effects at Week 24 | 95.41 score | Standard Deviation 12.99 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 6 | 63.87 score | Standard Deviation 16.93 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 24 | 79.69 score | Standard Deviation 13.13 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Convenience at Week 6 | 80.59 score | Standard Deviation 13.98 |
| Placebo | Treatment Satisfaction Questionnaire for Medication (TSQM) | Global satisfaction at Week 24 | 66.29 score | Standard Deviation 15.04 |
Secondary
Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24)
Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: Baseline and 24 weeks
Population: Patients with observations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24) | 0.00 °C |
| Placebo | Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24) | 0.00 °C |
| Placebo | Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24) | 0.00 °C |
Secondary
Vital Signs: Height
Height in centimeters was recorded without shoes. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: at Screening
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Height | 170.0 cm |
| Placebo | Vital Signs: Height | 167.0 cm |
| Placebo | Vital Signs: Height | 168.0 cm |
Secondary
Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24)
Pulse had to be measured with the patient in a seated position, after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: Baseline and 24 weeks
Population: Patients with observations
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24) | 0.0 beats per minute |
| Placebo | Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24) | 0.0 beats per minute |
| Placebo | Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24) | -1.0 beats per minute |
Secondary
Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24)
Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: Baseline and 24 weeks
Population: Patients with observations
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24) | 0.0 breaths/min |
| Placebo | Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24) | 0.0 breaths/min |
| Placebo | Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24) | 0.0 breaths/min |
Secondary
Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24)
Blood pressure (systolic and diastolic) had to be measured with the patient in a seated position, after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: Baseline and 24 weeks
Population: Patients with observations
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Systolic blood pressure | 0.0 mmHg |
| IMU-838 (45 mg/Day) | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Diastolic blood pressure | 0.0 mmHg |
| Placebo | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Systolic blood pressure | 0.0 mmHg |
| Placebo | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Diastolic blood pressure | 0.0 mmHg |
| Placebo | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Systolic blood pressure | 0.0 mmHg |
| Placebo | Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) | Diastolic blood pressure | 0.0 mmHg |
Secondary
Vital Signs: Weight (Absolute Change From Baseline at Week 24)
Weight in kilograms was recorded without shoes. Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.
Time frame: Baseline and 24 weeks
Population: Patients with observations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMU-838 (45 mg/Day) | Vital Signs: Weight (Absolute Change From Baseline at Week 24) | 0.00 kg |
| Placebo | Vital Signs: Weight (Absolute Change From Baseline at Week 24) | 0.00 kg |
| Placebo | Vital Signs: Weight (Absolute Change From Baseline at Week 24) | 0.00 kg |