Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2 Trial Assessing the Effect of IMU-838 on Disease Activity, as Measured by Magnetic Resonance Imaging (MRI), as Well as Safety and Tolerability in Patients With Relapsing-remitting Multiple Sclerosis (RRMS)
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- Immunic AG
- Enrollment
- 210
- Locations
- 38
- Primary Endpoint
- Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, 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.
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
IMU-838 (30 mg/day)
IMU-838 tablet containing 15 mg Vidofludimus calcium (IM90838). Once-daily oral dose of 30 mg consists of 2 tablets IMU-838.
Duration: until the end of the main treatment period (24 weeks). In the optional extended treatment period, patients were randomized to receive either 30 mg/day or 45 mg/day IMU-838 (up to 9.5 years for the main trial).
Intervention: IMU-838 (30 mg/day) (Drug)
IMU-838 (45 mg/day)
Tablet containing 22.5 mg Vidofludimus calcium (IM90838). Once-daily oral dose of 45 mg consists of 2 tablets.
Duration: until the end of the main treatment period (24 weeks). In the optional extended treatment period, patients were randomized to receive either 30 mg/day or 45 mg/day IMU-838.
Intervention: IMU-838 (45 mg/day) (Drug)
Placebo
Tablet containing no active ingredient. The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. Once-daily oral dose consists of 2 active compound-free tablets.
Duration: until the end of the main treatment period (24 weeks). The placebo is not applicable in the optional extended treatment period, in which participants who were receiving placebo in the main treatment period were re-randomized to IMU-838 for the extended treatment period.
Intervention: Placebo (Drug)
IMU-838 (10 mg/day) - Cohort 2
Cohort 2 sub-trial: additional sub-trial with a small double-blind, placebo-controlled, randomized, parallel-group assessment of a low IMU-838 dose (i.e. 10 mg/day) to provide additional data for pharmacodynamic modelling.
Tablet containing 5 mg Vidofludimus calcium (IM90838). Once-daily oral dose of 10 mg consists of 2 tablets.
Duration: until the end of the main treatment period (24 weeks). In the optional extended treatment period, patients were randomized to receive either 30 mg/day or 45 mg/day IMU-838 (up to 8.5 years for the cohort 2 sub-trial).
Intervention: IMU-838 (10 mg/day) (Drug)
Outcomes
Primary Outcomes
Difference Between 45 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions
Time Frame: 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 Outcomes
- Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions(Up to Week 24)
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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)
- 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)
- Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels(At Week 24)
- Number of Participants With AEs(Up to 24 weeks)
- Number of Participants With Serious AEs(Up to 24 weeks)
- Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator)(Up to 24 weeks)
- Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity(Up to 24 weeks)
- Number of Participants With AEs of Special Interest: Hematuria(Up to 24 weeks)
- Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis(Up to 24 weeks)
- 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)
- 12-lead Electrocardiogram (ECG): Heart Rate(Up to 24 weeks)
- 12-lead Electrocardiogram (ECG): PQ-interval(Up to 24 weeks)
- 12-lead Electrocardiogram (ECG): QRS-interval(Up to 24 weeks)
- 12-lead Electrocardiogram (ECG): QT-interval(Up to 24 weeks)
- 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula)(Up to 24 weeks)
- Physical Examination(Up to 24 weeks)
- Vital Signs: Height(at Screening)
- Vital Signs: Weight (Absolute Change From Baseline at Week 24)(Baseline and 24 weeks)
- Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24)(Baseline and 24 weeks)
- Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24)(Baseline and 24 weeks)
- Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24)(Baseline and 24 weeks)
- Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24)(Baseline and 24 weeks)
- Micro Ribonucleic Acid (miR)-122 Expression(Change from Baseline to 4 hours after first dose)
- 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))
- Time to Treatment Discontinuation for Any Reason(Up to 24 weeks)
- Rate of Treatment Discontinuations up to Week 24(at Week 24)
- Population Pharmacokinetics: Minimum IMU-838 Plasma Concentration Over the Dosing Interval (Cmin)(At Week 6 (3-10 hours post-dose))
- Population Pharmacokinetics: Maximum IMU-838 Plasma Concentration Over the Dosing Interval (Cmax)(At Week 6 (3-10 hours post-dose))
- 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))
- Population Pharmacokinetics: IMU-838 Apparent Clearance Following Oral Dosing (CL/F)(At Week 6 (3-10 hours post-dose))
- Population Pharmacokinetics: IMU-838 Apparent Volume of Distribution (V/F)(At Week 6 (3-10 hours post-dose))
- Plasma Trough Levels of IMU-838(At Day 7 and Weeks 6, 12, 18, and 24)
- 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 Th17 Lymphocyte Subset as Measured by Flow Cytometry(At Weeks 6 and 24 (in selected Biomarker Centers only))
- 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 Serum Neurofilament(At Week 6 and Week 24)
- 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)
- 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)