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Trial record 1 of 1 for:    03846219
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MRI Trial to exPlore the efficAcy and Safety of IMU-838 in Relapsing Remitting Multiple Sclerosis (EMPhASIS) (EMPhASIS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03846219
Recruitment Status : Active, not recruiting
First Posted : February 19, 2019
Results First Posted : July 23, 2021
Last Update Posted : February 11, 2022
Sponsor:
Information provided by (Responsible Party):
Immunic AG

Study Description
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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.


Condition or disease Intervention/treatment Phase
Relapsing-Remitting Multiple Sclerosis (RRMS) Drug: IMU-838 (30 mg/day) Drug: IMU-838 (45 mg/day) Drug: Placebo Drug: IMU-838 (10 mg/day) Phase 2

Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
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.
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 28, 2019
Actual Primary Completion Date : April 24, 2020
Estimated Study Completion Date : December 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 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).

 Drug: IMU-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.
Other Name: Vidofludimus Calcium, Oral Tablet (30 mg/day)
Experimental: 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.

 Drug: IMU-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.
Other Name: Vidofludimus Calcium, Oral Tablet (45 mg/day)
Placebo Comparator: 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.

 Drug: Placebo
  • 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.
Experimental: 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).

 Drug: IMU-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.
Other Name: Vidofludimus Calcium, Oral Tablet (10 mg/day)


Outcome Measures
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Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions [ Time Frame: 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).

  2. Difference Between 45 mg/Day IMU-838 and 30 mg/Day IMU-838 in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions [ Time Frame: 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).

  3. 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 [ Time Frame: 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.

  4. 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 [ Time Frame: 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.

  5. 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 [ Time Frame: 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".

  6. 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 [ Time Frame: 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.

  7. 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 [ Time Frame: 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.

  8. 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 [ Time Frame: 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.

  9. 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 [ Time Frame: 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.

  10. 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 [ Time Frame: 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.

  11. 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 [ Time Frame: 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.

  12. 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 [ Time Frame: 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.

  13. 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 [ Time Frame: 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.

  14. 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 [ Time Frame: 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.

  15. 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 [ Time Frame: 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.

  16. 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) [ Time Frame: 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.

  17. 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 [ Time Frame: 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.

  18. 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 [ Time Frame: 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.

  19. 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) [ Time Frame: 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.

  20. 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) [ Time Frame: 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.

  21. Correlation of MRI-based Assessments With Quartiles of IMU-838 Trough Levels [ Time Frame: 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.

  22. Number of Participants With AEs [ Time Frame: Up to 24 weeks ]
    The number of patients experiencing treatment-emergent adverse events during the main treatment period was assessed.

  23. Number of Participants With Serious AEs [ Time Frame: Up to 24 weeks ]
    The number of patients experiencing serious adverse events during the main treatment period was assessed.

  24. Number of Participants With Clinically Significant Laboratory Abnormalities (as Assessed by the Investigator) [ Time Frame: 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.

  25. Number of Participants With AEs of Special Interest: Red Blood Cell Urine Positive, at Least of Moderate Intensity [ Time Frame: 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.


  26. Number of Participants With AEs of Special Interest: Hematuria [ Time Frame: Up to 24 weeks ]
    The number of patients diagnosed with hematuria during the main treatment period were assessed.

  27. Number of Participants With AEs of Special Interest: Retroperitoneal Colicky Pain With Suspected or Confirmed Nephrolithiasis [ Time Frame: 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.

  28. 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: [ Time Frame: 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

  29. 12-lead Electrocardiogram (ECG): Heart Rate [ Time Frame: 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.

  30. 12-lead Electrocardiogram (ECG): PQ-interval [ Time Frame: 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.

  31. 12-lead Electrocardiogram (ECG): QRS-interval [ Time Frame: 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.

  32. 12-lead Electrocardiogram (ECG): QT-interval [ Time Frame: 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.

  33. 12-lead Electrocardiogram (ECG): Heart Rate-corrected QTc Interval (According to Bazett's Formula) [ Time Frame: 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.

  34. Physical Examination [ Time Frame: 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.


  35. Vital Signs: Height [ Time Frame: 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.

  36. Vital Signs: Weight (Absolute Change From Baseline at Week 24) [ Time Frame: 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.

  37. Vital Signs: Body Temperature (ºC) (Absolute Change From Baseline at Week 24) [ Time Frame: Baseline and 24 weeks ]
    Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.

  38. Vital Signs: Respiratory Rate (Absolute Change From Baseline at Week 24) [ Time Frame: Baseline and 24 weeks ]
    Changes in vital signs judged by the investigator as clinically significant were to be reported as an AE.

  39. Vital Signs: Pulse Rates (Absolute Change From Baseline at Week 24) [ Time Frame: 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.


  40. Vital Signs: Systolic and Diastolic Blood Pressures (Absolute Change From Baseline at Week 24) [ Time Frame: 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.


  41. Micro Ribonucleic Acid (miR)-122 Expression [ Time Frame: 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.

  42. Presence of John Cunningham Virus (JCV) Deoxyribonucleic Acid (DNA) in Urine in Patients With Detectable JCV-DNA in Urine [ Time Frame: 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.

  43. Time to Treatment Discontinuation for Any Reason [ Time Frame: Up to 24 weeks ]
    The time to treatment discontinuation up to Week 24 for any reason was determined.

  44. Rate of Treatment Discontinuations up to Week 24 [ Time Frame: at Week 24 ]
    The discontinuation rate during the main treatment period was assessed.

  45. Population Pharmacokinetics: Minimum IMU-838 Plasma Concentration Over the Dosing Interval (Cmin) [ Time Frame: 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.

  46. Population Pharmacokinetics: Maximum IMU-838 Plasma Concentration Over the Dosing Interval (Cmax) [ Time Frame: 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.

  47. Population Pharmacokinetics: Area Under the IMU-838 Plasma Concentration-time Curve Over the Dosing Interval (AUC0-τ) [ Time Frame: 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.

  48. Population Pharmacokinetics: IMU-838 Apparent Clearance Following Oral Dosing (CL/F) [ Time Frame: 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.

  49. Population Pharmacokinetics: IMU-838 Apparent Volume of Distribution (V/F) [ Time Frame: 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.

  50. Plasma Trough Levels of IMU-838 [ Time Frame: 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.

  51. Changes From Baseline in Th1 Lymphocyte Subset as Measured by Flow Cytometry [ Time Frame: 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.

  52. Changes From Baseline in Th17 Lymphocyte Subset as Measured by Flow Cytometry [ Time Frame: 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.

  53. Changes From Baseline in Treg Lymphocyte Subset as Measured by Flow Cytometry [ Time Frame: 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.

  54. Changes From Baseline in Serum Neurofilament [ Time Frame: At Week 6 and Week 24 ]
    The percentage change from Baseline in serum neurofilament was calculated.

  55. Treatment Satisfaction Questionnaire for Medication (TSQM) [ 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 ]

    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).


  56. 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. [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 exclusion criteria

  1. Any disease other than MS that may better explain the signs and symptoms, including history of complete transverse myelitis
  2. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from these
  3. Clinical signs or presence of laboratory findings suggestive for neuromyelitis optica (NMO) spectrum disorders or MOG-associated encephalomyelitis (i.e. presence of anti-NMO [aquaporin-4] antibodies or anti-MOG-antibodies)
  4. MS types other than RRMS
  5. Any MRI finding, atypical for MS, including but not limited to a longitudinally extensive spinal cord lesion
  6. Any active and uncontrolled coexisting autoimmune disease, other than MS (except for type 1 diabetes mellitus and inflammatory bowel disease)

  7. An MS relapse within 30 days before Screening Visit 1 and/or during the screening period (until Day 0)

    Therapy exclusion criteria

  8. Any previous or current use of the following MS treatments: monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, ocrelizumab, anti-CD4, rituximab or belimumab, including their biosimilars), total lymphoid irradiation, bone marrow transplantation, stem cell transplantation, or any use of DHODH inhibitors, including teriflunomide (Aubagio™) or leflunomide (Arava™)
  9. Any use of the following MS treatments within 12 months before the date of informed consent: any cytokine (other than interferon) or anti-cytokine therapy, intravenous immunoglobulin, mitoxantrone, cytotoxic or immunosuppressive therapy (including, but not limited to azathioprine and cyclophosphamide, excluding only systemic corticosteroids or adrenocorticotrophic hormone [ACTH]), tofacitinib, methotrexate, mycophenolate mofetil, mycophenolate sodium, fingolimod, any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus)
  10. Any use of the following MS treatments within 30 days before the date of informed consent: interferon-β, glatiramer acetate, dimethyl fumarate and plasmapheresis
  11. Within 30 days before the baseline MRI: Use of systemic corticosteroids (intravenous or oral) or ACTH

  12. Use of the following concomitant medications is prohibited at Screening Visit 1 and throughout the duration of the trial:

    • any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
    • treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib
    • any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
    • use of rosuvastatin at daily doses higher than 10 mg

  13. Use of any investigational product within 8 weeks or 5 x the respective half-life before the date of informed consent, whichever is longer, and throughout the duration of the trial

    Immune response exclusion criteria

  14. Conditions negatively affecting the immune response such as previous organ transplant

  15. Clinically significantly low lymphocyte and/or neutrophil count (Common Terminology Criteria for AEs Grade of 2 or higher), i.e.

    • lymphocyte count <800/mm³ (0.8 x 109/L), and/or
    • neutrophil count <1,500/mm³ (1.5 x 109/L)
  16. History of chronic systemic infections within 6 months before the date of informed consent, including but not limited to tuberculosis, human immunodeficiency virus (HIV), hepatitis B or C
  17. Positive IFNγ release assay for Mycobacterium tuberculosis at Screening Visit 1
  18. Positive hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (HBcAb), positive HCV-antibody (HCV-Ab) and/or HIV-antigen-antibody test at Screening Visit 1
  19. Any live vaccinations within 30 days before the date of informed consent except for the influenza vaccine Other medical history and concomitant disease exclusion criteria

  20. Presence of the following laboratory values at Screening Visit 1:

    • platelet count <100,000/mm³ (<100 109/L)
    • serum creatinine >1.5 x ULN
    • total bilirubin, ALT, or GGT >1.5 x ULN
    • Serum uric acid levels at Screening Visit 1 >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)
    • indirect (unconjugated) bilirubin >1.2 x ULN (i.e. >1.1 mg/dL)
  21. Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
  22. History or clinical diagnosis of gout
  23. Renal impairment defined as estimated glomerular filtration rate ≤60 mL/min/1.73m²
  24. Known or suspected Gilbert syndrome
  25. Diagnosis or suspected liver function impairment which may cause fluctuating liver function tests during this trial, as assessed by the investigator
  26. History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (New York Heart Association [NYHA] class 3 or 4) Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
  27. Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly controlled diabetes
  28. Concurrent malignancy or prior malignancy within the previous 10 years except for the following: adequately-treated non-melanoma skin cancer and adequately-treated cervical cancer
  29. History or presence of any major medical or psychiatric illness (such as severe depression, psychosis, bipolar disorder), history of suicide attempt, or current suicidal ideation that in the opinion of the investigator could create undue risk to the patient or could affect adherence with the trial protocol
  30. Epilepsy or seizures not adequately controlled by treatment

  31. Any other substantial medical condition that in the opinion of the investigator could create undue risk to the patient or could affect adherence with the trial protocol

    General exclusion criteria

  32. Current or past (within 12 months of Screening Visit 1) alcohol or drug abuse

  33. Any condition that would prevent the patient from undergoing an MRI scan, including:

    • claustrophobic conditions
    • unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to Gd based contrast agents, or severe renal insufficiency
    • presence of metallic implants incompatible with brain MRI
  34. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable to understand the patient information and informed consent form
  35. Pregnant or breastfeeding
  36. An employee of an investigator or sponsor or an immediate relative of an investigator
  37. Patients institutionalized due to judicial or administrative order

Exclusion criteria for optional extended treatment period

  1. Any ongoing, clinically significant (as assessed by the investigator) treatment-emergent (started after intake of IMP) AE or laboratory abnormality (including blood chemistry and urinalysis)
  2. Significant treatment or trial non-compliance during the main treatment period (as assessed by the investigator), and/or inability or unwillingness to follow instructions by trial personnel
  3. Treatment compliance <70% during the main treatment period
  4. Significant protocol deviations during the main treatment period that are assessed by the investigator to negatively affect further patient cooperation in this trial
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03846219


Locations
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Sponsors and Collaborators
Immunic AG
Investigators
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Study Director: Andreas Muehler Immunic AG
  Study Documents (Full-Text)

Documents provided by Immunic AG:
Study Protocol and Statistical Analysis Plan  [PDF] August 28, 2020

More Information
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Immunic AG
ClinicalTrials.gov Identifier: NCT03846219    
Other Study ID Numbers: P2-IMU-838-MS
2018-001896-19 ( EudraCT Number )
First Posted: February 19, 2019    Key Record Dates
Results First Posted: July 23, 2021
Last Update Posted: February 11, 2022
Last Verified: January 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Immunic AG:
RRMS
Multiple Sclerosis (MS)
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
 Autoimmune Diseases
Immune System Diseases
Calcium, Dietary
Calcium
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Bone Density Conservation Agents