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

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)

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 Overview

• Status: Active, not recruiting
• Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
• Intervention / Treatment: Drug: IMU-838 (30 mg/day); Drug: IMU-838 (45 mg/day); Drug: Placebo; Drug: IMU-838 (10 mg/day)

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • MHAT Pulse AD, Department of Neurology Diseases
  • Pleven, Bulgaria, 5800
    • UMHAT "Dr.Georgi Stranski" EAD Pleven Department of Professional Diseases
  • Pleven, Bulgaria, 5804
    • MHAT "Heart and brain" EAD Pleven Department of Neurology Diseases
  • Plovdiv, Bulgaria, 4001
    • UMHAT " Kaspela" EOOD, Department of Neurology Diseases
  • Ruse, Bulgaria, 7002
    • UMHAT "Kanev Ruse", Department of General and Vascular Neurology
  • Sofia, Bulgaria, 1113
    • MHATNP "Sveti Naum" EAD, Neurology Clinic for Movement Disorders, First Department of Neurology Diseases
  • Sofia, Bulgaria, 1113
    • MHATNPsy "Sveti Naum" EAD, Intensive Therapy Clinic Of Neurology Diseases
  • Sofia, Bulgaria, 1408
    • DCC "Neoclinic" EAD, Cabinet Neurology Diseases
  • Sofia, Bulgaria, 1431
    • UMHAT "Alexandrovska" EAD, Clinic of Neurology Diseases, Department of Inherited Degenerative and Immunoinflamatori Diseases at Peripheral Nervous System
  • Sofia, Bulgaria, 1431
    • UMHAT "Sveti Ivan Rilski" EAD Sofia Clinic of Neurological Diseases
  • Sofia, Bulgaria, 1431
    • UMHAT"Alexandrovska"EAD, Department of Degenerative and Immunoinflamatory Disease of the Central Nervous System
  • Sofia, Bulgaria, 1606
    • Central Clinical Base-Medical Institute - Ministry of Interior, Neurology Clinic
  • Sofia, Bulgaria, 1606
    • Military Medical Academy - Sofia, Clinic of Neurology Diseases
  • Sofia, Bulgaria, 1606
    • Military Medical Academy, Clinic of Functional Diagnostics of Nevous System
  • Varna, Bulgaria, 9010
    • UMHAT " Sveta Marina EAD, First Neurology Clinic
• Poland
  • Bydgoszcz, Poland, 85-065
    • Nasz Lekarz Osrodek Badan Klinicznych
  • Bydgoszcz, Poland, 85-796
    • Specjalistyczna Praktyka Lekarska Paweł Bochniak
  • Lublin, Poland, 20-016
    • Indywidualna Praktyka Lekarska prof. Konrad Rejdak
  • Nadarzyn, Poland, 05-830
    • BioResearch Group Sp. Z o.o
  • Warszawa, Poland, 01-684
    • Centrum Medyczne Neuroprotect
• Romania
  • Bucharest, Romania, 011025
    • S.C. Sana Monitoring Srl
  • Bucharest, Romania, 011461
    • Spitalul Universitar Elias Bucharesti
  • Bucharest, Romania, 012071
    • S.C. Quantum Medical Center SRL
  • Bucharest, Romania, 020125
    • Spitalul Clinic Colentina Bucharest, Neurologie 2
  • Constanta, Romania, 900123
    • Spitalul Clinic Cai Ferate Constanta
• Ukraine
  • Chernihiv, Ukraine, 14029
    • Chernihiv Regional Hospital, Department of Neurology
  • Dnipro, Ukraine, 49000
    • Dnipropetrovsk Municipal Hospital #5, Neurological Department of the inflammatory and demyelinating diseases of CNS
  • Dnipro, Ukraine, 49027
    • Ukrainian State Research Institute of Medical and Social Problems of Disability of MOH of Ukraine
  • Ivano-Frankivsk, Ukraine, 76000
    • Regional Clinical Hospital, Department of vascular Neurology
  • Kharkiv, Ukraine, 61000
    • Kharkiv Regional Clinical Hospital, Department of Neurology
  • Kharkiv, Ukraine, 61068
    • Institute of Neurology, Psychiatry and Narcology NAMSU
  • Kyiv, Ukraine, 03110
    • Kyiv City Clinical Hospital #4, Department of Neurology
  • Lutsk, Ukraine, 43005
    • Volyn Regional Clinical Hospital, Department of Neurology
  • Poltava, Ukraine, 36011
    • Poltava Regional Clinical Hospital n.a. Sklifosovskyi, Department of Neurology
  • Uzhgorod, Ukraine, 88018
    • Regional Clinical Centre of Neurosurgery and Neurology, Department #2
  • Vinnytsya, Ukraine, 21005
    • Vinnytsya Regional Psychoneurology Hospital n.a. Yushchenko, Department of Neurology #3
  • Zaporizhzhya, Ukraine, 69068
    • City Clinical Hospital #2, Department of Neurology
  • Zaporizhzhya, Ukraine, 69600
    • Zaporizhzhya Regional Clinical Hospital, Department of Neurology #1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: Vidofludimus Calcium, Oral Tablet (10 mg/day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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	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).	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	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.	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	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.	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	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".	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	MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T2 lesion load was calculated.	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	MRI scans were assessed centrally and adhered to a standardized MRI protocol. The percentage change from Baseline in T1 lesion load was calculated.	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	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.	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	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.	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	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.	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	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.	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	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.	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	MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with CUA lesions at Week 24 was assessed.	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	MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with Gd+ lesions at Week 24 was assessed.	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	MRI scans were assessed centrally and adhered to a standardized MRI protocol. The number of patients with T2 lesions at Week 24 was assessed.	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)	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: 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; Absence of fever or known infection (i.e. temperature [axillary, oral, or intra-auricular]≤37.5ºC); 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.	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	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.	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	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.	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)	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.	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)	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.	Week 12 and Week 24
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.	At Week 24
Number of Participants With AEs	The number of patients experiencing treatment-emergent adverse events during the main treatment period was assessed.	Up to 24 weeks
Number of Participants With Serious AEs	The number of patients experiencing serious adverse events during the main treatment period was assessed.	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
Number of Participants With AEs of Special Interest: Hematuria	The number of patients diagnosed with hematuria during the main treatment period were assessed.	Up to 24 weeks
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.	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:	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	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
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.	Up to 24 weeks
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.	at Screening
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.	Baseline and 24 weeks
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.	Baseline and 24 weeks
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.	Baseline and 24 weeks
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.	Baseline and 24 weeks
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.	Baseline and 24 weeks
Micro Ribonucleic Acid (miR)-122 Expression	The fold change in miR-122 from pre dose to 4 hours post dose was assessed.	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	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.	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	The time to treatment discontinuation up to Week 24 for any reason was determined.	Up to 24 weeks
Rate of Treatment Discontinuations up to Week 24	The discontinuation rate during the main treatment period was assessed.	at Week 24
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.	At Week 6 (3-10 hours post-dose)
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.	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)	One single measurement between 3 and 10 hours post-dose. Population pharmacokinetics have not been reported yet.	At Week 6 (3-10 hours post-dose)
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.	At Week 6 (3-10 hours post-dose)
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.	At Week 6 (3-10 hours post-dose)
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.	At Day 7 and Weeks 6, 12, 18, and 24
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.	At Weeks 6 and 24 (in selected Biomarker Centers only)
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.	At Weeks 6 and 24 (in selected Biomarker Centers only)
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.	At Weeks 6 and 24 (in selected Biomarker Centers only)
Changes From Baseline in Serum Neurofilament	The percentage change from Baseline in serum neurofilament was calculated.	At Week 6 and Week 24
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).	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.	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.	Baseline, Week 6, Week 12, Week 18, and Week 24

Collaborators and Investigators

• Sponsor: Immunic AG
• Investigators: Study Director: Andreas Muehler, Immunic AG

Publications and helpful links

General Publications

• Fox RJ, Wiendl H, Wolf C, De Stefano N, Sellner J, Gryb V, Rejdak K, Bozhinov PS, Tomakh N, Skrypchenko I, Muehler AR. A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis. Ann Clin Transl Neurol. 2022 Jul;9(7):977-987. doi: 10.1002/acn3.51574. Epub 2022 Jun 14.

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2019
• Primary Completion (Actual): April 24, 2020
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: January 21, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: RRMS; Multiple Sclerosis (MS)
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium; Calcium, Dietary
• Other Study ID Numbers: P2-IMU-838-MS; 2018-001896-19 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No