MRI Trial to exPlore the efficAcy and Safety of IMU-838 in Relapsing Remitting Multiple Sclerosis (EMPhASIS)
Condition: Relapsing-Remitting Multiple Sclerosis (RRMS)
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: IMU-838 (30 mg/day); IMU-838 (45 mg/day); Placebo; IMU-838 (10 mg/day)
Intervention description: 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.; 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.; 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.; 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.
Intervention MeSH terms: Calcium, Dietary; Calcium
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 210.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: RRMS; Multiple Sclerosis (MS)

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.
    

Eligibility 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