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

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