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

NCT ID: NCT03846219

Last Updated: 2024-04-24

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 210 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-28
• Study Completion Date: 2029-12-31

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.

Conditions

Relapsing-Remitting Multiple Sclerosis (RRMS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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).

Group Type: EXPERIMENTAL

IMU-838 (30 mg/day)

Intervention Type: DRUG

• 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.

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.

Group Type: EXPERIMENTAL

IMU-838 (45 mg/day)

Intervention Type: DRUG

• 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

• 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.

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).

Group Type: EXPERIMENTAL

IMU-838 (10 mg/day)

Intervention Type: DRUG

• 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Vidofludimus Calcium, Oral Tablet (30 mg/day); Vidofludimus Calcium, Oral Tablet (45 mg/day); Vidofludimus Calcium, Oral Tablet (10 mg/day)

Eligibility Criteria

Inclusion Criteria

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

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

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)

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

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

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

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Immunic AG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andreas Muehler

Role: STUDY_DIRECTOR

Immunic AG

Locations

MHAT Pulse AD, Department of Neurology Diseases

Blagoevgrad, , Bulgaria

UMHAT "Dr.Georgi Stranski" EAD Pleven Department of Professional Diseases

Pleven, , Bulgaria

MHAT "Heart and brain" EAD Pleven Department of Neurology Diseases

Pleven, , Bulgaria

UMHAT " Kaspela" EOOD, Department of Neurology Diseases

Plovdiv, , Bulgaria

UMHAT "Kanev Ruse", Department of General and Vascular Neurology

Rousse, , Bulgaria

MHATNP "Sveti Naum" EAD, Neurology Clinic for Movement Disorders, First Department of Neurology Diseases

Sofia, , Bulgaria

MHATNPsy "Sveti Naum" EAD, Intensive Therapy Clinic Of Neurology Diseases

Sofia, , Bulgaria

DCC "Neoclinic" EAD, Cabinet Neurology Diseases

Sofia, , Bulgaria

UMHAT "Alexandrovska" EAD, Clinic of Neurology Diseases, Department of Inherited Degenerative and Immunoinflamatori Diseases at Peripheral Nervous System

Sofia, , Bulgaria

UMHAT "Sveti Ivan Rilski" EAD Sofia Clinic of Neurological Diseases

Sofia, , Bulgaria

UMHAT"Alexandrovska"EAD, Department of Degenerative and Immunoinflamatory Disease of the Central Nervous System

Sofia, , Bulgaria

Central Clinical Base-Medical Institute - Ministry of Interior, Neurology Clinic

Sofia, , Bulgaria

Military Medical Academy - Sofia, Clinic of Neurology Diseases

Sofia, , Bulgaria

Military Medical Academy, Clinic of Functional Diagnostics of Nevous System

Sofia, , Bulgaria

UMHAT " Sveta Marina EAD, First Neurology Clinic

Varna, , Bulgaria

Nasz Lekarz Ośrodek Badań Klinicznych

Bydgoszcz, , Poland

Specjalistyczna Praktyka Lekarska Paweł Bochniak

Bydgoszcz, , Poland

Indywidualna Praktyka Lekarska Prof. Konrad Rejdak

Lublin, , Poland

BioResearch Group Sp. Z o.o

Nadarzyn, , Poland

Centrum Medyczne NeuroProtect

Warsaw, , Poland

S.C. Sana Monitoring Srl

Bucharest, , Romania

Spitalul Universitar Elias Bucharesti

Bucharest, , Romania

S.C. Quantum Medical Center Srl

Bucharest, , Romania

Spitalul Clinic Colentina Bucharest, Neurologie 2

Bucharest, , Romania

Spitalul Clinic Cai Ferate Constanta

Constanța, , Romania

Chernihiv Regional Hospital, Department of Neurology

Chernihiv, , Ukraine

Dnipropetrovsk Municipal Hospital #5, Neurological Department of the inflammatory and demyelinating diseases of CNS

Dnipro, , Ukraine

Ukrainian State Research Institute of Medical and Social Problems of Disability of MOH of Ukraine

Dnipro, , Ukraine

Regional Clinical Hospital, Department of vascular Neurology

Ivano-Frankivsk, , Ukraine

Kharkiv Regional Clinical Hospital, Department of Neurology

Kharkiv, , Ukraine

Institute of Neurology, Psychiatry and Narcology NAMSU

Kharkiv, , Ukraine

Kyiv City Clinical Hospital #4, Department of Neurology

Kyiv, , Ukraine

Volyn Regional Clinical Hospital, Department of Neurology

Lutsk, , Ukraine

Poltava Regional Clinical Hospital n.a. Sklifosovskyi, Department of Neurology

Poltava, , Ukraine

Regional Clinical Centre of Neurosurgery and Neurology, Department #2

Uzhhorod, , Ukraine

Vinnytsya Regional Psychoneurology Hospital n.a. Yushchenko, Department of Neurology #3

Vinnytsia, , Ukraine

City Clinical Hospital #2, Department of Neurology

Zaporizhzhya, , Ukraine

Zaporizhzhya Regional Clinical Hospital, Department of Neurology #1

Zaporizhzhya, , Ukraine

Countries

Bulgaria; Poland; Romania; Ukraine

References

Fox RJ, Wiendl H, Wolf C, De Stefano N, Sellner J, Gryb V, Rejdak K, Bozhinov PS, Vitt D, Kohlhof H, Slizgi J, Ondrus M, Sciacca V, Muehler AR; EMPhASIS investigators. Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200208. doi: 10.1212/NXI.0000000000200208. Epub 2024 Apr 25.

Reference Type: DERIVED

PMID: 38662979 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35698927 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2018-001896-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P2-IMU-838-MS

Identifier Type: -

Identifier Source: org_study_id