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

NCT03846219 | Active Not Recruiting Phase 2 Results

• 2 other identifiers: P2-IMU-838-MS2018-001896-19
• Study Type: interventional
• Target: 210
• Locations: 4 countries
• Sites: 38

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)

Keywords

RRMS; Multiple Sclerosis (MS)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (56)

• Difference Between 30 mg/Day IMU-838 and Placebo in the Cumulative Number of Combined Unique Active (CUA) MRI Lesions

  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

  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

  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

  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

  Throughout the main treatment period (Day 0 - Week 24)

Study Arms (4)

IMU-838 (30 mg/day)

EXPERIMENTAL

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)

IMU-838 (45 mg/day)

EXPERIMENTAL

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)

Placebo

PLACEBO COMPARATOR

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

IMU-838 (10 mg/day) - Cohort 2

EXPERIMENTAL

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)

Interventions

IMU-838 (30 mg/day) 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.

Also known as: Vidofludimus Calcium, Oral Tablet (30 mg/day)

IMU-838 (30 mg/day)

IMU-838 (45 mg/day) 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.

Also known as: Vidofludimus Calcium, Oral Tablet (45 mg/day)

IMU-838 (45 mg/day)

Placebo 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.

Placebo

IMU-838 (10 mg/day) 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.

Also known as: Vidofludimus Calcium, Oral Tablet (10 mg/day)

IMU-838 (10 mg/day) - Cohort 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female patient (age ≥18 to 55 years, inclusive)
• 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.
• 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)
• Expanded Disability Status Scale (EDSS) score between 0 and 4.0 (inclusive) at Screening Visit 1
• 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)

You may not qualify if:

• Any disease other than MS that may better explain the signs and symptoms, including history of complete transverse myelitis
• Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from these
• 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)
• MS types other than RRMS
• Any MRI finding, atypical for MS, including but not limited to a longitudinally extensive spinal cord lesion
• Any active and uncontrolled coexisting autoimmune disease, other than MS (except for type 1 diabetes mellitus and inflammatory bowel disease)
• An MS relapse within 30 days before Screening Visit 1 and/or during the screening period (until Day 0)
• 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™)
• 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)
• Any use of the following MS treatments within 30 days before the date of informed consent: interferon-β, glatiramer acetate, dimethyl fumarate and plasmapheresis
• Within 30 days before the baseline MRI: Use of systemic corticosteroids (intravenous or oral) or ACTH
• 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

Sponsors & Collaborators

• Immunic AG: lead

Study Sites (38)

MHAT Pulse AD, Department of Neurology Diseases

Blagoevgrad, 2700, Bulgaria

Location

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

Pleven, 5800, Bulgaria

Location

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

Pleven, 5804, Bulgaria

Location

UMHAT " Kaspela" EOOD, Department of Neurology Diseases

Plovdiv, 4001, Bulgaria

Location

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

Rousse, 7002, Bulgaria

Location

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

Sofia, 1113, Bulgaria

Location

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

Sofia, 1113, Bulgaria

Location

DCC "Neoclinic" EAD, Cabinet Neurology Diseases

Sofia, 1408, Bulgaria

Location

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

Sofia, 1431, Bulgaria

Location

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

Sofia, 1431, Bulgaria

Location

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

Sofia, 1431, Bulgaria

Location

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

Sofia, 1606, Bulgaria

Location

Military Medical Academy - Sofia, Clinic of Neurology Diseases

Sofia, 1606, Bulgaria

Location

Military Medical Academy, Clinic of Functional Diagnostics of Nevous System

Sofia, 1606, Bulgaria

Location

UMHAT " Sveta Marina EAD, First Neurology Clinic

Varna, 9010, Bulgaria

Location

Nasz Lekarz Ośrodek Badań Klinicznych

Bydgoszcz, 85-065, Poland

Location

Specjalistyczna Praktyka Lekarska Paweł Bochniak

Bydgoszcz, 85-796, Poland

Location

Indywidualna Praktyka Lekarska Prof. Konrad Rejdak

Lublin, 20-016, Poland

Location

BioResearch Group Sp. Z o.o

Nadarzyn, 05-830, Poland

Location

Centrum Medyczne NeuroProtect

Warsaw, 01-684, Poland

Location

S.C. Sana Monitoring Srl

Bucharest, 011025, Romania

Location

Spitalul Universitar Elias Bucharesti

Bucharest, 011461, Romania

Location

S.C. Quantum Medical Center Srl

Bucharest, 012071, Romania

Location

Spitalul Clinic Colentina Bucharest, Neurologie 2

Bucharest, 020125, Romania

Location

Spitalul Clinic Cai Ferate Constanta

Constanța, 900123, Romania

Location

Chernihiv Regional Hospital, Department of Neurology

Chernihiv, 14029, Ukraine

Location

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

Dnipro, 49000, Ukraine

Location

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

Dnipro, 49027, Ukraine

Location

Regional Clinical Hospital, Department of vascular Neurology

Ivano-Frankivsk, 76000, Ukraine

Location

Kharkiv Regional Clinical Hospital, Department of Neurology

Kharkiv, 61000, Ukraine

Location

Institute of Neurology, Psychiatry and Narcology NAMSU

Kharkiv, 61068, Ukraine

Location

Kyiv City Clinical Hospital #4, Department of Neurology

Kyiv, 03110, Ukraine

Location

Volyn Regional Clinical Hospital, Department of Neurology

Lutsk, 43005, Ukraine

Location

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

Poltava, 36011, Ukraine

Location

Regional Clinical Centre of Neurosurgery and Neurology, Department #2

Uzhhorod, 88018, Ukraine

Location

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

Vinnytsia, 21005, Ukraine

Location

City Clinical Hospital #2, Department of Neurology

Zaporizhzhya, 69068, Ukraine

Location

Zaporizhzhya Regional Clinical Hospital, Department of Neurology #1

Zaporizhzhya, 69600, Ukraine

Location

Related Publications (2)

• 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.

  PMID: 38662979 DERIVED

• 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.

  PMID: 35698927 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis

Interventions

Tablets

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Andreas Muehler, MD
• Organization: Immunic AG

andreas.muehler@imux.com

+4917678738359

Study Officials

• Andreas Muehler

  Immunic AG

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 21, 2019
• First Posted: February 19, 2019
• Study Start: January 28, 2019
• Primary Completion: April 24, 2020
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 24, 2024
• Results First Posted: July 23, 2021

Record last verified: 2024-04

Locations

BU (15); UA (13); PL (5); RO (5)