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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03846219
• Date of registration: 21/01/2019
• Prospective Registration: Yes
• Primary sponsor: Immunic AG
• Public title: MRI Trial to exPlore the efficAcy and Safety of IMU-838 in Relapsing Remitting Multiple Sclerosis (EMPhASIS) EMPhASIS
• Scientific title: 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)
• Date of first enrolment: January 28, 2019
• Target sample size: 210
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/show/NCT03846219
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Bulgaria, Poland, Romania, Ukraine

Contacts

• Name: Andreas Muehler
• Affiliation: Immunic AG

Key inclusion & exclusion 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-ß, glatiramer acetate, dimethyl fumarate and plasmapheresi


Age minimum: 18 Years
Age maximum: 55 Years
Gender: All

Health Condition(s) or Problem(s) studied

Relapsing-Remitting Multiple Sclerosis (RRMS)

Intervention(s)

Drug: IMU-838 (30 mg/day)

Drug: IMU-838 (45 mg/day)

Drug: Placebo

Primary Outcome(s)

Difference between 45 mg/day IMU-838 and placebo in the cumulative number of combined unique active (CUA) MRI lesions [Time Frame: Up to Week 24]

Difference between 30 mg/day IMU-838 and placebo in the cumulative number of combined unique active (CUA) MRI lesions [Time Frame: Up to Week 24]

Secondary Outcome(s)

12-lead electrocardiogram (ECG): PQ-interval [Time Frame: Throughout the clinical trial, up to 10 years]

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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Micro ribonucleic acid-122 expression [Time Frame: Change from Baseline to 4 hours after first dose]

Number of Participants with AEs of special interest: Red blood cell urine positive, at least of moderate intensity [Time Frame: Throughout the clinical trial, up to 10 years]

Changes from Baseline in Th17 lymphocyte subset as measured by flow cytometry [Time Frame: At Weeks 6 and 24 (in selected Biomarker Centers only)]

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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Number of Participants with ClinicallySignificant Laboratory Abnormalities (as assessed by the investigator) [Time Frame: Throughout the clinical trial, up to 10 years]

Physical examination [Time Frame: Throughout the clinical trial, up to 10 years]

Population Pharmacokinetics: area under the IMU-838 plasma concentration-time curve over the dosing interval (AUC0-t) [Time Frame: At Week 6 (3-10 hours post-dose)]

Population Pharmacokinetics: maximum IMU-838 plasma concentration over the dosing interval (Cmax) [Time Frame: At Week 6 (3-10 hours post-dose)]

Presence of John Cunningham virus (JCV) deoxyribonucleic acid (DNA) in urine in patients with detectable JCV-DNA in urine [Time Frame: At Screening Visit 1, at Week 24, and at end of study visit (EoS visit 30 days (+14 days) after last IMP intake)]

12-lead electrocardiogram (ECG): QT-interval [Time Frame: Throughout the clinical trial, up to 10 years]

Correlation of MRI-based assessments with quartiles of IMU-838 trough levels [Time Frame: 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 the Cumulative number of new Gd+ lesions up to Weeks 6, 12, 18 and 24 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Changes from Baseline in Th1 lymphocyte subset as measured by flow cytometry [Time Frame: At Weeks 6 and 24 (in selected Biomarker Centers only)]

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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Changes from Baseline in serum neurofilament [Time Frame: At 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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Vital signs: body temperature (ºC) [Time Frame: Throughout the clinical trial, up to 10 years]

12-lead electrocardiogram (ECG): heart rate-corrected QTc interval (according to Bazett's formula) [Time Frame: Throughout the clinical trial, up to 10 years]

12-lead electrocardiogram (ECG): QRS-interval [Time Frame: Throughout the clinical trial, up to 10 years]

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 [Time Frame: 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 Proportion of patients without new Gd+ lesions over 24 weeks [Time Frame: 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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Differences between treatments in changes of disease activity as measured by the Proportion of patients with EDSS progression during the main and extended period (every 12 weeks starting at Week 12, and cumulatively) [Time Frame: Throughout the clinical trial, up to 10 years]

Number of Participants with AEs of special interest: Hematuria [Time Frame: Throughout the clinical trial, up to 10 years]

Changes from Baseline in Treg lymphocyte subset as measured by flow cytometry [Time Frame: At Weeks 6 and 24 (in selected Biomarker Centers only)]

Difference between 45 mg/day IMU-838 and 30 mg/day IMU-838 in the cumulative number of combined unique active (CUA) MRI lesions [Time Frame: At Week 24]

Vital signs: height [Time Frame: at Screening]

Vital signs: systolic and diastolic blood pressures [Time Frame: Throughout the clinical trial, up to 10 years]

Rate of treatment discontinuations up to Week 24 [Time Frame: at Week 24]

Treatment Satisfaction Questionnaire for Medication (TSQM) [Time Frame: At Week 6, Week 24 and end of study visit (EoS visit 30 days (+14 days) after last IMP intake)]

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) [Time Frame: Throughout the main (Day 0 - Week 24) and extended treatment period (up to 9.5 years)]

Vital signs: pulse rates [Time Frame: Throughout the clinical trial, up to 10 years]

Vital signs: respiratory rate [Time Frame: Throughout the clinical trial, up to 10 years]

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 Proportion of patients with CUA lesions at Week 24 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Number of Participants with AEs of special interest: Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis [Time Frame: Throughout the clinical trial, up to 10 years]

Number of Participants with serious AEs [Time Frame: Throughout the clinical trial, up to 10 years]

Plasma trough levels of IMU-838 [Time Frame: At Days 7 and Weeks 6, 12, 18, and 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 Proportion of patients with Gd+ lesions at Week 24 [Time Frame: 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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Time to treatment discontinuation for any reason [Time Frame: Throughout the clinical trial, up to 10 years]

Vital signs: weight [Time Frame: Throughout the clinical trial, up to 10 years]

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 [Time Frame: Throughout the main treatment period (Day 0 - Week 24)]

Population Pharmacokinetics: minimum IMU-838 plasma concentration over the dosing interval (Cmin) [Time Frame: At Week 6 (3-10 hours post-dose)]

Proportion 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: [Time Frame: Throughout the clinical trial, up to 10 years]

Population Pharmacokinetics: IMU-838 apparent volume of distribution (V/F) [Time Frame: At Week 6 (3-10 hours post-dose)]

12-lead electrocardiogram (ECG): heart rate [Time Frame: Throughout the clinical trial, up to 10 years]

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 Proportion of patients with T2 lesions at Week 24 [Time Frame: 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 Proportion of patients without new or enlarging T2-weighted lesions over 24 weeks [Time Frame: 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 [Time Frame: Throughout the main (Day 0 - Week 24) and extended treatment period (up to 9.5 years)]

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) [Time Frame: Throughout the clinical trial, up to 10 years]

Number of Participants with AEs [Time Frame: Throughout the clinical trial, up to 10 years]

Population Pharmacokinetics: IMU-838 apparent clearance following oral dosing (CL/F) [Time Frame: At Week 6 (3-10 hours post-dose)]

Secondary ID(s)

P2-IMU-838-MS

2018-001896-19

Source(s) of Monetary Support

Please refer to primary and secondary sponsors