| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsing-remitting multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Cohort 1 (i.e. the main study):
Primary
• To evaluate the efficacy of 45 mg/day IMU-838 in the treatment of RRMS based on MRI assessments
Cohort 2 (i.e. the sub-study):
Primary
• To obtain more efficacy and safety data of IMU-838 in patients with RRMS and to allow pharmacodynamic modelling of the dose response. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary
• To evaluate the efficacy of 30 mg/day IMU-838 in the treatment of RRMS based on magnetic resonance imaging (MRI) assessments
• To evaluate the safety and tolerability of 30 mg/day and 45 mg/day IMU-838 in RRMS patients
Tertiary
• To evaluate PD effects of IMU-838 in RRMS patients
• To evaluate IMU-838 trough values and population PK
• To evaluate the effects of IMU-838 on treatment satisfaction in patients with RRMS |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The sub-study has the same title, date and version as the main study. It is a double-blind, placebo-controlled, randomized, parallel-group sub-trial of P2-IMU-838-MS to assess the efficacy and safety of once-daily oral 10 mg/day IMU-838 compared to placebo in patients with RRMS and evidence of active disease. The objective of this sub-trial is to obtain more efficacy and safety data of IMU-838 in patients with RRMS and to allow pharmacodynamic modelling of the dose response. |
|
| E.3 | Principal inclusion criteria |
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
o 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
o ≥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
o 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
o 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
o abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s usual form of birth control/lifestyle choice), or
o use adequate barrier contraception during treatment with the IMP and until at least 30 days after the last intake of the IMP, and
o if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 5
o 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. Compleated 24 weeks of main treatment
2. Baseline MRI, a 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 |
|
| E.4 | Principal 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)
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:
o claustrophobic conditions
o unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to Gd-based contrast agents, or severe renal insufficiency
o 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 a normality (including blood chemistry and urinalysis)7
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
Cohort 1 (C1): Difference between 45 mg/day IMU-838 and placebo in the cumulative number of combined unique active (CUA) MRI lesions up to Week 24
Cohort 2 (C2): Between-treatment differences in the cumulative number of CUA MRI and Gd+ lesions up to Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary (hierarchical testing to primary efficacy)
Efficacy
C1: Difference between 30 mg/day IMU-838 and placebo in the cumulative number of CUA MRI lesions up to Week 24
Secondary
Efficacy
• C1: Difference between 45 mg/day IMU-838 and 30 mg/day IMU-838 in the cumulative number of CUA MRI lesions at Week 24
• C1: 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 following MRI parameters and C2: Between-treatment differences in the following MRI parameters:
o C1+C2: Mean number of CUA lesions per patient per scan at Weeks 6, 12, 18 and 24
o C1: Cumulative number of CUA MRI lesions up to Weeks 6, 12, and 18
o C2: Cumulative number of CUA MRI lesions up to Weeks 6, 12, 18, and 24
o C1: Volume changes of T2 lesions at Weeks 6, 12, 18 and 24 compared to Baseline
o C1+C2: T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline
o C1+C2: T1-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline
o C1+C2: Cumulative number of new Gd+ lesions up to Weeks 6, 12, 18 and 24
o C1+C2: Cumulative number of new T2 lesions up to Weeks 6, 12, 18 and 24
o C1+C2: Cumulative number of new T1 lesions up to Weeks 6, 12, 18 and 24
o C1+C2: Proportion of patients without new Gd+ lesions over 24 weeks
o C1+C2: Proportion of patients without new or enlarging T2-weighted lesions over 24 weeks
o C1: Proportion of patients with CUA lesions at Week 24
o C1: Proportion of patients with Gd+ lesions at Week 24
o C1: Proportion of patients with T2 lesions at Week 24
• C1: Differences between individual treatments and between the pooled 30 mg/day and 45 mg/day groups and placebo in the following relapse-related clinical endpoints:
o Mean annualized relapse rate (during main and extended treatment period)
o Proportion of relapse-free patients up to Week 24 and at extended periods thereafter
o Time to relapse at time of final analysis of main part
• C2: Number of relapses in each treatment arm
• C1: Differences between treatments in changes of disease activity as measured by the following clinical parameters:
o Mean change in the EDSS as compared to Baseline during the main and extended period (every 12 weeks starting at Week 12)
o Proportion of patients with EDSS progression during the main and extended period (every 12 weeks starting at Week 12, and cumulatively)
• C2: Change of EDSS from Baseline to Weeks 12 and 24
• C1: Correlation of MRI-based assessments with quartiles of IMU-838 trough levels at Week 6 and Week 24
• C2: Correlation of MRI-based assessments with quartiles of IMU-838 trough levels at Week 24
Safety
• C1+C2: AEs, serious AEs and clinically significant laboratory abnormalities (as assessed by the investigator)
• C1+C2: AEs of special interest:
o Red blood cell urine positive, at least of moderate intensity
o Hematuria
o Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis
• C1: 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 / C2: Proportion of patients treated with 10 mg/day as compared to placebo who experienced at least one of the following AEs:
o Neutropenia
o Lymphopenia
o Diarrhea
o Alopecia
o Hemorrhage
o Abnormalities in alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, and total bilirubin with both elevations > 1.5 x ULN and ≥ 35% elevated compared to Baseline
• ECG, physical examination, and vital signs
• C1: Micro ribonucleic acid-122 expression (Change from Baseline to 4 hours after first dose)
• C1: Presence of John Cunningham virus (JCV) deoxyribonucleic acid (DNA) in urine in patients with detectable JCV-DNA in urine at Screening Visit 1, at Week 24, and at EoS
• C1+C2: Time to treatment discontinuation for any reason
• C1+C2: Rate of treatment discontinuations up to Week 24
Pharmacokinetics
• C1+C2: Population PK at Week 6 (3-10 hours post-dose)
• C1+C2: Plasma trough levels of IMU-838 at Days 7 and Weeks 6, 12, 18, and 24
Pharmacodynamics
• C1: Changes from Baseline in lymphocyte subset parameters as measured by flow cytometry at Weeks 6 and 24 (in selected Biomarker Centers only)
• C1: Changes from Baseline in biased T-cell clonal repertoire based on T-cell receptor deep sequencing at Weeks 6 and 24 (in selected Biomarker Centers only)
• C1+C2: Changes from Baseline in serum neurofilament at Week 24
• C2: Changes in serum C4 (7α-hydroxy-4-cholesten-3-one)
• C2: Changes in serum fibroblast growth factor 19 (FGF-19)
Health outcome (C1)
• Treatment Satisfaction Questionnaire for Medication at Week 6, Week 24 and EoS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary (hierarchical testing to primary efficacy)
Efficacy: up to Week 24
Secondary
Efficacy: Baseline, Weeks 6, 12, 18 and 24
Safety: Screening, throughout Main and Extended Treatment Period, all Unscheduled Visits and EoS
Pharmacokinetics: Days 7 and Weeks 6, 12, 18, and 24
Pharmacodynamics: Baseline, Weeks 6 and 24
Health outcome: Week 6, Week 24 and EoS |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| Bulgaria |
| Germany |
| Poland |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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