| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive forms of 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 | 26.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053395 |
| E.1.2 | Term | Progressive 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 |
To evaluate the efficacy of IMU-838 versus placebo as measured by
quantitative magnetic resonance imaging (MRI) analysis for whole brain
atrophy in progressive multiple sclerosis (PMS) patients with the
Structural Image Evaluation using Normalization of Atrophy (SIENA)
method during the Main Treatment (MT) period |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of IMU-838 versus placebo as measured by
quantitative MRI analysis for whole-brain atrophy in PMS patients with
the Structural Image Evaluation using the Brain Parenchymal Fraction
(BPF) method during the MT period.
To evaluate the efficacy of IMU-838 compared to placebo in terms of
disability worsening during the MT period.
To evaluate the efficacy of IMU-838 compared to placebo in terms of
disability and other clinical assessments during the MT period.
To evaluate the efficacy of IMU-838 compared to placebo in terms of MRI
parameters during the MT period.
To evaluate the efficacy of IMU-838 compared to placebo in terms of
neurofilament light chain (NfL) level.
To evaluate the safety and tolerability of IMU-838 compared to placebo
during the MT period and evaluate the long-term safety and tolerability
of IMU-838 during the open-label extension (OLE) period. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult patients, age 18 to 65 years (inclusive).
2. No evidence of relapse in the last 24 months before randomization, AND
Patients diagnosed with either
a) SPMS, in patients showing evidence of Gd+ MRI lesions (active SPMS) in the brain or spinal cord, or without Gd+ MRI lesions (non-active SPMS) in the last 12 months, OR
b) PPMS
according to 2017 revised McDonald Criteria and the 2013 revised
classification of disease courses with a disease duration of the
progressive disease of ≤10 years
3. EDSS score at screening between 3.0 to 6.5 (both inclusive).
4. Evidence of disability worsening not temporarily related to a relapse
in the last 24 months before randomization, adjudicated by a central
independent reviewer, and documented as:
a) An increase of EDSS of at least 1.0 point with Screening EDSS of up to
5.5 (inclusive) and 0.5 point for Screening EDSS 6.0 or 6.5 (as
documented in patient files in the last 24 months before randomization),
OR
b) A 20% worsening (or more) in 25-foot walk time or 9-hole peg test
time in either hand (as documented in patient files in the last 24 months
before randomization),
OR
c) A written summary of the clinical evidence of disability worsening in
the previous 24 months before randomization through a retrospective
assessment of disease worsening from patient files.
5. Female patients:
a) Must be of non-childbearing potential, i.e., surgically sterilized
(hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least
6 weeks before SV1) or postmenopausal (where postmenopausal is
defined as no menses for 12 months without an alternative medical
cause), or
b) If of childbearing potential, must have a negative pregnancy test at
SV1 (blood test) and before the first IMP intake at Day 1 (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 study consent and 30 days after
the last intake of the IMP.
c) Highly effective forms of birth control are those with a failure rate of
less than 1% per year and include:
i) Oral, intravaginal, or transdermal combined (estrogen and
progestogen containing) hormonal contraceptives associated with
inhibition of ovulation.
ii) Oral, injectable, or implantable progestogen-only hormonal
contraceptives associated with inhibition of ovulation.
iii) Intrauterine device or intrauterine hormone-releasing system.
iv) Bilateral tubal occlusion.
v) Vasectomized partner (i.e., the patient's male partner underwent
effective surgical sterilization before the female patient entered the
clinical study. And is the sole sexual partner of the female patient during
the clinical study).
vi) 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
not acceptable methods of contraception).
d) Barrier methods of contraception include:
i) Condom.
ii) 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 SV1, throughout the clinical study, and for 30 days after the
last intake of the IMP. Male patients must also:
a) Abstain from sexual intercourse with a female partner (acceptable
only if it is the patient's usual form of birth control/lifestyle choice), or
b) Use adequate barrier contraception during treatment with the IMP
and until at least 30 days after the last intake of the IMP, and
Note: Simultaneous use of male and female condoms with or without any
other contraception methods is not permitted.
c) If they have a female partner of childbearing potential, the partner
should use a highly effective contraceptive method as outlined in
inclusion criterion 4.
d) 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 by the patient before the beginning of
any study-related procedure.
For more information, please refer to Clinical Study Protocol.
Inclusion Criteria for the OLE Period
1. Completed 120 weeks of MT period or have confirmed 24-week
disability worsening or the patient was in the MT period when the study
reached the MT termination event, at which time, the patient could enter
the OLE treatment period. |
|
| E.4 | Principal exclusion criteria |
MS-related exclusion criteria:
1. Any disease other than MS that may better explain the signs and
symptoms, including a history of complete transverse myelitis.
2. Clinical signs or presence of laboratory findings suggestive for
neuromyelitis optica spectrum disorders (NMOSD) or myelin
oligodendrocyte glycoprotein (MOG)-associated encephalomyelitis (i.e.,
presence of aquaporin-4 antibodies or anti-MOG antibodies).
3. Any MRI finding, atypical for MS, including but not limited to a
longitudinally extensive spinal cord lesion.
4. Any active and uncontrolled coexisting autoimmune disease, other
than MS (except for type 1 diabetes mellitus and inflammatory bowel
disease).
Therapy-related exclusion criteria:
5. Any previous or current use of the following MS treatments:
a) alemtuzumab or belimumab, including their biosimilars,
b) cladribine,
c) total lymphoid irradiation, and
d) bone marrow or stem cell transplantation.
6. Any use of the following MS treatments before the date of randomization (see table in study protocol)
7. Any use of adrenocorticotrophic hormone (ACTH) or occasional use of
systemic corticosteroids (oral or intravenous) 30 days before SV2.
8. Use of any investigational product within 8 weeks or 5× the respective
PK half-life before the date of informed consent, whichever is longer,
and throughout the study. For some investigational products, prolonged
biological effects beyond 8 weeks should be considered.
For more information, please refer to Clinical Study Protocol.
Exclusion Criteria for the OLE Period:
Patients meeting any of the following criteria will be ineligible to
participate in the OLE
Period of the study:
1. Any ongoing, clinically significant (as assessed by the Investigator)
treatment-emergent AE or laboratory abnormality (including blood
biochemistry and urinalysis) that can jeopardize the patient's safety, in
agreement with the medical monitor.
2. Significant study or treatment non-compliance (<80% or >125%)
during the MT period, and/or inability or unwillingness to follow
instructions by study personnel.
3. The lack of interpretable BL or EoMT MRI or the omission of more than
one other MRI during the MT.
4. Use of experimental/investigational drug (except for COVID-19
vaccines approved by emergency use authorization or similar expanded
access schemes) and/or participation in another clinical study of an
investigational drug throughout the duration of the OLE treatment
period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annualized rate of percent brain volume change (PBVC) during MT period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be analyzed on the mITT analysis set. The
annualized rate of PBVC between BL and EoMT (or the last available
MRI) will be assessed within a random intercept, random slope mixed
model, accounting for treatment effect, and stratified for the same
factors for which randomization was stratified. The null hypothesis of
equal mean slopes of the 2 treatment arms will be tested (at a two-sided
5% level).
Sensitivity analyses will be performed to assess the effect of different
ICE handling strategies. |
|
| E.5.2 | Secondary end point(s) |
Annualized rate of change in BPF during MT period
Time to 24-week confirmed disability worsening based on expanded disability status scale (EDSS) during the MT period |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section 14.3.4.2. of clinical study protocol. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| North Macedonia |
| Moldova, Republic of |
| Ukraine |
| Canada |
| Serbia |
| United States |
| Bulgaria |
| Czechia |
| Germany |
| Netherlands |
| Poland |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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