This is a randomized, placebo-controlled, double-blind, multi-center, phase 2 study of
subcutaneous cladribine in non-relapsing, secondary progressive multiple sclerosis. Eligible
patients will be randomly allocated in a 1:1 ratio to receive either placebo or subcutaneous
cladribine at a dose of 1.8 mg/kg of body weight. The study will consist of three periods:
screening, treatment, and follow-up. During the screening, the investigators will assess
patient eligibility. During the treatment, cladribine will be given over 6 visit every 5-6
weeks. During the follow-up of 96 weeks, safety and efficacy assessments will be carried out
on five visits: the first visit will take place 4 weeks after the last cladribine dose, and
the remaining visits will take place every 24 weeks.
There will a rescue option of unblinding and treatment with a full dose of cladribine
(cladribine arm) or approved medications (placebo arm) for patients with a severe relapse or
≥ 2 non-severe relapses after enrolment or with a substantial neuroimaging disease activity ≥
4 Gd+ lesions in any scan, ≥ 3 Gd+ lesions in any two scans, ≥ 2 Gd+ lesions in any three
scans, or ≥ 9 new/enlarging T2 lesions on any scan compared with baseline).
All raters will be blinded to treatment allocation. All neuroimaging examinations will be
evaluated at a central neuroimaging unit by investigators blinded to treatment allocation.
Study type: interventional (clinical trial) Planned enrolment: 188 patients Allocation:
randomized Masking: Double (Participant, Investigator) Primary purpose: Treatment Start Date:
October 2022
Study design: The study aims to assess the safety and efficacy of subcutaneous cladribine in
patients with SPMS who have not experienced relapses over a year and with or without active
lesions on neuroimaging. The study will be randomized, placebo-controlled, and double blind.
Because no treatment is approved for inactive SPMS, placebo was chosen as the comparator.
Patients receiving other treatments for SPMS or immunosuppressant will not be included.
The study will consist of the following phases:
Screening phase (about 4 weeks)
Treatment phase, patients will be randomized 1:1 ratio of either cladribine 1,8mg/kg or
placebo (30 weeks)
Follow-up phase , patients will be followed every 24 weeks for up to 122 weeks for
safety and efficacy of the treatment;
Patients: The group of 188 patients fulfilling inclusion criteria and not-fulfilling
exclusion criteria will enrolled to the study. All patient has to sign written informed
consent form approved by Ethics Committee.
Blinding: Randomization and blinding will be done by "dual assessor" approach . Every site
will have two teams of blinded and blinded investigators . The blinded investigators include
Principal or treating investigators and rating investigators, as well as blinded treating
nurse. The unblinded team includes: Randomizing investigator responsible also for laboratory
assessment and unblinded nurse/pharmacist responsible for preparing drugs.
Intervention:
Experimental arm Drug: Cladribine at a dose of 1.8 mg/kg of body weight. Cladribine will be
given subcutaneously over 6 visits every 5-6 weeks.
Comparator: Placebo matched to the subcutaneous injection of cladribine.
Follow-up: Patients will be assessed and baseline visit, and every 24 weeks over 24 months
since the last dose of the interventional drug. The evaluations include:
Medical history, concomitant medication, relapse history
Physical examination, neurological examination
Clinical assessment: EDSS, T25FWT, 9-HPT,
MsQoL and CSSR scale
MRI of head and spinal cord (baseline, every 6 months for head and every 12 months for
spinal cord)
Laboratory and biomarkers evaluation (hematology, coagulation, HIV serology, Hepatitis
virus B and C serology, tuberculosis tests (Quantiferron test if necessary), ,
The primary end point will be percentage brain volume change between the last dose (week 24)
and end of study (week 122). The primary endpoint was selected based on the widely discussed
indications for designing studies in the SPMS. The main secondary clinical end points will
assess the change in neurological function on the Expanded Disability Status Scale, Timed 25
Foot Walk, and 9-Hole Peg Test, which measures upper limb function. The change in cognitive
function will be assessed with various neuropsychological tests. The main secondary
neuroimaging end points will include change in the number of contrast-enhancing lesions, the
number of T1-hypointesne lesions ("black holes"), and the volume of T2 lesions. The main
exploratory end point will be the change in QSM rim+ lesions on brain neuroimaging; these
lesions are markers of chronic, smoldering neuroinflammation that may take place behind an
intact blood-brain barrier. Change in the concentrations of neurofilament light chain and
glial fibrillary acidic protein, which are markers of brain tissue damage, will be main
laboratory end points. An exploratory analysis of inflammatory protein biomarkers will be
carried out in serum and cerebrospinal fluid of a selected patients (Luminex). The study will
assess the safety of cladribine and its effect on quality of life.
The proposed intervention is well supported by the current evidence. Cladribine is among the
few drugs that penetrate an intact blood-brain barrier, which allows action on lymphocytes
resident in the central nervous system. The study will assess whether cladribine slows down
disease progression clinically and it will use the best currently available indicators of
disease progression: brain and cervical cord atrophy and the number of demyelinating lesions.
Additionally, it will be assessed whether the presence of QSM rim+ lesions is associated with
disease course and the therapeutic effect of cladribine. For example, a reduction in the
number of these lesions during cladribine treatment would supports an action of the drug
behind the blood-brain barrier. An association between QSM rim+ lesions and the therapeutic
effect of cladribine could help select a subgroup of patients most likely to benefit from
anti-inflammatory treatments. The measurement of serum biomarkers will enable an assessment
of the activation of the peripheral immune system (cytokine, chemokines) and of the
therapeutic effect of cladribine (NfL, GFAP). The positive results of the current project
will allow the design of a phase 3 trial. A practical benefit of the proposed study is that
patients with SPSM, who are currently not eligible for any treatment options, will have a
choice to receive a potentially effective therapy, which costs substantially less compared to
other therapies in MS.
Background: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating
disease of the central nervous system, with about 2.5 million patients worldwide, including
45 thousand in Poland. Most patients have relapsing-remitting MS (RRMS) at the start of the
disease, in which neurological symptoms appear during relapses and may subside. There is a
dozen of disease-modifying treatments for this form of the disease. Several years after the
diagnosis of RRMS, the disease progresses into SPMS, in which disability worsens gradually
independently of relapses. Patients with SPMS suffer from restricted mobility (need walking
aids, wheelchair), cognitive impairment, (difficulties in workplace and in managing everyday
life), depression, pain due to spasticity, chronic fatigue, lack of sphincter control, or
sexual dysfunction. These patients need more medical help (office visits, rehabilitation,
hospitalization), are more often unemployed, and have a lower quality of life than do
patients with RRMS. Currently, three disease-modifying treatments are available for patients
with SPMS in Europe: interferon beta-1b (low efficacy), mitoxantrone (serious adverse
effects), and siponimod. However, these medications can be used only in patients with active
disease, i.e., in those with still observed relapses or active brain lesions on magnetic
resonance imaging. Therefore, about a half of patients with SPMS cannot receive any
disease-modifying treatment. The current understanding of the pathogenesis of MS suggests
that there are two types of neuroinflammation since disease onset. Type-1 neuroinflammation
is characterized by an acute, focal infiltration of pathogenic lymphocytes and
autoantibodies, which is associated with blood-brain barrier disruption. This type of
neuroinflammation may be responsible for relapses and contrast-enhancing lesions. Type-2
neuroinflammation is a chronic, smoldering process that takes place behind a closed
blood-brain barrier, and it is characterized by slowly expanding lesions and follicle-like
lymph structures in the meninges, and diffuse inflammatory changes in white matter and
cortex. Other characteristics of type-2 neuroinflammation include microglial and astroglial
activation, delayed maturation of oligodendrocytes, and inhibition of remyelination. These
processes cause disease progression independently of relapses. Both types of
neuroinflammation occur simultaneously since disease onset, but type-2 neuroinflammation is
thought to predominate in the secondary progressive phase. Standard neuroimaging methods
cannot pinpoint lesions that are specific for type 2 neuroinflammation, but longitudinal
brain atrophy and enlargement of lesions can indirectly measure its magnitude. Quantitative
susceptibility mapping (QSM), a new imaging technique, can indicate chronic inflammatory
lesions that are surrounded by active microglia at the lesion border. Microglia because of
iron load form a hypointense rim, and might be thus shown by QSM technique (rim+ lesions).
However, QSM is not currently used in clinical practice it is now recommended for use in
clinical trials.
The currently available disease modifying-treatments for SPMS act solely or mainly on type-1
neuroinflammation, and because of that they are approved for patients with relapses or active
lesions only. Cladribine is approved for the treatment of RRMS. Cladribine substantially
decreases the number of contrast-enhancing lesions and relapse frequency in patients with
RRMS (an effect on type-1 neuroinflammation). Cladribine may also act on type-2
neuroinflammation i.e. on the autoreactive lymphocytes resident in the central nervous
system, including tertiary lymphoid structures, because cladribine penetrates into the
central nervous system through an intact blood-brain barrier. The effect on type-2
neuroinflammation is supported by the observation that oligoclonal bands disappear in
patients with RRMS and SPMS after cladribine treatment.