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:
1. Screening phase (about 4 weeks)
2. Treatment phase, patients will be randomized 1:1 ratio of either cladribine 1,8mg/kg
or placebo (30 weeks)
3. 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:
1. Medical history, concomitant medication, relapse history. 2. Physical examination, neurological examination. 3. Clinical assessment: EDSS, T25FWT, 9-HPT,
4. MsQoL and CSSR scale. 5. MRI of head and spinal cord (baseline, every 6 months for head and every 12 months
for spinal cord)
6. 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.
