Primary: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in nrSPMSSecondary: 1. To evaluate safety, tolerability, and efficacy of SAR442168 compared to placebo on clinical endpoints, MRI lesions,…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the time to onset of CDP (confirmed for at
least 6 months) assessed by the EDSS score.
Secondary outcome
The secondary endpoints from time to event will be analyzed in a similar manner
to the primary efficacy endpoint.
• Time to start of composite CDP
• Time to start of 3 months CDP
• Time to CDI
• Total number of new and / or growing hyperintense T2 lesions using MRI
• Percentage change in brain volume loss using MRI
• Change in cognitive function using the SDMT
• Change in the score on the "quality of life" questionnaire
• Adverse reactions (AEs), serious adverse events (SAEs), safety results on
MRI, and possible clinically significant abnormalities in laboratory results,
on electrocardiogram (ECG) or in vital signs during the study period.
Background summary
The Bruton's tyrosine kinase (BTK) pathway is critical for signaling in B
lymphocytes and myeloid cells including the central nervous system (CNS)
microglia. Each of these cell types is involved in the pathophysiology of
multiple sclerosis (MS).
SAR442168, a CNS penetrant BTK inhibitor, has the potential for a dual
mechanism of action by modulation and subsequently inhibition of
antigen-induced B cell activation responsible for inflammation and by
modulating macrophages and poorly adapted microglial cells linked to neuro
-inflammation in the brain and spinal cord.
Even the most recent high-efficiency disease modifying therapies primarily work
on adaptive immunity in the periphery with only a modest or temporary ability
to stop neuro-inflammatory and neurodegenerative processes and stop disease
progression
Chronic disability accumulation remains a significant, unfulfilled problem for
people with MS. Individuals with progressive disease, including secondary
progressive MS (SPMS), need treatment to reduce disability accumulation.The
recent approval of siponimod reflects the perception that this type of drug
reduced acute inflammatory activity rather than directly reducing "progression
independent of relapse activity (PIRA)".
In a phase 2 dose-finding study involving participants with relapsing MS (RMS)
(DRI15928), SAR442168 was shown to reach pharmacologically relevant
concentrations in cerebrospinal fluid (CSF) with the potential to inhibit
microgliocytes and infiltrating macrophages from the bone marrow, which are
believed to be responsible for stimulating neuro-inflammation linked to disease
progression.
Study objective
Primary: To determine the efficacy of SAR442168 compared to placebo in delaying
disability progression in nrSPMS
Secondary:
1. To evaluate safety, tolerability, and efficacy of SAR442168 compared to
placebo on clinical endpoints, MRI lesions, cognitive performance, physical
function, and quality of life
2. To evaluate the pharmacokinetics and pharmacodynamics of SAR442168.
Study design
A Phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel group,
multicenter, event-driven (6-month CDP) trial with a variable treatment
duration ranging from approximately 24 to 48 months in participants with
nrSPMS.
Intervention
Enrolled participants will be randomly assigned in a 2: 1 ratio to 60 mg oral
SAR442168 (obtained from dose determination study DRI15928) or placebo
corresponding daily.
Randomisation will be stratified for absence / presence of gadolinium (Gd)
enhancing T1 lesions at baseline (number of Gd enhancing lesions = 0 versus >=1)
and geographical origin (US versus non-US).
Study burden and risks
Risks related to blood sampling / MRI and side effects of the study drug and
contrast medium.
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
Inclusion criteria
*previous diagnosis of RRMS in accordance with the 2017 revised McDonald
criteria
*18 to 60 year old male or female with nrSPMS
*Demonstrated active disability progression since last year
*EDSS (at screening) of 3 (minimal disability) to 6.5 points (use of
intermittent or unilateral assistance to walk about 100 meters)
*Without:
-Relapse in last 24 months
-Recent use of MS treatments
*If female of childbearing potential:
--not pregnant or breastfeeding, and agrees to use acceptable contraceptive
method during the intervention period (at a minimum until after the last IMP
dose)
Exclusion criteria
-History of infection or at risk for infection
-Presence of psychiatric disturbance or substance abuse
-Excess bleeding risk or use of antiplatelets/anticoagulants
-Significant other concomitant illness/short life expectancy
-Confirmed laboratory or ECG abnormalities, during the screening visit, deemed
by the investigator to be clinically significant.
-Conditions that would adversely affect participation in study or make primary
efficacy endpoint
-Receiving strong inducers or inhibitors of cytochrome P450 3A (CYP3A) or
CYP2C8 hepatic enzymes
-Receiving anticoagulant/antiplatelet therapies
-Sensitivity to study interventions, or drug or other allergy that, per
Investigator, contraindicates participation in the study.
-Previously exposed to any BTK inhibitor, including SAR442168.
-Taken other investigational drugs within 3 months or 5 half-lives, whichever
is longer, before SCR.
-Contraindication for MRI (People with contraindication to gadolinium (Gd) can
be enrolled but cannot receive Gd during MRI scan.)
-Institutionalized because of regulatory or legal order; prisoners or
participants who are legally institutionalized.
-Any country-related regulation that would prevent entering the study, if
applicable.
-Not suitable for participation, whatever the reason, as judged by
Investigator, including medical or clinical conditions, or participants
potentially at risk of noncompliance to study procedures or not able to follow
protocol assessments
-Dependent on Sponsor or Investigator
-Employees of study site or directly involved in conduct of study, or immediate
family members of such individuals.
-Any other situation during study course that may raise ethics considerations.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000647-30-NL |
| CCMO | NL73813.029.20 |
| Other | U1111-1246-7768 |