Primary: To determine the efficacy of SAR442168 compared to a daily dose of 14 mgteriflunomide (Aubagio) in decreasing relapses in RMS.Secondary:1. To evaluate safety, tolerability, and efficacy of SAR442168 compared to placebo on clinical endpoints…
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 annualized adjudicated relapse rate(AARR).
Secondary outcome
The secondary endpoints from time to event will be analysed 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
The ability of SAR442168 to reduce formation of new, active brain lesions in MS
was assessed in a Phase 2b dose-finding trial in participants with RMS
(DRI15928). This radiographic outcome has been established as a highly reliable
predictive biomarker for clinical efficacy in pivotal studies in MS including
Phase 3 RMS studies.
Study objective
Primary: To determine the efficacy of SAR442168 compared to a daily dose of 14
mg
teriflunomide (Aubagio) in decreasing relapses in RMS.
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
This is a Phase 3, randomized, double-blind, double-dummy, 2-arm,
active-controlled, parallel
group, multicenter, event-driven (6-month CDP (confirmed disability
progression)) trial with a variable treatment duration ranging from
approximately 18 to 36 months in participants with RMS.
Intervention
Participants will be randomly assigned at a 1:1 ratio to receive the 60 mg
selected dose
(established from dose-finding Study DRI15928) of oral SAR442168 daily as well
as a placebo to
match the teriflunomide tablet, or 14 mg oral teriflunomide as well as a
placebo to match the
SAR442168 tablet daily. Randomization will be stratified by EDSS score at
screening (<4 versus >=4) and geographic region (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
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Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
Inclusion criteria
*18 to 55 year old male or female with RMS
*EDSS score of <= 5.5 points at screening
*At least 1 of the following prior to screening:
- >=1 documented relapse within the previous year OR
- >=2 documented relapses within the previous 2 years, OR
- >=1 documented Gd-enhancing brain lesion on an MRI scan within the previous
year.
*Without:
-PPMS diagnosis
-Significant infection/at increased infection risk
-Significant psychiatric disease or substance abuse
-Excess bleeding risk or use of antiplatelets/anticoagulants
-Recent use of MS treatments
-Significant other concomitant illness/short life expectancy
*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)
Note. The initial clinical demyelinating episode of MS should be counted as a
relapse for the
first 2 criteria.
Exclusion criteria
-Diagnose of PPMS
-History of infection or at risk for infection
-Presence of psychiatric disturbance or substance abuse
-Confirmed laboratory or ECG abnormalities, during the screening visit, deemed
by the investigator to be clinically significant.
-Conditions that may predispose the participant to excessive bleeding
-Conditions that would adversely affect participation in study or make primary
efficacy endpoint non-evaluable
-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.
-A relapse in the 30 days prior to randomization
-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
Medical products/devices used
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 | EUCTR2020-000644-55-NL |
| ClinicalTrials.gov | NCT04410978 |
| CCMO | NL74113.029.20 |