The goal of the fenebrutinib development program in MS is to evaluate the benefits and risks of fenebrutinib treatment across the spectrum of patients with MS. Based on the existing toxicology, pharmacology, and clinical experience with fenebrutinib…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy objective for this study is to evaluate the efficacy of
fenebrutinib compared with teriflunomide on the basis of the primary endpoint
of Annualized Relapse Rate (see Section 4.5.11 for protocol-defined relapse).
A detailed description of the primary estimands is provided in Sections 2.1.1
and 6.4.1.
Secondary outcome
The secondary efficacy objective for this study is to evaluate the efficacy of
fenebrutinib treatment compared with teriflunomide on the basis of the
following endpoints:
* Time to onset of composite 12-week confirmed disability progression (cCDP12),
defined as the time from baseline to the first occurrence of a progression
event according to at least one of the following three criteria; must be
confirmed at a regularly scheduled visit that is at least 12 weeks after the
initial disability progression:
- An increase from baseline in EDSS score of >=1.0 point in patients with
a baseline EDSS score of <= 5.5 or an increase of >= 0.5 points in
patients with a baseline EDSS score of > 5.5 (confirmed disability
progression [CDP])
- >= 20% increase from baseline in the T25FWT
- >= 20% increase from baseline in time to complete the 9-HPT
* Time to onset of 24-week CDP (CDP24)
* Total number of T1Gd+ lesions as detected by MRI
* Total number of new and/or enlarging T2-weighted lesions as detected by MRI
* Rate of percent change in total brain volume from Week 24 as assessed by MRI
* Change in patient-reported physical impacts of MS, as measured by the
Multiple Sclerosis Impact Scale (29-Item), Version 2 (MSIS-29 v2) physical
scale)
* Time to onset of 12-week confirmed 4-point worsening in Symbol Digit
Modalities Test (SDMT) score
* Change from baseline to Week 48 in the concentration of serum neurofilament
light chain (NfL)
The secondary endpoints above do not reflect order of statistical hierarchy.
Background summary
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and
degenerative disease of the CNS that affects approximately 900,000 people in
the United States (Wallin et al. 2019) and 2.3 million people worldwide (GBD
2016 Multiple Sclerosis Collaborators 2019).
Currently, the quantitative relationship between 90% inhibition of BTK and
proposed clinical endpoint (i.e., ARR) in MS is unknown. The role of BTK
inhibition in MS has been established by the results from two Phase II
randomized clinical trials, one study (NCT02975349) evaluated the safety and
efficacy of evobrutinib in patients with RMS (Clinicaltrials.gov 2016;
Montalban et al. 2019) and one study (NCT03889639) evaluated SAR442168 in
patients with RMS (Clinicaltrials.gov 2020; Sanofi Virtual Scientific Meeting
2020). Given the similar mechanism of action, the results of these Phase II
trials suggest that fenebrutinib will have a positive treatment effect on MS
pathophysiology and thus support further study of this BTK inhibitor
(fenebrutinib) in MS. See section 1 of the protocol.
Study objective
The goal of the fenebrutinib development program in MS is to evaluate the
benefits and risks of fenebrutinib treatment across the spectrum of patients
with MS. Based on the existing toxicology, pharmacology, and clinical
experience with fenebrutinib 200 mg BID in other autoimmune diseases combined
with the efficacy observed in patients with MS with other BTK inhibitors, the
potential effect on DA and progression biology together with the favorable
safety profile in other autoimmune indications provides a reasonable
expectation that evaluating fenebrutinib in patients with MS will result in a
favorable benefit-risk assessment.
Study design
Study GN41851 is a Phase III, randomized, multicenter, double-blind,
double-dummy, parallel-group study to evaluate the efficacy and safety of
fenebrutinib compared with teriflunomide in adult patients with RRMS and active
secondary progressive MS, collectively referred to as RMS. All eligible
patients will be randomized 1:1 through an interactive voice or web-based
response system (IxRS) to either one of two arms:
* Fenebrutinib treatment arm: fenebrutinib (200 mg by mouth [PO] BID) with
teriflunomide-matching placebo
* Teriflunomide treatment arm: teriflunomide (14 mg PO QD) with
fenebrutinib-matching placebo in a blinded fashion
Intervention
This study will consist of the following phases:
* Screening phase
* Double-blind treatment (DBT) phase
* Post-DBT*safety follow-up (post-DBT*SFU) phase
* Optional open-label extension (OLE) phase
* OLE safety follow-up (OLE-SFU) phase
Details for each study phase can be found in Sections 3.1.2, 3.1.3, 3.1.5, and
3.1.6. The study duration will vary for each patient as a result of the primary
analysis being event driven.
Double-blind treatment (DBT) phase:
Patients will either receive fenebrutinib 200 mg PO BID with
teriflunomide-matching placebo or to teriflunomide 14 mg PO QD with
fenebrutinib- matching placebo in the DBT phase. Every 2 weeks for the first 16
weeks, then every 4 weeks until week 24 and every 12 weeks thereafter patients
must visit the site. Semi-structured telephone interviews will be conducted
during the DBT phase every 6 weeks (+- 3 days) between study visits.
Study burden and risks
The general burden for the patient consists, among others things, coming to
hospital on regular basis (every 2 weeks first 16 weeks, then every 4 weeks
until week 24, after this every 12 weeks) and blood sampling (each visit) and
various test and interviews.
The patients need to take the drug daily and keep record of this. IMP may lead
to various adverse events.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
• Age 18-55 years
• Expanded Disability Status Scale score (EDSS) of 0.0-5.5 at screening
• A diagnosis of RMS in accordance with the revised 2017 McDonald Criteria
• Neurologically stable for at least 30 days prior to randomization and
baseline assessments
• Ability to complete the 9-HPT for each hand in < 240 seconds
• Ability to perform the timed 25-Foot Walk Test in < 150 seconds
• For women of childbearing potential: agreement to remain abstinent or use
contraception, and agreement to refrain from donating eggs, women must remain
abstinent or use contraceptive methods with a failure rate of < 1% per year
during the treatment period, for 8 weeks after the final dose of study
medication, and until the teriflunomide elimination protocol is completed
• For men: agreement to remain abstinent or use a condom, and agreement to
refrain from donating sperm, with a female partner of childbearing potential or
pregnant female partner, men must remain abstinent or use a condom during the
treatment phase, for 8 weeks after the final dose of study drug, and until
completion of the teriflunomide elimination protocol. Men must also refrain
from donating sperm during this same period.
See 4.1.1 of the protocol for all inclusion criteria
Exclusion criteria
• A diagnosis of PPMS or non-active SPMS
• Disease duration of > 10 years from the onset of symptoms and an EDSS score
at screening < 2.0
• Any known or suspected active infection at screening or baseline, or any
major episode of infection requiring hospitalization or treatment with IV
anti-microbials within 8 weeks prior to and during screening or treatment with
oral anti-microbials within 2 weeks prior to and during screening.
Onychomycosis is not exclusionary unless it is being treated with systemic
therapy.
• History of cancer including hematologic malignancy and solid tumors within 10
years of screening.
• Known presence of other neurological disorders that could interfere with the
diagnosis of MS or assessments of efficacy or safety during the study,
clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic,
endocrine, metabolic or gastrointestinal disease
• Any concomitant disease that may require chronic treatment with systemic
corticosteroids, immunosuppressants during the course of the study.
• History of alcohol or other drug abuse within 12 months prior to screening
• Any previous treatment with immunomodulatory or immunosuppressive medication
without an appropriate washout period
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to
randomization
• Female participants who are pregnant or breastfeeding or intending to become
pregnant during the study or 8 weeks (with accelerated teriflunomide
elimination procedure (ATEP)) after final dose of study drug
• Male participants intending to father a child during the study or 8 weeks
(with ATEP) after final dose of study drug
• Presence of cirrhosis (Child-Pugh Class C) or Gilbert's Syndrome
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 | EUCTR2019-004857-10-NL |
| ClinicalTrials.gov | NCT04586010 |
| CCMO | NL75413.056.20 |