Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03233230
• Date of registration: 25/07/2017
• Prospective Registration: Yes
• Primary sponsor: EMD Serono Research & Development Institute, Inc.
• Public title: Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis
• Scientific title: A Phase IIb, Randomized, Double-blind Study in Subjects With Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared With Placebo in Subjects With an Inadequate Response to Methotrexate
• Date of first enrolment: September 18, 2017
• Target sample size: 390
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03233230
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Argentina, Brazil, Bulgaria, Chile, Colombia, Czechia, Germany, Hungary, Mexico, Poland, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Ukraine, United States

Contacts

• Name: Medical Responsible
• Affiliation: EMD Serono Research & Development Institute, Inc.

Key inclusion & exclusion criteria

Inclusion Criteria:

- In Japan, if a participant is less than (<) 20 years, the written informed consent
from the participant's parent or guardian will be required in addition to the
participant's written consent.

- Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at
least 6 months duration prior to Screening

- Persistently active moderate to severe RA at both Screening and Randomization (if
significant surgical treatment of a joint has been performed, that joint cannot be
counted for entry or enrollment purposes), as defined by: >= 6 swollen joints (of 66
assessed) and >= 6 tender joints (of 68 assessed).

- An hsCRP >= 5.0 milligram/liter (mg/L) at Screening

- Treatment for >= 16 weeks with 7.5 to 25 mg/week Methotrexate (MTX) at a stable dose
and route of administration (oral or parenteral) for at least 8 weeks prior to dosing
with the Investigational Medicinal Product (IMP) and maintained throughout the trial

- For participants entering the trial on MTX doses < 15 mg/week (< 10 mg/week in Japan),
there must be clear documentation in the medical record that higher doses of MTX were
not tolerated or that the dose of MTX is the highest acceptable dose based on local
clinical practice guidelines.

- For MRI Sub-study participants, participants must have palpable synovitis of the wrist
and/or >= 1 of metacarpophalangeal joints 1 to 5, defined as loss of bony contours
with palpable joint effusion and/or swelling, in the MRI-designated hand (that is.,
the hand being used in MRI assessments).

Exclusion Criteria:

- ACR functional class IV as defined by the ACR classification of functional status or
wheelchair/bedbound

- Use of oral corticosteroids greater than (>) 10 mg daily prednisone equivalent, or
change in dose of corticosteroids within 2 weeks prior to Screening or during
Screening

- Use of injectable corticosteroids (including intra-articular corticosteroids) or
intra-articular hyaluronic acid within 4 weeks prior to Screening or during Screening

- Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs)
(including low-dose aspirin and cyclooxygenase-2 inhibitors) within 2 weeks prior to
dosing with the IMP

- High potency opioid analgesics are prohibited within 2 weeks prior to Screening and
during the trial; other analgesics are allowed (that is, acetaminophen, codeine,
hydrocodone*, propoxyphene*, or tramadol), although not within 24 hours of study
visits with clinical assessments (*not approved in Japan)

- Current or prior treatment with any of the following:

- Biologic Disease-modifying anti-rheumatic drugs (DMARDs) (approved or
investigational), including but not limited to:

- Tumor necrosis factor (TNF) antagonists or biosimilars of these agents (approved or
investigational), or any investigational TNF antagonist

- Interleukin-6 antagonists

- Abatacept (CTLA4-Fc)

- Anakinra* (IL-1 receptor antagonist) (*not approved in Japan)

- B cell-depleting antibodies (example, rituximab, ocrelizumab*, ofatumumab,
obinutuzumab*, ocaratuzumab*, veltuzumab*, or any biosimilars of these agents
[approved or investigational]) (*not approved in Japan)

- Anti-BLyS (B lymphocyte stimulator) agents (example, belimumab, tabalumab*) (*not
approved in Japan)

- Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (that is,
atacicept*, RCT-18*) (*not approved in Japan)

- Targeted synthetic DMARDs, specifically:

- Janus kinase inhibitors

- Other Bruton's tyrosine kinase (BTK) inhibitors

- Alkylating agents (example, chlorambucil*, cyclophosphamide) (*not approved in Japan).

- The following restrictions on nonbiologic DMARD must be followed:

- Auranofin (Ridaura), minocycline, penicillamine, sulfasalazine, cyclosporine,
mycophenolate (mycophenolate sodium not approved in Japan), tacrolimus, azathioprine:
must have been discontinued for 4 weeks prior to dosing with the IMP

- Leflunomide (Arava) must have been discontinued 12 weeks prior to dosing with the IMP
if no elimination procedure is followed. Alternately, it should have been discontinued
with the following elimination procedure at least 4 weeks prior to dosing with the
IMP:

- Cholestyramine at a dosage of 8 gram 3 times a day for at least 24 hours, or activated
charcoal at a dosage of 50 gram 4 times a day for at least 24 hours.

- Injectable Gold (aurothioglucose* or aurothiomalate): must have been discontinued for
8 weeks prior to dosing with the IMP (*not approved in Japan)

- Anti-malarials (hydroxychloroquine, chloroquine*) will be allowed in this trial.
Participants may be taking oral hydroxychloroquine (=< 400 mg/day) or chloroquine (=<
250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with
the IMP, and will need to be continued at that stable dose for the duration of the
trial. If discontinued prior to this trial, they must have been discontinued for 4
weeks prior to dosing with the IMP (*not approved in Japan).

- For MRI Substudy:

- Inability to comply with MRI scanning, including contraindications to MRI such as
known allergy to gadolinium contrast media, claustrophobia (if the site does not have
ability to scan extremities only), presence of a pacemaker, cochlear implants,
ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, and nerve
stimulators.

- More than 25% of applicable joints of the target hand and wrist having had prior
surgery or showing maximum Genant-modified Sharp erosion (3.0) or joint-space
narrowing (4.0) scores, based on single posteroanterior radiographs of target hand and
wrist read centrally.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis

Intervention(s)

Drug: M2951 75 mg QD

Drug: Placebo

Drug: M2591 25 mg QD

Drug: M2951 50 mg BID

Primary Outcome(s)

Percentage of Participants Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Time Frame: Week 12]

Secondary Outcome(s)

Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12 [Time Frame: Week 12]

Change From Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Time Frame: Baseline, Week 12]

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [Time Frame: up to Week 16]

Percent Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16 [Time Frame: Baseline, Week 2, 4, 8, 12 and 16]

Percent Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP) [Time Frame: Baseline, Week 12]

Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Time Frame: up to Week 16]

Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings [Time Frame: up to Week 16]

Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12 [Time Frame: Baseline, Week 12]

Percentage of Participants Achieving American College of Rheumatology 50% Response Criteria (ACR50) [Time Frame: Week 12]

Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters [Time Frame: up to Week 16]

Percentage of Participants Achieving American College of Rheumatology 70% Response Criteria (ACR70) [Time Frame: Week 12]

Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12 [Time Frame: Baseline, Week 12]

Percentage of Participants With Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Time Frame: Week 12]

Percentage of Participants With Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Time Frame: Week 12]

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12 [Time Frame: Baseline, Week 12]

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [Time Frame: up to Week 16]

Percent Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Time Frame: Baseline, Week 12]

Percent Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12 [Time Frame: Baseline, Week 12]

Percent Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in B Cell Count at Week 2, 4, 8, 12 and 16 [Time Frame: Baseline, Week 2, 4, 8, 12 and 16]

Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12 [Time Frame: Week 12]

Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12 [Time Frame: Baseline, Week 12]

Change From Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12 [Time Frame: Baseline, Week 12]

Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12 [Time Frame: Baseline, Week 12]

Percent Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12 [Time Frame: Baseline, Week 12]

Percentage of Participants With Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12 [Time Frame: Week 12]

Percentage of Participants With Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12 [Time Frame: Week 12]

Secondary ID(s)

MS200527-0060

2017-000384-32

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Merck KGaA, Darmstadt, Germany

Results

• Results available: Yes
• Date Posted: 28/09/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03233230