Phase IIb in Rheumatoid Arthritis

• Register: EUCTR
• Last refreshed on: 31 August 2020
• Main ID: EUCTR2017-000384-32-BG
• Date of registration: 12/07/2017
• Prospective Registration: Yes
• Primary sponsor: Merck KGaA
• Public title: Phase IIb in 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 - N/A
• Date of first enrolment: 02/11/2017
• Target sample size: 363
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000384-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: yes; Other specify the comparator: Different dosage of IMP (25mg QD, 75 mg QD, 50 mg BID); Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Brazil, Bulgaria, Chile, Colombia, Czech Republic, Germany, Japan, Mexico, Poland, Russian Federation, Serbia, South Africa, Ukraine, United States

Contacts

• Name: Communication Center
• Affiliation: Merck KGaA

• Name: Communication Center
• Affiliation: Merck KGaA

Key inclusion & exclusion criteria

Inclusion criteria:
The current trial will enroll subjects who fulfill the following key inclusion criteria:
• Consenting male or female subjects, 18 to 75 years of age
• 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:
o = 6 swollen joints (of 66 assessed) and
o = 6 tender joints (of 68 assessed).
• An hsCRP = 5.0 mg/L (= 0.50 mg/dL) at Screening
• Treatment for = 16 weeks with 7.5 to 25 mg/week MTX at a stable dose and route of administration (oral or parenteral) for at least 8 weeks prior to dosing with the IMP and maintained throughout the trial
• For subjects entering the trial on MTX doses < 15 mg/week, 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.
MRI Substudy Subjects:
In addition to meeting the inclusion criteria for the study, subjects must have palpable synovitis of the wrist and/or = 1 of MCP joints #1 to #5, defined as loss of bony contours with palpable joint effusion and/or swelling, in the MRI-designated hand (i.e., the hand being used in MRI assessments).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 308
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 55

Exclusion criteria:
Subjects who fulfill any of the following key exclusion criteria should not be enrolled into this trial:
• ACR functional class IV as defined by the ACR classification of functional status or wheelchair/bedbound
• Use of oral corticosteroids > 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 COX-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 (e.g., acetaminophen, codeine, hydrocodone, propoxyphene, or tramadol), although not within 24 hours of study visits with clinical assessments.
• Current or prior treatment with ANY of the following:
o Biologic DMARDs (approved or investigational), including but not limited to:
-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)
- B cell-depleting antibodies (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab, ocaratuzumab, veltuzumab, or any biosimilars of these agents [approved or investigational])
- Anti-BLyS (B lymphocyte stimulator) agents (e.g., belimumab, tabalumab)
- Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (e.g., atacicept, RCT-18).
o Targeted synthetic DMARDs (approved or investigational), specifically:
- Janus kinase inhibitors
- Other Bruton’s tyrosine kinase (BTK) inhibitors
o Alkylating agents (e.g., chlorambucil, cyclophosphamide).
• The following restrictions on non-biologic DMARD must be followed, otherwise the subject is excluded:
o Auranofin (Ridaura®), minocycline, penicillamine, sulfasalazine, cyclosporine, mycophenolate, tacrolimus, azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP
o 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 g 3 times a day for at least 24 hours, or activated charcoal at a dosage of 50 g 4 times a day for at least 24 hours.
o Injectable Gold (aurothiglucose or aurothiomalate): must have been discontinued for 8 weeks prior to dosing with the IMP
o Anti-malarials (hydroxychloroquine, chloroquine) will be allowed in this trial. Subjects 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.
MRI Substudy Subjects:
• 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 cli

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Rheumatoid Arthritis
MedDRA version: 20.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Product Name: Evobrutinib
Product Code: M2951
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Evobrutinib
CAS Number: N/A
Current Sponsor code: M2951
Other descriptive name: M2951
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib compared with placebo in subjects with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR) on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by American College of Rheumatology (ACR) 20% (ACR20) response assessed using high-sensitivity C-reactive protein (hsCRP) at Week 12

Timepoint(s) of evaluation of this end point: Week 12

Secondary Objective: • To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by DAS28-hsCRP low disease activity (DAS28 < 3.2) rate at Week 12
• To further evaluate the efficacy of 12 weeks of treatment with evobrutinib compared to placebo in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by DAS28-hsCRP remission (DAS28 < 2.6) rate at Week 12
• To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by ACR50 and ACR70 at Week 12
• To evaluate the safety of evobrutinib in MTX-IR subjects with RA on stable MTX thera

Primary end point(s): Number of Subjects With ACR20 response assessed using hsCRP (ACR20-CRP)

Secondary Outcome(s)

Secondary end point(s): 1) Number of subjects With DAS28-hsCRP low disease activity (DAS28 < 3.2) rate
2) Number of subjects With DAS28-hsCRP remission (DAS28 < 2.6) rate
3) Number of subjects with ACR 50% (ACR50) response assessed using hsCRP (ACR50-CRP)
4) Number of subjects with ACR 70% (ACR70) response assessed using hsCRP (ACR70-CRP)
5) Nature, severity and Occurrences of Subjects With of AEs and serious AEs (SAEs)
6)Absolute value in vital signs
7) Absolute value in ECG parameters including RR interval, PR interval,
QRS duration, QT interval, and QTcF interval
8) Absolute value in Serum Ig levels (IgG, IgA, IgM)
9) Absolute value in Total B cell counts
10) Absolute value in Clinical laboratory parameters

Timepoint(s) of evaluation of this end point: 1-4:Week 12
5-10 Baseline up to Week 12

Secondary ID(s)

N/A

MS200527-0060

Source(s) of Monetary Support

EMD Serono Research & Development Institute, Inc.

Merck KGaA

Ethics review

Status: Approved
Approval date: 02/11/2017
Contact: