Clinical trial NCT01999192: Study to Investigate the Safety and Efficacy of Tregalizumab in Subjects (MTX-IR) With Active Rheumatoid Arthritis
Official title: A 24-week Phase IIb, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Investigate the Efficacy and Safety of Tregalizumab (BT061) in Combination With Methotrexate in the Treatment of Subjects With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Alone, Followed by a 24-week Extension Phase: T Cell REgulating Arthritis Trial 2b (TREAT 2b)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: inadequate response to MTX
Methotrexate
rheumatoid Arthritis
Phase 2b
Lead sponsor: Biotest
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
First posted: 2013-12-03
Enrollment: 321
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the efficacy and safety of three different Tregalizumab doses in combination with Methotrexate (MTX) in subjects who have active rheumatoid arthritis and an inadequate response to MTX alone.

The overall study duration is 24 weeks followed by a 24 week extension phase.

Detailed description: The planned clinical study 986 (TREAT 2b) is a 24-week study in patients with Active rheumatoid arthritis (RA) who have had an inadequate response to Methotrexate (MTX) alone. The main phase of this study is followed by a 24-week extension phase for subjects meeting the respective entry criteria. Patients will be randomized to one of three different Active treatment groups or Placebo. The primary efficacy variable is the proportion of subjects with an ACR20 response after 12 weeks of double blinded treatment with the study medication based on observed cases in the FAS.

At Week 12, all subjects who had a minimum improvement of at least 20% (from baseline) in their tender joint count (TJC) and swollen joint count (SJC) continued on the same treatment. Subjects who had not demonstrated an improvement of at least 20% of TJC and SJC were assessed as non-responders. Non-responders who received placebo were randomized to an active treatment dose in a blinded manner. Non-responders who received active treatment were rolled up to the next highest dose in a blinded manner, apart from those already on the highest dose. These subjects remained on the highest dose.

Eligibility criteria: Inclusion Criteria:

1. Subject demonstrates active RA according to the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA with functional class I-III for ≥6 months.
2. Subject receives oral or parenteral MTX treatment for ≥12 weeks (overall), with an unchanged mode of application and stable MTX dose of ≥15 mg per week (or ≥12.5 mg per week in case of MTX intolerance), but no more than the highest locally approved dose for RA, for ≥8 weeks prior to baseline. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for safety reasons. If applicable, the dose of folic acid must be unchanged for ≥8 weeks prior to baseline.
3. Subject meets the following two criteria at both screening and baseline: - At least 6 swollen joints at 28-joint assessment. - At least 6 tender joints at 28-joint assessment.
4. Subject has an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) above the upper limit of normal (ULN) at screening. These tests may be repeated once during the screening period at the discretion of the investigator.
5. Subject is ≥18 and ≤75 years of age.
6. Subject has a body mass index ≥18 and ≤35 kg/m².
7. Subject receives treatment with corticosteroids ≤10 mg prednisone equivalent, stable for at least 4 weeks prior to baseline and during the study, if applicable.
8. Subject receives treatment with non-steroidal anti-inflammatory drugs (NSAIDs), stable for at least 2 weeks prior to baseline and during the study, if applicable.
9. Female subjects of childbearing potential: has both a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.
10. Subject is judged to be in good general health as determined by the investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (within 3 months before screening date is acceptable), and 12-lead electrocardiogram (ECG).
11. Subject has a cluster of differentiation 4 (CD4) cell count of \> 400/µl at screening.

Exclusion Criteria:

1. Subject has previous exposure to any systemic biologic therapy (e.g., etanercept, adalimumab, rituximab, abatacept, tocilizumab), to Janus kinase (JAK) or spleen tyrosine kinase (SYK) inhibitors, or to Tregalizumab. Previous treatment with an anti-TNF agent is allowed only, if all of the following criteria apply: - treatment was stopped for reasons other than lack of efficacy or adverse events (AEs) - treatment was stopped at least 12 weeks or five half-lives of the compound prior to baseline (whichever is longer), and - the treatment period did not exceed 6 weeks.
2. Subject received treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) apart from MTX in the 12 weeks prior to baseline, and for DMARD leflunomide in the 24 weeks prior to baseline (except where specific leflunomide wash-out procedures were completed, following applicable guidelines).
3. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the 4 weeks prior to baseline. Inhaled corticosteroids for stable medical conditions are allowed.
4. Subject has undergone joint surgery in the 12 weeks prior to baseline (at joints to be assessed within the study) or has undergone major surgery (e.g., abdominal surgery) in the 8 weeks prior to baseline.
5. Subject has a history of acute inflammatory joint disease of an origin other than RA or subject has any other rheumatic disease other than RA (e.g., mixed connective tissue disease, seronegative spondylarthropathy, psoriatic arthritis, Reiter's syndrome, fibromyalgia, systemic lupus erythematosus or any arthritis with onset prior to age 17 years). However, subjects may have secondary Sjögren's syndrome.

Primary outcomes:
measure: The Proportion of Subjects Who Achieve an ACR20 at Week 12 Following Treatment With Tregalizumab + MTX Compared With Subjects Treated on Placebo + MTX
timeFrame: Week 12
Secondary outcomes:
measure: Proportions of Subjects With an ACR 20 Response.
timeFrame: Week 24
measure: Proportions of Subjects With an ACR 50 & 70 Response.
timeFrame: Week 12 & Week 24
measure: Proportions of Subjects With an Disease Activity Score DAS28 <2.6
timeFrame: Week 12 & Week 24
measure: Proportions of Subjects With Low Disease Activity DAS28 ≤3.2
timeFrame: Week 12 & Week 24
measure: ACR Score
timeFrame: up to 48 weeks
measure: Simple Disease Activity Index [SDAI] ≤11
timeFrame: week 12 & 24
measure: Clinical Disease Activity Index [CDAI] ≤10
timeFrame: week 12 & 24
measure: DAS28
timeFrame: up to 48 weeks
measure: EULAR Response
timeFrame: up to 48 weeks
measure: ACR Score Individual Components
timeFrame: up to 48 weeks
measure: DAS28 Score Individual Components
timeFrame: up to 48 weeks
Other outcomes:
measure: Pharmacokinetics
timeFrame: up to 48 weeks
measure: Evaluation of Safety, Patient Reported Outcomes & Blood Tests.
timeFrame: up to 48 weeks
Locations:
city: Paradise Valley
country: United States
facility: Study Site 07
state: Arizona
city: Springfield
country: United States
facility: Study Site 01
state: Illinois
city: Lincoln
country: United States
facility: Study Site 03
state: Nebraska
city: Clifton
country: United States
facility: Study Site 02
state: New Jersey
city: North Charleston
country: United States
facility: Study Site 04
state: South Carolina
city: Jackson
country: United States
facility: Study Site 05
state: Tennessee
city: Houston
country: United States
facility: Study Site 09
state: Texas
city: Katy
country: United States
facility: Study Site 10
state: Texas
city: Plovdiv
country: Bulgaria
facility: Study Site 01
city: Plovdiv
country: Bulgaria
facility: Study Site 06
city: Sofia
country: Bulgaria
facility: Study Site 02
city: Sofia
country: Bulgaria
facility: Study Site 04
city: Sofia
country: Bulgaria
facility: Study Site 07
city: Stara Zagora
country: Bulgaria
facility: Study Site 05
city: Varna
country: Bulgaria
facility: Study Site 03
city: Rimouski
country: Canada
facility: Study Site 02
state: Quebec
city: St-Jérôme
country: Canada
facility: Study Site 01
state: Quebec
city: Bruntal
country: Czechia
facility: Study Site 03
city: Ostrava
country: Czechia
facility: Study Site 05
city: Praha
country: Czechia
facility: Study Site 01
city: Praha
country: Czechia
facility: Study Site 04
city: Praha
country: Czechia
facility: Study Site 08
city: Praha
country: Czechia
facility: Study Site 09
city: Uherske Hradiste
country: Czechia
facility: Study Site 02
city: Uherske Hradiste
country: Czechia
facility: Study Site 07
city: Zlin
country: Czechia
facility: Study Site 06
city: Tallinn
country: Estonia
facility: Study Site 01
city: Berlin
country: Germany
facility: Study Site 03
city: Frankfurt
country: Germany
facility: Study Site 04
city: Muenchen
country: Germany
facility: Study Site 06
city: Ratingen
country: Germany
facility: Study Site 02
city: Zerbst
country: Germany
facility: Study Site 01
city: Balatonfüred
country: Hungary
facility: Study Site 03
city: Budapest
country: Hungary
facility: Study Site 02
city: Budapest
country: Hungary
facility: Study Site 04
city: Budapest
country: Hungary
facility: Study Site 05
city: Gyula
country: Hungary
facility: Study Site 06
city: Veszprem
country: Hungary
facility: Study Site 01
city: Kaunas
country: Lithuania
facility: Study Site 01
city: Vilnus
country: Lithuania
facility: Study Site 02
city: Mexico
country: Mexico
facility: Study Site 05
state: Distrito Federal
city: Mexico
country: Mexico
facility: Study Site 08
state: Distrito Federal
city: Leon
country: Mexico
facility: Study Site 06
state: Guanajuato
city: Chihuahua
country: Mexico
facility: Study Site 02
city: Distrito Federal
country: Mexico
facility: Study Site 03
city: Bialystok
country: Poland
facility: Study Site 08
city: Bydgoszcz
country: Poland
facility: Study Site 05
city: Elblag
country: Poland
facility: Study Site 10
city: Gdynia
country: Poland
facility: Study Site 04
city: Katowice
country: Poland
facility: Study Site 02
city: Krakow
country: Poland
facility: Study Site 03
city: Krakow
country: Poland
facility: Study Site 06
city: Poznan
country: Poland
facility: Study Site 09
city: Warszawa
country: Poland
facility: Study Site 01
city: Warszawa
country: Poland
facility: Study Site 07
city: Kemerovo
country: Russian Federation
facility: Study Site 08
city: Kemerovo
country: Russian Federation
facility: Study Site 11
city: Kursk
country: Russian Federation
facility: Study Site 04
city: Moscow
country: Russian Federation
facility: Study Site 03
city: Moscow
country: Russian Federation
facility: Study Site 07
city: Moscow
country: Russian Federation
facility: Study Site 10
city: Omsk
country: Russian Federation
facility: Study Site 05
city: Saratov
country: Russian Federation
facility: Study Site 09
city: Smolensk
country: Russian Federation
facility: Study Site 06
city: Tomsk
country: Russian Federation
facility: Study Site 01
city: Yaroslavl
country: Russian Federation
facility: Study Site 02
city: Belgrade
country: Serbia
facility: Study Site 01
city: Belgrade
country: Serbia
facility: Study Site 02
city: Belgrade
country: Serbia
facility: Study Site 04
city: Niska Banja
country: Serbia
facility: Study Site 03
city: Bratislava
country: Slovakia
facility: Study Site 03
city: Kosice - Saca
country: Slovakia
facility: Study Site 04
city: Lucenec
country: Slovakia
facility: Study Site 05
city: Povazska Bystrica
country: Slovakia
facility: Study Site 02
city: Rimavska Sobota
country: Slovakia
facility: Study Site 01
city: Donetsk
country: Ukraine
facility: Study Site 08
city: Kharkiv
country: Ukraine
facility: Study Site 01
city: Kharkiv
country: Ukraine
facility: Study Site 02
city: Kyiv
country: Ukraine
facility: Study Site 03
city: Kyiv
country: Ukraine
facility: Study Site 04
city: Vinnytsia
country: Ukraine
facility: Study Site 05
city: Vinnytsia
country: Ukraine
facility: Study Site 06
city: Vinnytsia
country: Ukraine
facility: Study Site 07
city: Zaporizhzhia
country: Ukraine
facility: Study Site 09
Study officials:
affiliation: Karolinska Universitetssjukhuset, Solna
name: Ronald van Vollenhoven, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Vollenhoven RF, Keystone EC, Strand V, Pacheco-Tena C, Vencovsky J, Behrens F, Racewicz A, Zipp D, Rharbaoui F, Wolter R, Knierim L, Schmeidl R, Zhou X, Aigner S, Dalken B, Wartenberg-Demand A; TREAT2b study team. Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase IIb, randomised, placebo-controlled trial. Ann Rheum Dis. 2018 Apr;77(4):495-499. doi: 10.1136/annrheumdis-2017-212478. Epub 2018 Jan 17.