Study to Investigate the Safety and Efficacy of Tregalizumab in Subjects (MTX-IR) With Active Rheumatoid Arthritis (986)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Tregalizumab; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria
    • Study site 01
  • Plovdiv, Bulgaria
    • Study site 06
  • Sofia, Bulgaria
    • Study site 02
  • Sofia, Bulgaria
    • Study site 04
  • Sofia, Bulgaria
    • Study Site 07
  • Stara Zagora, Bulgaria
    • Study site 05
  • Varna, Bulgaria
    • Study site 03
• Canada
  • Quebec
    • Rimouski, Quebec, Canada
      • Study site 02
    • St-Jérôme, Quebec, Canada
      • Study site 01
• Czechia
  • Bruntal, Czechia
    • Study site 03
  • Ostrava, Czechia
    • Study site 05
  • Praha, Czechia
    • Study site 01
  • Praha, Czechia
    • Study site 04
  • Praha, Czechia
    • Study Site 08
  • Praha, Czechia
    • Study site 09
  • Uherske Hradiste, Czechia
    • Study site 02
  • Uherske Hradiste, Czechia
    • Study Site 07
  • Zlin, Czechia
    • Study site 06
• Estonia
  • Tallinn, Estonia
    • Study site 01
• Germany
  • Berlin, Germany
    • Study site 03
  • Frankfurt, Germany
    • Study site 04
  • Muenchen, Germany
    • Study site 06
  • Ratingen, Germany
    • Study site 02
  • Zerbst, Germany
    • Study site 01
• Hungary
  • Balatonfüred, Hungary
    • Study site 03
  • Budapest, Hungary
    • Study site 02
  • Budapest, Hungary
    • Study site 04
  • Budapest, Hungary
    • Study site 05
  • Gyula, Hungary
    • Study site 06
  • Veszprem, Hungary
    • Study site 01
• Lithuania
  • Kaunas, Lithuania
    • Study site 01
  • Vilnus, Lithuania
    • Study site 02
• Mexico
  • Chihuahua, Mexico
    • Study site 02
  • Distrito Federal, Mexico
    • Study site 03
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico
      • Study site 05
    • Mexico, Distrito Federal, Mexico
      • Study Site 08
  • Guanajuato
    • Leon, Guanajuato, Mexico
      • Study site 06
• Poland
  • Bialystok, Poland
    • Study Site 08
  • Bydgoszcz, Poland
    • Study site 05
  • Elblag, Poland
    • Study site 10
  • Gdynia, Poland
    • Study site 04
  • Katowice, Poland
    • Study site 02
  • Krakow, Poland
    • Study site 03
  • Krakow, Poland
    • Study site 06
  • Poznan, Poland
    • Study site 09
  • Warszawa, Poland
    • Study site 01
  • Warszawa, Poland
    • Study Site 07
• Russian Federation
  • Kemerovo, Russian Federation
    • Study Site 08
  • Kemerovo, Russian Federation
    • Study site 11
  • Kursk, Russian Federation
    • Study site 04
  • Moscow, Russian Federation
    • Study site 03
  • Moscow, Russian Federation
    • Study Site 07
  • Moscow, Russian Federation
    • Study site 10
  • Omsk, Russian Federation
    • Study site 05
  • Saratov, Russian Federation
    • Study site 09
  • Smolensk, Russian Federation
    • Study site 06
  • Tomsk, Russian Federation
    • Study site 01
  • Yaroslavl, Russian Federation
    • Study site 02
• Serbia
  • Belgrade, Serbia
    • Study site 01
  • Belgrade, Serbia
    • Study site 02
  • Belgrade, Serbia
    • Study site 04
  • Niska Banja, Serbia
    • Study site 03
• Slovakia
  • Bratislava, Slovakia
    • Study site 03
  • Kosice - Saca, Slovakia
    • Study site 04
  • Lucenec, Slovakia
    • Study site 05
  • Povazska Bystrica, Slovakia
    • Study site 02
  • Rimavska Sobota, Slovakia
    • Study site 01
• Ukraine
  • Donetsk, Ukraine
    • Study Site 08
  • Kharkiv, Ukraine
    • Study site 01
  • Kharkiv, Ukraine
    • Study site 02
  • Kyiv, Ukraine
    • Study site 03
  • Kyiv, Ukraine
    • Study site 04
  • Vinnytsia, Ukraine
    • Study site 05
  • Vinnytsia, Ukraine
    • Study site 06
  • Vinnytsia, Ukraine
    • Study Site 07
  • Zaporizhzhia, Ukraine
    • Study site 09
• United States
  • Arizona
    • Paradise Valley, Arizona, United States, 85253
      • Study Site 07
  • Illinois
    • Springfield, Illinois, United States, 62704
      • Study site 01
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Study site 03
  • New Jersey
    • Clifton, New Jersey, United States, 07012
      • Study site 02
  • South Carolina
    • North Charleston, South Carolina, United States, 29406
      • Study site 04
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • Study site 05
  • Texas
    • Houston, Texas, United States, 77004
      • Study site 09
    • Katy, Texas, United States, 77450
      • Study site 10

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1 Tregalizumab; 25mg Tregalizumab s.c. weekly	Drug: Tregalizumab; humanized anti-CD4 mAb; Other Names: BT061
Experimental: Dose Level 2 Tregalizumab; 100mg Tregalizumab s.c. weekly	Drug: Tregalizumab; humanized anti-CD4 mAb; Other Names: BT061
Experimental: Dose Level 3 Tregalizumab; 200mg Tregalizumab s.c. weekly	Drug: Tregalizumab; humanized anti-CD4 mAb; Other Names: BT061
Placebo Comparator: Placebo; Placebo s.c. weekly	Drug: Placebo; identical end formulation buffer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Subjects Who Achieve an ACR20 at Week 12 Following Treatment With Tregalizumab + MTX Compared With Subjects Treated on Placebo + MTX	The primary efficacy variable was the proportion of subjects with an ACR20 response after 12 weeks of double-blind treatment with the study medication. The analysis of the primary endpoint was performed using observed cases (OC) on the FAS.	Week 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportions of Subjects With an ACR 20 Response.	Week 24
Proportions of Subjects With an ACR 50 & 70 Response.	Week 12 & Week 24
Proportions of Subjects With an Disease Activity Score DAS28 <2.6	Week 12 & Week 24
Proportions of Subjects With Low Disease Activity DAS28 ≤3.2	Week 12 & Week 24
ACR Score	up to 48 weeks
Simple Disease Activity Index [SDAI] ≤11	week 12 & 24
Clinical Disease Activity Index [CDAI] ≤10	week 12 & 24
DAS28	up to 48 weeks
EULAR Response	up to 48 weeks
ACR Score Individual Components	up to 48 weeks
DAS28 Score Individual Components	up to 48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics	AUC, Cmax, Tmax at baseline, and at Week (W) 2/Visit (V) 4, W4/V5, W8/V7, W12/V8, W24/V10, W3/V122, W48 (end of Treatment [EoT]/ early termination ET), and at follow-up (post EoT/post ET).	up to 48 weeks
Evaluation of Safety, Patient Reported Outcomes & Blood Tests.		up to 48 weeks

Collaborators and Investigators

• Sponsor: Biotest
• Collaborators: AbbVie
• Investigators: Principal Investigator: Ronald van Vollenhoven, Prof. MD, Karolinska Universitetssjukhuset, Solna

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: November 17, 2013
• First Submitted That Met QC Criteria: December 2, 2013
• First Posted (Estimate): December 3, 2013

Study Record Updates

• Last Update Posted (Actual): August 24, 2017
• Last Update Submitted That Met QC Criteria: July 25, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Methotrexate; Phase 2b; rheumatoid Arthritis; inadequate response to MTX
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: 986_TREAT 2b; 2013-000114-38 (EudraCT Number); BT986 (Other Identifier: Biotest AG)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO