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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01709578




Registration number
NCT01709578
Ethics application status
Date submitted
15/10/2012
Date registered
18/10/2012
Date last updated
8/08/2017

Titles & IDs
Public title
To Evaluate The Effect Of SAR153191 (REGN88) Added To Other RA Drugs In Patients With RA Who Are Not Responding To Or Intolerant Of Anti-TNF Therapy (SARIL-RA-TARGET)
Scientific title
A Randomized, Double-blind, Parallel, Placebo-controlled Study Assessing the Efficacy and Safety of Sarilumab Added to Non-biologic DMARD Therapy in Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF-a Antagonists
Secondary ID [1] 0 0
U1111-1115-8466
Secondary ID [2] 0 0
EFC10832
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Osteoarthritis
Inflammatory and Immune System 0 0 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sarilumab
Treatment: Drugs - placebo
Treatment: Drugs - hydroxychloroquine
Treatment: Drugs - methotrexate
Treatment: Drugs - sulfasalazine
Treatment: Drugs - leflunomide

Placebo comparator: Placebo q2w - Placebo matched to sarilumab once every 2 weeks (q2w) was added to one or a combination of the nonbiologic DMARD (hydroxychloroquine, methotrexate, sulfasalazine and/or Leflunomide), except for simultaneous combination use of leflunomide and methotrexate for 24 weeks.

Experimental: Sarilumab 150 mg q2w - Sarilumab 150 mg q2w was added to one or a combination of the nonbiologic DMARD (hydroxychloroquine, methotrexate, sulfasalazine and/or Leflunomide), except for simultaneous combination use of leflunomide and methotrexate for 24 weeks.

Experimental: Sarilumab 200 mg q2w - Sarilumab 200 mg q2w was added to one or a combination of the nonbiologic DMARD (hydroxychloroquine, methotrexate, sulfasalazine and/or Leflunomide), except for simultaneous combination use of leflunomide and methotrexate for 24 weeks.


Treatment: Drugs: Sarilumab
Pharmaceutical form:solution Route of administration: subcutaneous

Treatment: Drugs: placebo
Pharmaceutical form:solution Route of administration: subcutaneous

Treatment: Drugs: hydroxychloroquine
Dispensed according to the local practice.

Treatment: Drugs: methotrexate
Dispensed according to the local practice.

Treatment: Drugs: sulfasalazine
Dispensed according to the local practice.

Treatment: Drugs: leflunomide
Dispensed according to the local practice.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants Who Achieved at Least 20% Improvement in the American College of Rheumatology (ACR20) Criteria at Week 24
Timepoint [1] 0 0
Week 24
Primary outcome [2] 0 0
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
Timepoint [2] 0 0
Baseline, Week 12
Secondary outcome [1] 0 0
Change From Baseline in Disease Activity Score for 28 Joints -C-Reactive Protein (DAS28--CRP) Score at Week 24
Timepoint [1] 0 0
Baseline, Week 24
Secondary outcome [2] 0 0
Percentage of Participants Achieving ACR50 Criteria at Week 24
Timepoint [2] 0 0
Week 24
Secondary outcome [3] 0 0
Percentage of Participants Achieving ACR70 Criteria at Week 24
Timepoint [3] 0 0
Week 24
Secondary outcome [4] 0 0
Percentage of Participants Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 24
Timepoint [4] 0 0
Week 24
Secondary outcome [5] 0 0
Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24
Timepoint [5] 0 0
Baseline, Week 24
Secondary outcome [6] 0 0
Change From Baseline in HAQ-DI at Week 24
Timepoint [6] 0 0
Baseline, Week 24
Secondary outcome [7] 0 0
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Component Summary Scores (PCS) at Week 24
Timepoint [7] 0 0
Baseline, Week 24
Secondary outcome [8] 0 0
Change From Baseline in SF-36 MCS at Week 24
Timepoint [8] 0 0
Baseline, Week 24
Secondary outcome [9] 0 0
Change From Baseline in the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) Score at Week 24
Timepoint [9] 0 0
Baseline, Week 24
Secondary outcome [10] 0 0
Change From Baseline in Morning Stiffness VAS at Week 24
Timepoint [10] 0 0
Baseline, Week 24
Secondary outcome [11] 0 0
Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to RA
Timepoint [11] 0 0
Baseline, Week 24
Secondary outcome [12] 0 0
Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by = 50% Due to RA
Timepoint [12] 0 0
Baseline, Week 24
Secondary outcome [13] 0 0
Change From Baseline in WPS-RA at Week 24: RA Interference With Work Productivity
Timepoint [13] 0 0
Baseline, Week 24
Secondary outcome [14] 0 0
Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to RA
Timepoint [14] 0 0
Baseline, Week 24
Secondary outcome [15] 0 0
Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by = 50% Due to RA
Timepoint [15] 0 0
Baseline, Week 24
Secondary outcome [16] 0 0
Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to RA
Timepoint [16] 0 0
Baseline, Week 24
Secondary outcome [17] 0 0
Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to RA
Timepoint [17] 0 0
Baseline, Week 24
Secondary outcome [18] 0 0
Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity
Timepoint [18] 0 0
Baseline, Week 24
Secondary outcome [19] 0 0
Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Scores at Week 24
Timepoint [19] 0 0
Baseline, Week 24
Secondary outcome [20] 0 0
Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) VAS Scores at Week 24
Timepoint [20] 0 0
Baseline, Week 24
Secondary outcome [21] 0 0
Percentage of Participants Achieving ACR20, ACR50 and ACR70 Criteria at Week 12
Timepoint [21] 0 0
Week 12
Secondary outcome [22] 0 0
Change From Baseline in DAS28-CRP at Week 12
Timepoint [22] 0 0
Baseline, Week 12
Secondary outcome [23] 0 0
Percentage of Participants Achieving Clinical Remission Score (DAS28--CRP <2.6) at Week 12
Timepoint [23] 0 0
Week 12
Secondary outcome [24] 0 0
Change From Baseline in SF-36 at Week 12
Timepoint [24] 0 0
Baseline, Week 12
Secondary outcome [25] 0 0
Change From Baseline in WPS-RA at Week 12: Work Days Missed Due to RA
Timepoint [25] 0 0
Baseline, Week 12
Secondary outcome [26] 0 0
Change From Baseline in WPS-RA at Week 12: Days With Work Productivity Reduced by = 50% Due to RA
Timepoint [26] 0 0
Baseline, Week 12
Secondary outcome [27] 0 0
Change From Baseline in WPS-RA at Week 12: RA Interference With Work Productivity
Timepoint [27] 0 0
Baseline, Week 12
Secondary outcome [28] 0 0
Change From Baseline in WPS-RA at Week 12: House Work Days Missed Due to RA
Timepoint [28] 0 0
Baseline, Week 12
Secondary outcome [29] 0 0
Change From Baseline in WPS-RA at Week 12: Days With Household Work Productivity Reduced by = 50% Due to RA
Timepoint [29] 0 0
Baseline, Week 12
Secondary outcome [30] 0 0
Change From Baseline in WPS-RA at Week 12: Days With Family/Social/Leisure Activities Missed Due to RA
Timepoint [30] 0 0
Baseline, Week 12
Secondary outcome [31] 0 0
Change From Baseline in WPS-RA at Week 12: Days With Outside Help Hired Due to RA
Timepoint [31] 0 0
Baseline, Week 12
Secondary outcome [32] 0 0
Change From Baseline in WPS-RA at Week 12: RA Interference With Household Work Productivity
Timepoint [32] 0 0
Baseline, Week 12
Secondary outcome [33] 0 0
Change From Baseline in the FACIT-fatigue at Week 12
Timepoint [33] 0 0
Baseline, Week 12
Secondary outcome [34] 0 0
Change From Baseline in EQ-5D-3L VAS Scores at Week 12
Timepoint [34] 0 0
Baseline, Week 12
Secondary outcome [35] 0 0
Change From Baseline in RAID Scores at Week 12
Timepoint [35] 0 0
Baseline, Week 12
Secondary outcome [36] 0 0
Change From Baseline in Individual ACR Components - TJC and SJC at Week 12 and Week 24
Timepoint [36] 0 0
Baseline, Week 12 and Week 24
Secondary outcome [37] 0 0
Change From Baseline in Individual ACR Component - Physician Global VAS, Participant Global VAS and Pain VAS at Week 12 and Week 24
Timepoint [37] 0 0
Baseline, Week 12 and Week 24
Secondary outcome [38] 0 0
Change From Baseline in Individual ACR Component - CRP Level at Week 12 and Week 24
Timepoint [38] 0 0
Baseline, Week 12 and Week 24
Secondary outcome [39] 0 0
Change From Baseline in Individual ACR Component - HAQ-DI at Week 12 and Week 24
Timepoint [39] 0 0
Baseline, Week 12 and Week 24

Eligibility
Key inclusion criteria
Inclusion criteria:

Diagnosis of RA =6 months duration, according to the ACR /European League against Rheumatism (EULAR) 2010 RA Classification Criteria

ACR Class I-III functional status, based on 1991 revised criteria

Anti-TNF therapy failures, defined by the investigator as participants with an inadequate clinical response, after being treated for at least 3 consecutive months, and/or intolerance to at least 1 anti-TNF blocker(s), resulting in or requiring their discontinuation:

* TNF-blockers included, but were not limited to, etanercept, infliximab, adalimumab, golimumab and/or certolizumab

Moderate-to-severely active RA

Continuous treatment with one or a combination of DMARDs (except for simultaneous combination use of leflunomide and methotrexate) for at least 12 weeks prior to baseline and on a stable dose(s) for at least 6 weeks prior to screening:

* Methotrexate - 6 to 25 mg/week orally or parenterally
* Leflunomide - 10 to 20 mg orally daily
* Sulfasalazine - 1000 to 3000 mg orally daily
* Hydroxychloroquine - 200 to 400 mg orally daily
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:

Participants <18 years of age or legal adult age

Past history of, or current, autoimmune or inflammatory systemic or localized joint disease(s) other than RA

History of juvenile idiopathic arthritis or arthritis onset prior to age 16

Severe active systemic RA, including but not limited to vasculitis, pulmonary fibrosis, and/or Felty's syndrome.

Treatment with anti-TNF agents, as follows:

* Within 28 days prior to the baseline visit - etanercept
* Within 42 days prior to the baseline visit - infliximab, adalimumab, golimumab, certolizumab pegol

Treatment with previous RA-directed biologic agents with other than TNF antagonist mechanisms:

Within 28 days prior to the randomization (baseline) visit - anakinra Within 42 days prior to the randomization (baseline) visit - abatacept

Within 6 months prior to the randomization (baseline) visit - any cell depleting agents including but not limited to rituximab without a normal lymphocyte and cluster of differentiation (CD) 19+ lymphocyte count

Treatment with any DMARD other than those allowed per protocol and limited to the maximum specified dosage within 12 weeks prior to baseline

Treatment with prednisone >10 mg or equivalent per day, or change in dosage within 4 weeks prior to baseline visit

Any parenteral or intra-articular glucocorticoid injection within 4 weeks prior to baseline

Prior treatment with anti-interleukin (IL) -6 or IL-6 receptor antagonist therapies, including tocilizumab or sarilumab, participation in a prior study of sarilumab, irrespective of treatment arm

Prior treatment with a Janus kinase inhibitor (such as tofacitinib)

New treatment or dose-adjustment to ongoing medication for dyslipidemia within 6 weeks prior to randomization, ie, stable dose for at least 6 weeks prior to randomization

Participation in any clinical research study evaluating another investigational drug or therapy within 5 half-lives or 60 days of first investigational medicinal product (IMP) administration, whichever was longer

History of alcohol or drug abuse within 5 years prior to the screening visit

Participants with a history of malignancy other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell or basal cell carcinoma of the skin, within 5 years prior to the randomization (baseline) visit. Nonmalignant lymphoproliferative disorders were also excluded

Participants with active tuberculosis or latent tuberculosis infection

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/03/2015
Sample size
Target
Accrual to date
Final
546
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Investigational Site Number 036014 - Victoria Park
Recruitment postcode(s) [1] 0 0
6100 - Victoria Park
Recruitment outside Australia
Country [1] 0 0
United States of America
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Alabama
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Colorado
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Florida
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Kentucky
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North Carolina
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South Carolina
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Tennessee
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Texas
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Washington
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West Virginia
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Caba
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Capital Federal
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Cordoba
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La Plata
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Argentina
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Ramos Mejia
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Rosario
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Argentina
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San Miguel De Tucuman
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Argentina
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Zarate
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Austria
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Stockerau
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Austria
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Wien
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Brazil
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Goiania
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Juiz De Fora
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Rio De Janeiro
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Canada
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Toronto
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Trois-Rivières
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Canada
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Victoria
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Chile
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Temuco
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Colombia
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Bogota
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Colombia
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Bogotá
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Bucaramanga
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Chia
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Medellin
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Hostivice
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Ostrava
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Praha 2
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Uherske Hradiste
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Zlin
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Cuenca
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Ecuador
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Quito
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Berlin
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Deggingen
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Erlangen
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Halle/Saale
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Osnabrück
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Tübingen
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Zerbst
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Greece
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Heraklion
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Greece
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Thessaloniki
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Guatemala
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Guatemala City
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Budapest
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Debrecen
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Israel
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Israel
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Tel Hashomer
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Italy
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Catania
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Italy
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Firenze
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Italy
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Genova
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Italy
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Milano
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Italy
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Udine
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Korea, Republic of
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Daejeon
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Korea, Republic of
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Seoul
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Lithuania
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Kaunas
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Lithuania
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Klaipeda
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Lithuania
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Vilnius
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Mexico
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Chihuahua
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Guadalajara
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Mexicali
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Monterrey
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México
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Queretaro
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Hamilton
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Nelson
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Otahuhu
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New Zealand
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Timaru
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New Zealand
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Wellington
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Peru
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Lima
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Bialystok
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Bydgoszcz
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Elblag
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Warszawa
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Lisboa
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Portugal
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Ponte De Lima
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Romania
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Bucuresti
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Romania
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Iasi
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Russian Federation
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Moscow
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Russian Federation
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Novosibirsk
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Russian Federation
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Saint-Petersburg
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Russian Federation
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Samara
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Slovakia
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Kosice
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Spain
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Barakaldo
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Spain
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Barcelona
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Spain
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Cadiz
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Spain
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La Coruña
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Spain
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Málaga
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Spain
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Sabadell
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Spain
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Santiago De Compostela
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Spain
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Sevilla
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Taiwan
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Kaohsiung
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Taiwan
State/province [123] 0 0
Taipei
Country [124] 0 0
Taiwan
State/province [124] 0 0
Taoyuan County
Country [125] 0 0
Turkey
State/province [125] 0 0
Edirne
Country [126] 0 0
Turkey
State/province [126] 0 0
Gaziantep
Country [127] 0 0
Turkey
State/province [127] 0 0
Samsun
Country [128] 0 0
Ukraine
State/province [128] 0 0
Kharkiv
Country [129] 0 0
Ukraine
State/province [129] 0 0
Kyiv
Country [130] 0 0
Ukraine
State/province [130] 0 0
Vinnytsia
Country [131] 0 0
Ukraine
State/province [131] 0 0
Zaporizhzhya

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Sanofi
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Regeneron Pharmaceuticals
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Primary Objective:

To demonstrate that sarilumab added to disease modifying anti-rheumatic drugs (DMARDs) were effective for:

* reduction of signs and symptoms at Week 24 and
* improvement of physical function at Week 12

in participants with active rheumatoid arthritis (RA) who were inadequate responders or intolerant to tumor necrosis factor alpha (TNF-a) antagonists.

Secondary Objectives:

The secondary objectives were to investigate the effects of SAR153191 (REGN88) when added to DMARD therapy, in participants with active RA who were inadequate responders or intolerant to TNF-a antagonists, for:

* Reduction of signs and symptoms at Week 12;
* Improvement in physical function at Week 24;
* Improvement in disease activity score as measured by other American College of Rheumatology (ACR) derived components at Weeks 12 and 24;
* Improvement in quality of life as measured by participant reported outcomes (PROs) at intermediate visits and Week 24.

To assess the exposure of sarilumab added to DMARD therapy in this population.

To assess the safety of sarilumab in this population.
Trial website
https://clinicaltrials.gov/study/NCT01709578
Trial related presentations / publications
Fleischmann R, van Adelsberg J, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, Graham NM, van Hoogstraten H, Bauer D, Burmester GR. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2017 Feb;69(2):277-290. doi: 10.1002/art.39944.
Rubbert-Roth A, Furst DE, Fiore S, Praestgaard A, Bykerk V, Bingham CO, Charles-Schoeman C, Burmester G. Association between low hemoglobin, clinical measures, and patient-reported outcomes in patients with rheumatoid arthritis: results from post hoc analyses of three phase III trials of sarilumab. Arthritis Res Ther. 2022 Aug 25;24(1):207. doi: 10.1186/s13075-022-02891-x.
Rehberg M, Giegerich C, Praestgaard A, van Hoogstraten H, Iglesias-Rodriguez M, Curtis JR, Gottenberg JE, Schwarting A, Castaneda S, Rubbert-Roth A, Choy EHS; MOBILITY, MONARCH, TARGET, and ASCERTAIN investigators. Identification of a Rule to Predict Response to Sarilumab in Patients with Rheumatoid Arthritis Using Machine Learning and Clinical Trial Data. Rheumatol Ther. 2021 Dec;8(4):1661-1675. doi: 10.1007/s40744-021-00361-5. Epub 2021 Sep 14. Erratum In: Rheumatol Ther. 2021 Dec;8(4):1921-1922. doi: 10.1007/s40744-021-00389-7.
Fleischmann R, Genovese MC, Maslova K, Leher H, Praestgaard A, Burmester GR. Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors. Rheumatology (Oxford). 2021 Nov 3;60(11):4991-5001. doi: 10.1093/rheumatology/keab355.
Genovese MC, Burmester GR, Hagino O, Thangavelu K, Iglesias-Rodriguez M, John GS, Gonzalez-Gay MA, Mandrup-Poulsen T, Fleischmann R. Interleukin-6 receptor blockade or TNFalpha inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials. Arthritis Res Ther. 2020 Sep 9;22(1):206. doi: 10.1186/s13075-020-02229-5.
Genovese MC, Fleischmann R, Kivitz A, Lee EB, van Hoogstraten H, Kimura T, St John G, Mangan EK, Burmester GR. Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis Res Ther. 2020 Jun 10;22(1):139. doi: 10.1186/s13075-020-02194-z.
Gossec L, Strand V, Proudfoot C, Chen CI, Guillonneau S, Kimura T, van Hoogstraten H, Mangan E, Reaney M. Effects of Sarilumab on Rheumatoid Arthritis as Reported by Patients Using the Rheumatoid Arthritis Impact of Disease Scale. J Rheumatol. 2019 Oct;46(10):1259-1267. doi: 10.3899/jrheum.180904. Epub 2019 Mar 15.
Gabay C, Msihid J, Zilberstein M, Paccard C, Lin Y, Graham NMH, Boyapati A. Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study. RMD Open. 2018 Mar 14;4(1):e000607. doi: 10.1136/rmdopen-2017-000607. eCollection 2018.
Strand V, Reaney M, Chen CI, Proudfoot CW, Guillonneau S, Bauer D, Mangan E, Graham NM, van Hoogstraten H, Lin Y, Pacheco-Tena C, Fleischmann R. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors. RMD Open. 2017 Mar 7;3(1):e000416. doi: 10.1136/rmdopen-2016-000416. eCollection 2017.
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Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01709578