Clinical trial • Phase IV • Immunology

Methotrexate for Rheumatoid arthritis | Seropositive rheumatoid arthritis | Seronegative rheumatoid arthritis

Phase IV trial of Methotrexate for Rheumatoid arthritis | Seropositive rheumatoid arthritis | Seronegative rheumatoid arthritis.

Overview

Trial Therapeutic Area: Immunology
Trial Disease: Rheumatoid arthritis | Seropositive rheumatoid arthritis | Seronegative rheumatoid arthritis
Trial Stage: Phase IV
Drug Modality: Small molecule | Monoclonal antibody

Key dates

Initial CTIS Submission Date: 05-09-2024
First CTIS Authorization Date: 01-10-2024

Trial design

Randomised, open-label, two arms: routine care versus tailor-made approach. routine care initial therapy: methotrexate (mtx) + intramuscular glucocorticoids (gcs) once; intensification steps (if das≥2.4 every 3 months): (1) triple dmard therapy (mtx + sulfasalazine + hydroxychloroquine), (2) mtx + filgotinib, (3) mtx + tnf inhibitor, (4) mtx + 2nd tnf inhibitor. tailor-made approach initial therapy depends on autoantibody status: patients without autoantibodies receive hydroxychloroquine + intramuscular gcs; patients with autoantibodies start with mtx + intramuscular gcs. tailor-made approach allows medication alterations after 1 and 4 months depending on response (good response defined as das<2.4 or δdas>0.6).-controlled, adaptive Phase IV trial in Netherlands.

Randomised: Yes
Open Label: Yes
Comparator: Two arms: Routine care versus Tailor-made approach. Routine care initial therapy: methotrexate (MTX) + intramuscular glucocorticoids (GCs) once; intensification steps (if DAS≥2.4 every 3 months): (1) Triple DMARD therapy (MTX + sulfasalazine + hydroxychloroquine), (2) MTX + filgotinib, (3) MTX + TNF inhibitor, (4) MTX + 2nd TNF inhibitor. Tailor-made approach initial therapy depends on autoantibody status: patients without autoantibodies receive hydroxychloroquine + intramuscular GCs; patients with autoantibodies start with MTX + intramuscular GCs. Tailor-made approach allows medication alterations after 1 and 4 months depending on response (good response defined as DAS<2.4 OR ΔDAS>0.6).
Adaptive: True, treatment is adaptively adjusted according to disease activity (treat-to-target). Adaptive elements: intensification if DAS≥2.4; in the tailor-made arm additional early assessment/alteration at 1 and 4 months based on response (good response = DAS<2.4 OR ΔDAS>0.6).
Biomarker Stratified: True, biomarker: autoantibodies (presence vs absence) used to determine initial therapy strata
Target Sample Size: 300
Trial Duration For Participant: 304

Eligibility

Recruits 300 No vulnerable populations selected (isVulnerablePopulationSelected: false). Only adults (Age ≥18 years) are eligible. Informed consent is used (subject information and informed consent form document available: "L1_SIS and ICF PRIMERA trial"). Language requirement/exclusion: "Unable to understand, speak and write in Dutch.".

Pregnancy Exclusion: Pregnant or nursing (lactating) women
Vulnerable Population: No vulnerable populations selected (isVulnerablePopulationSelected: false). Only adults (Age ≥18 years) are eligible. Informed consent is used (subject information and informed consent form document available: "L1_SIS and ICF PRIMERA trial"). Language requirement/exclusion: "Unable to understand, speak and write in Dutch."

Inclusion criteria

{"criterion_text":"- Newly diagnosed, DMARD-naive RA patients, according to 2010 criteria\n- Age ≥18 years"}

Exclusion criteria

{"criterion_text":"- Current or previous treatment of arthritis with DMARDs\n- Glucocorticoids (GCs) in the 3 months prior to randomization\n- (Relative) contraindications for study medication: a. Evidence of ongoing infectious or malignant process obtained within 3 months prior to screening and evaluated by a qualified health care professional. b. Pregnant or nursing (lactating) women c. Female participants of child bearing potential and male participants whose partner is of child bearing potential who are not willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter as in standard practice. d. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests (LFT) such as aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/ serum glutamic pyruvic transaminase (ALT/SGPT), alkaline phosphatase, or serum bilirubin. The Investigator should be guided by the following criteria: Any single parameter may not exceed 2 x upper limit of normal (ULN). A single parameter elevated up to and including 2 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrollment/randomization, to rule out laboratory error. e. History of renal trauma, glomerulonephritis, or subjects with one kidney only, or a glomerular filtration rate (GFR) < 30 ml/min. f. Other underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions which in the opinion of the Investigator immunocompromises the patient and/or places the patient at unacceptable risk for participation in an immunomodulatory therapy.\n- Unable to understand, speak and write in Dutch."}

Endpoints

Primary endpoints

{"endpoint_text":"- The primary outcomes for the clinical effectiveness consists of 2 parts, namely the difference in (1) proportion of patients using a b- or tsDMARD after 10 months of treatment and (2) disease activity, measured with the disease activity score (DAS) over time. The primary outcome for the cost-effectiveness analysis will be the incremental cost-effectiveness ratio (ICER), which is the ratio of the difference in costs to incremental benefits between both management approaches.","definition_or_measurement_approach":"Part 1: Proportion of patients using a b- or tsDMARD after 10 months of treatment (binary proportion at 10 months). Part 2: Disease activity measured over time using the Disease Activity Score (DAS). Cost-effectiveness primary outcome: incremental cost-effectiveness ratio (ICER) = difference in costs divided by incremental benefits between management approaches."}

Secondary endpoints

{"endpoint_text":"- Disease activity (states) at 10 months, measured with the DAS.","definition_or_measurement_approach":"Disease activity states at 10 months measured using the Disease Activity Score (DAS)."}
{"endpoint_text":"- To investigate whether (changes in) biomarker(s) (levels) can adequately predict treatment response.","definition_or_measurement_approach":"Exploratory biomarker analysis assessing whether biomarker levels/changes predict treatment response (no specific biomarker assay detailed here)."}
{"endpoint_text":"- Self-reported disease activity, measured with the Routine Assessment of Patient Index Data 3 (RAPID3).","definition_or_measurement_approach":"Self-reported disease activity using RAPID3 questionnaire."}
{"endpoint_text":"- Morning stiffness (severity and duration), measured with a 10-point Likert scale.","definition_or_measurement_approach":"Severity and duration of morning stiffness assessed on a 10-point Likert scale."}
{"endpoint_text":"- General Health, measured with a visual analogue scale (VAS, 0 – 100 mm)","definition_or_measurement_approach":"General health measured by VAS (0–100 mm)."}
{"endpoint_text":"- Fatigue, measured with a visual analogue scale (VAS, 0 – 100 mm)","definition_or_measurement_approach":"Fatigue measured by VAS (0–100 mm)."}
{"endpoint_text":"- Pain, measured with Generalized Pain Questionnaire(GPQ) and PainDetect.","definition_or_measurement_approach":"Pain assessed using GPQ and PainDetect instruments."}
{"endpoint_text":"- Functional ability, measured with the health assessment questionnaire (HAQ).","definition_or_measurement_approach":"Functional ability assessed by HAQ."}
{"endpoint_text":"- Quality of life, measured with the Dutch EuroQol questionnaire with 5 dimensions (EQ-5D) with 5 levels.","definition_or_measurement_approach":"Quality of life measured using EQ-5D-5L (Dutch version)."}
{"endpoint_text":"- Patient satisfaction, compliance and patient participation is respectively measured with the the Treatment Satisfaction Questionnaire for Medication (TSQM) and VAS, the Medication Adherence Report Scale (MARS-5) and the 9-Item Shared Decision Making Questionnaire (SDMQ9).","definition_or_measurement_approach":"Patient satisfaction: TSQM and VAS; compliance: MARS-5; patient participation: SDM-Q9."}
{"endpoint_text":"- The Impact on Participation and Autonomy questionnaire (IPAQ) focuses on autonomy and participation of patients with chronic conditions.","definition_or_measurement_approach":"Autonomy and participation assessed by the IPAQ instrument."}
{"endpoint_text":"- Worker productivity, measured with the Work Productivity and Activity Impairment (WPAI) questionnaire, which includes presentism and absenteeism.","definition_or_measurement_approach":"Worker productivity assessed using WPAI questionnaire (includes presenteeism and absenteeism measures)."}

Recruitment

Planned Sample Size: 300
Recruitment Window Months: 47
Consent Approach: Informed consent obtained from adult participants (≥18 years) using the provided Subject Information and Informed Consent Form (document "L1_SIS and ICF PRIMERA trial"). Participants must be able to understand, speak and write Dutch (exclusion: "Unable to understand, speak and write in Dutch."). No assent from minors (minors excluded by age ≥18 requirement).

Geography

Total Number Of Sites: 11
Total Number Of Participants: 300

Netherlands

Earliest CTIS Part Ii Submission Date: 13-09-2024
Latest Decision Or Authorization Date: 01-10-2024
Processing Time Days: 18
Number Of Sites: 11
Number Of Participants: 300

Sites

Site Name: Admiraal De Ruyter Ziekenhuis B.V.
Department Name: Rheumatology
Principal Investigator Name: J.H. van der Kaap
Principal Investigator Email: j.vanderkaap@adrz.nl
Contact Person Name: J.H. van der Kaap
Contact Person Email: j.vanderkaap@adrz.nl

Site Name: Sint Franciscus Vlietland Groep Stichting
Department Name: Rheumatology
Principal Investigator Name: L. Korswagen
Principal Investigator Email: l.korswagen@franciscus.nl
Contact Person Name: L. Korswagen
Contact Person Email: l.korswagen@franciscus.nl

Site Name: Medisch Spectrum Twente
Department Name: Rheumatology
Principal Investigator Name: H.E. Vonkeman
Principal Investigator Email: h.vonkeman@mst.nl
Contact Person Name: H.E. Vonkeman
Contact Person Email: h.vonkeman@mst.nl

Site Name: Leids Universitair Medisch Centrum (LUMC)
Department Name: Rheumatology
Principal Investigator Name: C.F. Allaart
Principal Investigator Email: c.f.allaart@lumc.nl
Contact Person Name: C.F. Allaart
Contact Person Email: c.f.allaart@lumc.nl

Site Name: Haga Hospital
Department Name: Rheumatology
Principal Investigator Name: Y.P.M. Goekoop-Ruiterman
Principal Investigator Email: y.ruiterman@hagaziekenhuis.nl
Contact Person Name: Y.P.M. Goekoop-Ruiterman
Contact Person Email: y.ruiterman@hagaziekenhuis.nl

Site Name: IJsselland Ziekenhuis
Department Name: Rheumatology
Principal Investigator Name: R.C. Padmos
Principal Investigator Email: r.padmos@erasmusmc.nl
Contact Person Name: R.C. Padmos
Contact Person Email: r.padmos@erasmusmc.nl

Site Name: Universitair Medisch Centrum Utrecht
Department Name: Rheumatology
Principal Investigator Name: J. Spierings
Principal Investigator Email: j.spierings@umcutrecht.nl
Contact Person Name: J. Spierings
Contact Person Email: j.spierings@umcutrecht.nl

Site Name: Amphia Hospital
Department Name: Rheumatology
Principal Investigator Name: P.A.J.M. Vos
Principal Investigator Email: pvos@amphia.nl
Contact Person Name: P.A.J.M. Vos
Contact Person Email: pvos@amphia.nl

Site Name: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Department Name: Rheumatology
Principal Investigator Name: Pascal de Jong
Principal Investigator Email: p.h.p.dejong@erasmusmc.nl
Contact Person Name: Pascal de Jong
Contact Person Email: p.h.p.dejong@erasmusmc.nl

Site Name: Maasstad Ziekenhuis Stichting
Department Name: Rheumatology
Principal Investigator Name: A. Willemze
Principal Investigator Email: WillemzeA@maasstadziekenhuis.nl
Contact Person Name: A. Willemze
Contact Person Email: WillemzeA@maasstadziekenhuis.nl

Site Name: Albert Schweitzer Ziekenhuis
Department Name: Rheumatology
Principal Investigator Name: I. Tchetverikov
Principal Investigator Email: i.tchetverikov@asz.nl
Contact Person Name: I. Tchetverikov
Contact Person Email: i.tchetverikov@asz.nl

Sponsor

Primary sponsor

Full Name: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Organisation Type: Hospital/Clinic/Other health care facility
Country Of Registered Address: Netherlands

Third parties

{"country":"","full_name":"Galapagos N.V.","duties_or_roles":"Source of monetary support","organisation_type":""}

Investigational products

Investigational Product Name: Methotrexate 2,5 mg film-coated tablets
Active Substance: Methotrexate
Modality: Small molecule
Routes Of Administration: ORAL
Route: ORAL
Authorisation Status: Authorised
Maximum Dose: 3.6 mg

Investigational Product Name: Simponi 50 mg solution for injection in pre-filled syringe.
Active Substance: Golimumab
Modality: Monoclonal antibody
Routes Of Administration: SUBCUTANEOUS INJECTION
Route: SUBCUTANEOUS INJECTION
Authorisation Status: Authorised
Maximum Dose: 3.6 mg

Investigational Product Name: Hydroxychloroquine sulfate 200mg film-coated Tablets
Active Substance: Hydroxychloroquine sulfate
Modality: Small molecule
Routes Of Administration: ORAL
Route: ORAL
Authorisation Status: Authorised
Maximum Dose: 400 mg

Investigational Product Name: Cimzia 200 mg solution for injection in pre-filled syringe
Active Substance: Certolizumab pegol
Modality: Monoclonal antibody
Routes Of Administration: SUBCUTANEOUS INJECTION
Route: SUBCUTANEOUS INJECTION
Authorisation Status: Authorised
Maximum Dose: 14.29 mg

Investigational Product Name: Depo-Medrol 80 mg/2 ml Injektionssuspension
Active Substance: Methylprednisolone acetate
Modality: Small molecule
Routes Of Administration: INTRAMUSCULAR INJECTION
Route: INTRAMUSCULAR INJECTION
Authorisation Status: Authorised
Maximum Dose: 120 mg

Investigational Product Name: Leflunomide Aurobindo 20 mg compresse rivestite con film
Active Substance: Leflunomide
Modality: Small molecule
Routes Of Administration: ORAL
Route: ORAL
Authorisation Status: Authorised
Maximum Dose: 20 mg

Investigational Product Name: Enbrel 50 mg solution for injection in pre-filled syringe
Active Substance: Etanercept
Modality: Monoclonal antibody
Routes Of Administration: SUBCUTANEOUS INJECTION
Route: SUBCUTANEOUS INJECTION
Authorisation Status: Authorised
Maximum Dose: 7.14 mg

Investigational Product Name: Humira 40 mg solution for injection in pre-filled syringe
Active Substance: Adalimumab
Modality: Monoclonal antibody
Routes Of Administration: SUBCUTANEOUS
Route: SUBCUTANEOUS
Authorisation Status: Authorised
Maximum Dose: 3 mg

Investigational Product Name: Sulfasalazine 500 mg Tablets
Active Substance: Sulfasalazine
Modality: Small molecule
Routes Of Administration: ORAL
Route: ORAL
Authorisation Status: Authorised
Maximum Dose: 2000 mg

Investigational Product Name: Jyseleca 200 mg film-coated tablets
Active Substance: Filgotinib
Modality: Small molecule
Routes Of Administration: ORAL
Route: ORAL
Authorisation Status: Authorised
Maximum Dose: 200 mg

Investigational Product Name: Kenacort-A 40, suspensie voor injectie 40 mg/ml
Active Substance: Triamcinolone acetonide
Modality: Small molecule
Routes Of Administration: INTRAMUSCULAR INJECTION
Route: INTRAMUSCULAR INJECTION
Authorisation Status: Authorised
Maximum Dose: 80 mg

Investigational Product Name: Remicade 100 mg powder for concentrate for solution for infusion.
Active Substance: Infliximab
Modality: Monoclonal antibody
Routes Of Administration: INTRAVENOUS
Route: INTRAVENOUS
Authorisation Status: Authorised
Maximum Dose: 5 mg/kg

Combination Treatment: Yes

Related trials

Other published trials that may interest you.