Condition category
Musculoskeletal Diseases
Date applied
09/06/2020
Date assigned
27/10/2020
Last edited
27/10/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Rheumatoid arthritis is a long-term condition that causes pain, swelling and stiffness in the joints. The condition usually affects the hands, feet and wrists. There may be periods where symptoms become worse, known as flare-ups or flares.
Current management recommendations still adopt a ‘one-size-fits-all’ treatment approach, where ideally individualized treatment, or personalized medicine, is preferred. The prerequisite for precision medicine is the ability to classify individuals into groups that differ in their response to a specific treatment, which for RA still needs to be unravelled. However, we do believe that it is nowadays possible to individualize RA management by taking into account the presence of autoantibodies and the quick response to treatments such as glucocorticoids and targeted synthetic (ts)DMARDs.
Therefore, the aim of this project is to compare the effectiveness of our tailor-made management approach with routine care from a clinical, patient’s as well as an economic point of view. In addition, we will investigate if our tailor-made management approach can be improved by adding biomarkers.

Who can participate?
Newly diagnosed, DMARD-naive, adult rheumatoid arthritis patients, according to the ACR/EULAR 2010 classification criteria

What does the study involve?
Patients will be assessed every 3 months with additional visits in month 1, 2 and 4.
Our tailor-made management approach is superior to routine care if treatment goals are attained faster without the use of more b- or tsDMARDs. 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.
Patients are randomized into routine care or our tailor-made approach.
Both management approaches use a treat-to-target strategy, aiming for low disease activity. In routine care medication can be intensified every 3 months, reflecting current daily practice.

What are the possible benefits and risks of participating?
All patients will receive active treatment for their recently diagnosed rheumatoid arthritis. Although all prescribed medication within this trial is approved and used according to label, patients can still experience side effects. Common side effects, which depend on the given medication, are pneumonia, sinusitis, pharyngitis, headache, abdominal pain, nausea, vomiting, anemia, leucopenia, neutropenia, elevated liver enzymes and injection site reactions.

Where is the study run from?
Erasmus Medical Center, Rotterdam (The Netherlands)

When is the study starting and how long is it expected to run for?
The trial will start in December 2020 and will run for 3 years

Who is funding the study?
Galapagos N.V. (Belgium)

Who is the main contact?
Dr. P.H.P. de Jong (p.h.p.dejong@erasmusmc.nl)

Trial website

Contact information

Type

Scientific

Primary contact

Dr Pascal de Jong

ORCID ID

http://orcid.org/0000-0001-6628-6222

Contact details

Dr. Molewaterplein 40
Rotterdam
3015 GD
Netherlands
+31 (0)653995477
p.h.p.dejong@erasmusmc.nl

Additional identifiers

EudraCT number

2020-002802-21

ClinicalTrials.gov number

Nil known

Protocol/serial number

PRIMERA001

Study information

Scientific title

PeRsonalIzed MEdicine in Rheumatoid Arthritis (PRIMERA trial): a multicenter, single-blinded, randomized controlled trial comparing usual care with a tailor-made approach

Acronym

PRIMERA

Study hypothesis

We hypothesize that treatment of RA can be individualized by taking into account the presence of autoantibodies and quick response to glucocorticoids and tsDMARDs. Therefore, the aims of this trial are:
1. To compare clinical effectiveness between our tailor-made management approach and routine care in newly diagnosed, DMARD naive, rheumatoid arthritis patients, by looking at:
a. Proportion of patients using a b- or tsDMARD after 9 months of treatment.
b. Disease Activity Score (DAS) over time
Noteworthy is the fact that our tailor-made management approach is only superior to routine care if treatment goals are attained faster without the use of more b- or tsDMARDs
2. To evaluate the cost-effectiveness of our tailor-made treatment approach versus routine care, by using the incremental cost-effectiveness ratio (ICER) as outcome, which is the ratio of the difference in costs to incremental benefits between both management approaches
3. To evaluate if patient participation, satisfaction and compliance is increased with our tailor-made management approach compared to routine care
4. To explore whether our tailor-made management approach can be more individualized by adding biomarker(s)

Ethics approval

Approval pending, Medisch Ethische Toetsings Commissie (METC) Erasmus Medical Center (Dr. Molenwaterplein 40, Rotterdam, 3015 GD, The Netherlands)

Study design

Multicenter single-blinded randomized controlled clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Rheumatoid arthritis

Intervention

In this trial the effectiveness of a tailor-made management approach is compared to routine care, from a clinical, patients as well as an economic point of view, in patients with rheumatoid arthritis (RA).

Patients are randomized into routine care or our tailor-made approach using minimisation randomization stratified for center, by an independent call center.

In routine care patients are initially treated with methotrexate(MTX) and glucocorticoids(GCs) once intramuscularly (im). The initial therapy of patients randomized to our tailor-made approach depends on the presence of autoantibodies. Patients without auto-antibodies will receive hydroxychloroquine(HCQ)+GCs im, while patients with auto-antibodies start with MTX+GCs im.

Both management approaches use a treat-to-target strategy, aiming for low disease activity (DAS<2.4). If DAS ≥2.4 treatment is intensified until the aforementioned target is reached. In routine care medication can be intensified every 3 months, reflecting current daily practice. The intensifications steps are in following order: (1) Triple DMARD therapy (TDT), consisting of MTX, sulfasalazine (SASP) and HCQ; (2) MTX + Filgotinib (FIL); (3) MTX + TNF inhibitor (TNFi); and (4) MTX + 2nd TNFi. In our tailor-made approach besides the possible 3 monthly treatment intensification, medication alterations can also occur after 1 month and 4months, depending on the response to respectively GCs im and filgotinib (FIL). A good response to GCs im and FIL after respectively 1 and 4 months is defined as a DAS <2.4 OR ΔDAS >0.6. The intensifications steps in the tailor-made management approach are the same as routine care.

The prescribed medication within this trial are all approved and used according to label. DMARD dosages are MTX 25 mg/week orally (week 1 15mg/week; week 2 20mg/week and week 3 and thereafter 25mg/week),SASP 2 g/day (week 1 500mg bid; week 2 500mg tid; and week 3 and thereafter 1000mg bid) and HCQ 400 mg/day. GCs are givenonce intramuscularly with either methylprednisolone 120mg or triamcinolone acetonide 80mg. Filgotinib is a once-daily oral therapy of 200mg. The TNFi, including adalimumab 40mg/2 weeks s.c; etanercept 50mg/week s.c; certolizumab pegol 200mg/2 weeks s.c(after loading doses of 400mg/2 weeks at week 0, 2 and 4).; golimumab 50mg/4 weeks s.c.; and infliximab 3-5mg/kg at week 0, 2and 6 and 8 weekly thereafter, is free of choice for the treating rheumatologist. Concurrent treatment with NSAIDs and intra-articular GC injections (maximum of 2 per 3 months) will be allowed during follow-up.

Intervention type

Drug

Phase

Phase III/IV

Drug names

csDMARDs
1. Methotrexate
2. Sulfasalazine
3. Hydroxychloroquine

tsDMARDs
4. Filgotinib

bDMARDs
5. Etanercept
6. Adalimumab
7. Certolizumab pegol
8. Golimumab
9. Infliximab

Others:
10. Glucocorticoids
11. NSAIDs (i.e. naproxen, diclofenac, ibuprofen)

Primary outcome measure

1. Clinical effectiveness:
1.1. Proportion of patients using a b- or tsDMARD after 10 months of treatment measured using patient records
1.2. Disease activity, measured with the disease activity score (DAS) every 3 months with additional visits at months 1,2 and 4. (The DAS is a pooled index that involves the incorporation of a graded 53-joint count for tenderness (Ritchie Articular Index, RAI), a 44-joint count for swelling, erythrocyte sedimentation rate (ESR) and general health (GH, measured with a VAS 0 - 100mm) into a formula to obtain a numerical indicator of disease activity)

2. Cost-effectiveness:
2.1. Quality Adjusted Life Years (QALYs). QALYs are determined by calculating the area under the curve of dutch EuroQol questionnaire with 5 dimensions (EQ-5D) every 3 months with additional visits at months 1, 2 and 4
2.2. Total costs divided into direct and indirect costs:
2.2.1. Direct costs: Medication costs are calculated from doses reported in the patients’ case records, valued according to the Dutch college of health insurance. Medical consumption, including duration of hospitalizations and admission diagnosis, are recorded every 3 months with the iMTA medical consumption questionnaire. We will use the Dutch average length of stay by diagnosis if the duration of hospitalization is unknown.
2.2.2. Worker productivity is measured with the WorkProductivity and Activity Impairment (WPAI) questionnaire at ???, which includes presenteeism and absenteeism. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

Secondary outcome measures

Patients will be assessed every 3 months with additional visits at months 1, 2 and 4. At each visit patients will fill out all abovementioned questionnaires online and are seen by the research nurse, who calculates the DAS. Additional blood samples will be taken at baseline and 1 month and only at 2, 3 and 4 months if DAS ≥2.4 at the previous visit.

1. Clinical outcomes:
1.1. Disease activity (states) at 10 months, measured with the DAS
1.2. Biomarker(s) (levels). Blood will be collected at the indicated time points and inflammation markers will be measured using the Olink inflammation panel (92 proteins). In addition, immune pathway analysis will be performed on whole blood using RNAseq analysis

2. Patient-reported outcomes (PROs):
2.1. Self-reported disease activity, measured with the Routine Assessment of Patient Index Data 3 (RAPID3)
2.2. Morning stiffness (severity and duration), measured with a 10-point Likert scale
2.3. General Health, measured with a visual analogue scale (VAS, 0 – 100 mm
2.4. Fatigue, measured with a visual analogue scale (VAS, 0 – 100 mm)
2.5. Pain, measured with a visual analogue scale (VAS, 0 – 100 mm)
2.6. Functional ability, measured with the health assessment questionnaire (HAQ)
2.7. Quality of life, measured with the 36-Item Short Form Health Survey(SF-36) and dutch EuroQol questionnaire with 5 dimensions (EQ-5D) with 5 levels
2.6. Patient satisfaction measured with the Treatment SatisfactionQuestionnaire for Medication (TSQM) and VAS
2.7. Compliance measured with the Medication Adherence Report Scale (MARS-5)
2.8. Patient participation measured with the 9-Item Shared Decision Making Questionnaire (SDM-Q9)
2.7. Patient participation and autonomy measured using the Impact on Participation and Autonomy questionnaire (IPAQ)

3. Societal outcomes
3.1. Worker productivity, measured with the Work Productivity and Activity Impairment (WPAI) questionnaire

Overall trial start date

09/12/2019

Overall trial end date

01/12/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Newly diagnosed, DMARD-naive RA patients, according to 2010 criteria
2. Between 18 and 80 years of age
3. Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter as in standard practice

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

300

Participant exclusion criteria

1. Current or previous treatment of arthritis with DMARDs
2. Glucocorticoids (GCs) in the 3 months prior to randomization
3. (Relative) contraindications for study medication:
3.1. Evidence of ongoing infectious or malignant process obtained within 3 months prior to screening and evaluated by a qualified health care professional
3.2. Pregnant or nursing (lactating) women
3.3. 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.
3.4. 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
3.5. History of renal trauma, glomerulonephritis, or subjects with one kidney only, or a glomerular filtration rate (GFR) < 30 ml/min.
3.6. 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
4. Unable to understand, speak and write in Dutch

Recruitment start date

01/12/2020

Recruitment end date

01/07/2022

Locations

Countries of recruitment

Netherlands

Trial participating centre

Erasmus Medical Center
Dr. Molewaterplein 40
Rotterdam
3015 GD
Netherlands

Trial participating centre

Leiden University Medical Center
Albinusdreef 2
Leiden
2333 ZA
Netherlands

Trial participating centre

Maasstad Hospital
Maasstadweg 21
Rotterdam
3079 DZ
Netherlands

Trial participating centre

Franciscus Gasthuis & Vlietland
Kleiweg 500
Rotterdam
3045 PM
Netherlands

Trial participating centre

Franciscus Gasthuis & Vlietland
Vlietlandplein 2
Schiedam
3118 JH
Netherlands

Trial participating centre

Albert Schweitzer Hospital
Albert Schweitzerplaats 25
Dordrecht
3318 AT
Netherlands

Trial participating centre

Amphia Hospital
Molengracht 21
Breda
4818 CK
Netherlands

Trial participating centre

IJsselland Hospital
Prins Constantijnweg 2
Capelle aan den IJssel
2906 ZC
Netherlands

Trial participating centre

Admiraal de Ruyter Hospital
's-Gravenpolderseweg 114
Goes
4462 RA
Netherlands

Trial participating centre

Medisch Spectrum Twente
Koningstraat 1
Enschede
7512 KZ
Netherlands

Sponsor information

Organisation

Erasmus University Medical Center

Sponsor details

Dr. Molewaterplein 40
Rotterdam
3015 GD
Netherlands
+31 107034264
r.dolhain@erasmusmc.nl

Sponsor type

Hospital/treatment centre

Website

https://www.erasmusmc.nl/en/research/departments/rheumatology

Funders

Funder type

Industry

Funder name

Galapagos N.V.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date.

Intention to publish date

01/07/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

21/09/2020: Trial’s existence confirmed by Erasmus University Medical Center.