Clinical Trials Register

Summary
EudraCT Number:	2020-002802-21
Sponsor's Protocol Code Number:	PRIMERA001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-20
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-002802-21

A.3

Full title of the trial

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

Behandeling op maat: Feit of fictie? – Een multicenter, enkelblind gerandomiseerd onderzoek waarin behandeling op maat wordt vergeleken met standaard zorg in nieuw gediagnosticeerde reumatoïde artritis patiënten.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Comparing the effectiveness of our tailor-made management approach with routine care from a clinical, patient’s as well as an economic point of view. Tailoring of treatment is done by taking the presence of autoantibodies and the quick response to glucocorticoids and JAK inhibitors into account.

Het vergelijken van de effectiviteit van behandeling op maat met de huidige standaard zorg, vanuit een klinisch oogpunt, patiënten- en economisch perspectief. bij nieuw gediagnosticeerde reumatoïde artritis patiënten. Individualisering van de behandeling wordt gedaan door rekening te houden met de aan- of afwezigheid van autoantistoffen en het vroege effect van glucocorticoïden en JAK inhibitoren op de ziekte-activiteit.

A.3.2

Name or abbreviated title of the trial where available

PRIMERA

A.4.1

Sponsor's protocol code number

PRIMERA001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Erasmus Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Galapagos N.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus Medical Center
B.5.2	Functional name of contact point	Pascal H.P. de Jong
B.5.3	Address:
B.5.3.1	Street Address	Dr. Molewaterplein 40
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 GD
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031653995477
B.5.6	E-mail	p.h.p.dejong@erasmusmc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Jyseleca
D.2.1.1.2	Name of the Marketing Authorisation holder	Galapagos N.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Filgotinib
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid arthritis according to 2010 criteria

Reumatoïde artritis volgens de 2010 classificatie criteria

E.1.1.1

Medical condition in easily understood language

Symmetrical (small) joint inflammation with or without auto-antibodies (i.e. rheumatoid factor and/or anti-citrullinated protein antibodies)

Gewrichtsontstekings aan meerdere (kleine) gewrichten met of zonder auto-antistoffen (reumafactor en/of anti-CCP)

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.1
E.1.2	Level	LLT
E.1.2	Classification code	10040107
E.1.2	Term	Seropositive rheumatoid arthritis
E.1.2	System Organ Class	100000004859

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.1
E.1.2	Level	LLT
E.1.2	Classification code	10062719
E.1.2	Term	Seronegative rheumatoid arthritis
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

E.2.2

Secondary objectives of the trial

To investigate if patient reported outcomes, i.e. Self-reported disease activity, functional ability, morning stiffness, general health, pain, fatigue, functional ability, quality of life, worker productivity and social participation, differ between both management approaches

To evaluate if patient satisfaction, compliance and patient participation is increased with our tailor-made management approach compared to routine care

To explore whether our tailor-made management approach can be more individualized by adding biomarker(s).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Newly diagnosed, DMARD-naive RA patients, according to 2010 criteria
- Age ≥18 years

E.4

Principal 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:
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.

4. Unable to understand, speak and write in Dutch.

E.5 End points

E.5.1

Primary end point(s)

The primary outcomes for the clinical effectiveness is a composite measure that 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 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, an 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. The DAS formula is 0.53938√(RAI) + 0.06465(SJC44) + 0.33ln(ESR) + 0.00722(GH). Thresholds for remission and moderate-to-high disease activity for DAS are respectively <1.6 and ≥2.4. Our tailor-made management approach is superior to routine care if treatment goals (DAS<2.4) 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.
For the cost-effectiveness analysis we will calculate the Quality Adjusted Life Years (QALYs) and total costs. QALYs express the impact of the disease on patients’ health over time. Living in perfect health corresponds to a QALY of 1, a QALY of 0 reflects death. QALYs are determined by calculating the area under the curve of dutch EuroQol questionnaire with 5 dimensions (EQ-5D) with 5 levels.
Costs are divided in direct and indirect costs. We will analyse direct and indirect costs from a societal perspective. Direct costs are the costs of treatment and medical consumption, whereas indirect costs are costs due to loss of productivity (i.e. presenteeism and absenteeism).
Medication costs are calculated from doses reported in the patients’ case records, valued according to the Dutch college of health insurances. Medical consumption, including duration of hospitalizations and admission diagnosis are recorded every three 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.
Indirect costs include not fully functioning, sick leave and reduction in work time. Worker productivity is measured with the Work Productivity and Activity Impairment (WPAI) questionnaire, which includes presenteeism and absenteeism. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be assessed every 3 months with additional visits at months 1,2 and 4. At each visit patients will fill out online questionnaires, including EQ-5D-5L, WPAI and medical consumption, and are seen by the research nurse, who calculates the DAS

E.5.2

Secondary end point(s)

For our secondary endpoints the effectiveness after 10 months and over time, from a clinical, patient and societal perspective, will be compared between our tailor-made management approach and routine care.

Clinical outcomes:
• Disease activity (states) at 10 months, measured with the DAS. 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, an 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. The DAS formula is 0.53938√(RAI) + 0.06465(SJC44) + 0.33ln(ESR) + 0.00722(GH). Thresholds for remission and moderate-to-high disease activity for DAS are respectively <1.6 and ≥2.4.
• To investigate whether (changes in) biomarker(s) (levels) can adequately predict treatment response. For this, blood (sera, plasma and whole blood) will be collected at the indicated time points and stored at -80C. 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. Total RNA will be isolated and transcriptomic analysis will be performed using RNA-seq. Moreover, the phenotype of immune cells will be analysed using multi-color flow cytometry on isolated PBMCs. For all three approaches (biomarkers, immune pathway analysis and immune cell phenotyping) the focus will be on comparing ACPA negative with positive and treatment responders with non-responders.

Patient reported outcomes (PROs):
• Self-reported disease activity, measured with the Routine Assessment of Patient Index Data 3 (RAPID3). Thresholds for remission and moderate-to-high disease activity are respectively <1.1 and ≥2 if the 0 - 10 scale is used.
• Morning stiffness (severity and duration), measured with a 10-point Likert scale
• General Health, measured with a visual analogue scale (VAS, 0 – 100 mm), whereby higher scores reflect greater severity.
• Fatigue, measured with a visual analogue scale (VAS, 0 – 100 mm), whereby higher scores reflect greater severity.
• Pain, measured with Generalized Pain Questionnaire(GPQ) and PainDetect. The GPQ differentiates between pain presumably due to central nervous system hypersensitization and pain primarily due to local nociception or inflammation. The PainDETECT is designed to identify neuropathic pain components and its score ranges between 1 and 38. A score <13 and >18 respectively reflects the absence and presence of a neuropathic pain component.
• Functional ability, measured with the health assessment questionnaire (HAQ). Higher HAQ scores indicate poorer function.
• Quality of life, measured with the Dutch EuroQol questionnaire with 5 dimensions (EQ-5D) with 5 levels. Higher scores represent a higher quality of life.
• 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 (SDM-Q9). The TSQM measure treatment satisfaction and covers 4 domains, namely effectiveness, side effects, convenience and global satisfaction. Higher TSQM scores correspond with more treatment satisfaction. The MARS-5 is a questionnaire in which the patient assess how often he/she is non-complaint. Higher MARS-5 scores indicate higher levels of self-reported adherence. The SDM-Q9 measures the patient perception of the extent of SDM.39 Higher SDM-Q9 scores indicate higher levels of perceived SDM.
• The Impact on Participation and Autonomy questionnaire (IPAQ) focuses on autonomy and participation of patients with chronic conditions. The IPAQ covers 5 domains, namely (1) autonomy indoors, (2) autonomy outdoors, (3) family roles, (4) social relationships and (5) paid work and education and in each domain the scores are averaged. Higher IPAQ-domain scores correspond with lower participation or more problems experienced.

Societal outcomes:
• Worker productivity, measured with the Work Productivity and Activity Impairment (WPAI) questionnaire, which includes presentism and absenteeism. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

E.5.2.1

Timepoint(s) of evaluation of this end point

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, 1 and 3 months and only at 2 and 4 months if DAS≥2.4 at the previous visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The date of the last visit of the last subject to complete the entire follow-up of the trial, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

240

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The total follow-up duration within the trial is 10 months, continuation of medication at the end of the trial is left to the discretion of the treating rheumatologist.

De behandelend reumatoloog bepaalt de behandeling als patiënt niet meer deelneemt aan het onderzoek.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-18

P. End of Trial
P.	End of Trial Status	Ongoing

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