Clinical Trials Register

Summary
EudraCT Number:	2018-003432-72
Sponsor's Protocol Code Number:	DRESS-PS
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-09-13
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

2018-003432-72

A.3

Full title of the trial

Randomised controlled trial of dose reduction and withdrawal strategies of TNF inhibitors in Psoriatic Arthritis and Axial Spondyloarthritis.
“Dose REduction Strategy Study of TNF inhibitors in Psoriatic arthritis and axial Spondyloarthritis patients: DRESS-PS.”

“Onderzoek naar afbouw en stop behandelstrategieën van TNF remmers bij patiënten met artritis psoriatica en axiale spondylartritis”

A.3.1

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

Dose reduction and withdrawal of TNF inhibitors in patients with Psoriatic Arthritis and Axial Spondyloarthritis

Afbouwen en stoppen van TNF remmers bij patiënten met Artritis Psoriatica en Axiale Spondylartritis.

A.3.2

Name or abbreviated title of the trial where available

Dose reduction and withdrawal strategies of TNF inhibitors in PsA and axSpA.

Afbouw en stop behandelstrategieën van TNF remmers in PsA en axSpA.

A.4.1

Sponsor's protocol code number

DRESS-PS

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	Sint Maartenskliniek
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	Sint Maartenskliniek
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	Sint Maartenskliniek
B.5.2	Functional name of contact point	Alfons den Broeder
B.5.3	Address:
B.5.3.1	Street Address	Hengstdal 3
B.5.3.2	Town/ city	Ubbergen
B.5.3.3	Post code	6574 NA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031243659729
B.5.6	E-mail	A.denbroeder@maartenskliniek.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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	Tumor Necrosis Factor alpha (TNF-a) Inhibitors: Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie, Pfizer, MSD, UCB Pharma
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Adults diagnosed with Psoriatic Arthritis en Axial Spondyloarthritis.

Volwassenen gediagnosticeerd met artritis psoriatica en axiale spondylartritis.

E.1.1.1

Medical condition in easily understood language

Psoriatic arthritis and Axial Spondyloarthritis

Artritis psoriatica en axiale spondylartritis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of the study is to compare the proportion of patients with PsA and axSpA having LDA state for at least 6 months, at 12 months between usual care and dose reduction strategy against a prespecified non-inferiority margin In addition, a cost-effectiveness analysis will be performed to assess the cost effectiveness of dose reduction in comparison to usual care.

Het doel van deze studie is om het aantal patiënten met PsA en axSpA met een rustige ziekteactiviteit voor minstens 6 maanden, na 12 maanden tussen de afbouwstrategie en de standaardzorg groep te vergelijken, met een van tevoren vastgestelde non-inferioriteits marge Daarnaast zal een kosteneffectiviteitsanalyse verricht worden om de kosteneffectiviteit tussen de afbouwstrategie en standaardzorg groep te vergelijken.

E.2.2

Secondary objectives of the trial

- To determine the proportion of PsA and axSpA patients in the intervention group that can successfully reduce or discontinue TNFi use;
- To determine the change in PASDAS and ASDAS for each visit in both dose reduction and usual care groups;
- To determine the incidence of flare in both dose reduction and usual care groups;
- To determine the functioning in both groups;
- To determine the cost-effectiveness of dose reduction versus usual care;
- To determine the proportion of patients using NSAID, corticosteroid or cs/b/tsDMARD’s in both groups;
- To determine safety of dose reduction (adverse events and infections);
- To identify baseline factors which can predict successful and maintained dose reduction.

Vaststellen van:
- Het aantal PsA en axSpA patiënten in de interventiegroep die de TNF remmers succesvol kunnen afbouwen of stoppen;
- De verandering in PASDAS en ASDAS voor elke visit in zowel de reductiegroep en de standaardzorg groep;
- Het voorkomen/incidentie van flare in zowel de reductiegroep en de standaardzorg groep;
- Het functioneren in beide groepen;
- Het verschil in kosteneffectiviteit tussen de reductiegroep en de standaardzorg groep;
- Het aantal patiënten die NSAIDs, corticosteroïden of cs/b/tsDMARD’s in beide groepen;
- De veiligheid van het afbouwen van TNF remmers (bijwerkingen en infecties);
- Identificeren van baseline factoren die succesvol en behoud van afbouwen kunnen voorspellen.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients are > 18 years of age AND
- Fulfil the Classification Criteria for Psoriatic Arthritis (CASPAR) and have peripheral SpA of the psoriatic arthritis subtype diagnosed clinically by the rheumatologist and/or fulfil the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA AND
- Are using full dose, or at least > 50% of the authorized defmed daily dose (DDD), of an origmator or biosimilar TNFi (adalimumab, certolizumab, etanercept, golimumab, infliximab) AND
- Patients have to have stable LDA, Psoriatic Arthritis Disease Activity Score (PASDAS) s 3 2 and a skin measure of Body Surface Area mvolvement (modified BSA) using a target of 3% as used by rheumatologists in climcal practice for PsA and/or Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2 1 and an absence of active extra-articular symptoms such as Crohn’s disease, uveitis, colitis or psoriasis for axSpA, for at least 6 months, or when formal measurements are not available, judgement of physician and patiënt

- Patiënten zijn > 18 jaar EN
- Voldoen aan de classificatie criteria voor artritis psoriatica (CASPAR) en hebben perifere SpA, behorend bij artritis psoriatica, wat klinisch beoordeeld is door de reumatoloog en/of voldoen aan de Assessment of SpondyloArthritis international Society (ASAS) classificatie criteria voor axSpA EN
- Gebruiken de volledige dosis of minstens > 50% van de geautoriseerde standaarddagdosering (DDD) van een oorspronkelijke of van een biosimilar TNF remmer (adalimumab, certolizumab, etanercept, golimumab, infliximab) EN
- Patiënten moeten een stabiele lage ziekteactiviteit hebben, Psoriatic Arthritis Disease Activity Score (PASDAS) < 3 2 en Body Surface Area (modified BSA) < 3% wat door de reumatologen in de dagelijkse praktijk voor PsA gebruikt wordt en/of Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2 1 met afwezigheid van extra-articulaire symptomen zoals Morbus Crohn, uveitis, colitis of psoriasis voor axSpA Hieraan moeten ze minsten 6 maanden voldoen, of wanneer formele meetinstrumenten met beschikbaar zijn, zal het door de arts en patiënt beoordeeld moeten zijn

E.4

Principal exclusion criteria

- Previous recorded unsuccessful dose reduction of TNFi,
- Comorbidities expected to hamper successful dose reduction (e g Crohns disease, Ulcerative colitis, Psoriasis, Uveitis),
- Not able to have 12 months follow-up (life expectancy, planned relocation),
- Not able to measure outcome (language, other limitations)

- Patiënten waarbij eerder het afbouwen van TNF remmers met succesvol was
- Patiënten met comorbiditeiten waarvan verwacht wordt dat ze het succesvol afbouwen van TNF remmers zullen verhinderen (e g M Crohn, Colitis Ulcerosa, Psoriasis, Uveitis),
- Patiënten waarbij 12 maanden follow-up met mogelijk is (levensverwachting, verhuizing)
- Patiënten waarbij het met mogelijk is om de uitkomstmaat te meten (taal, andere limitaties)

E.5 End points

E.5.1

Primary end point(s)

The difference in proportion of patients between dose reduction arm versus usual care who are m LDA state (PASDAS <32 and modified BSA <3% of the skin (PsA)), ASDAS < 2 1 (axSpA) and an absence of active extra-articular symptoms) in the dose reduction arm versus usual care with TNFi at 12 months follow-up, compared to the prespecified non-inferiority margin of 0 2 (20%).

Vergelijken van het percentage patiënten tussen de afbouwstrategie en de standaardzorg groep dat na 12 maanden nog steeds een lage ziekteactiviteit (PASDAS <32 and modified BSA <3% of the skin (PsA)), ASDAS < 2 1 (axSpA) en afwezigheid van actieve extra-articulaire symptomen) heeft met een van tevoren vastgestelde non-inferioriteits marge (20%).

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 maanden

E.5.2

Secondary end point(s)

-To assess the proportion of patients in the intervention group able to reduce their TNFi dose, able to discontinue TNFi altogether, or not able to reduce TNFi dose without an increase in disease activity, respectively,
- To compare the differences in efficacy between the dose reduction arm versus usual care with TNFi measured by change in PASDAS and BSA of the skin and/or ASDAS at 3, 6, 9 and 12 months follow-up,
- To assess the difference in the change from baseline in functionmg measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) and Bath Ankylosing Spondylitis Functional Index (BASFI - axSpA only) between the dose reduction arm versus usual care with TNFi at 3, 6, 9, and 12 months follow-up,
- To estimate cost effectiveness ratio of the protocolised dose reduction/withdrawal strategy of TNFi compared to usual care,
- To compare (dosage and) proportion of patients using NSAID, corticosteroid’s or cs/b/tsDMARDs between intervention and usual care group at 12 months follow up,
- To predict m the intervention group which baseline factors (including [change in] serum drug levels and antidrug antibody levels) are associated with successful and maintained dose reduction,
- To compare the difference in cumulative incidence of flare between the dose reduction arm versus usual care at 12 months follow up,
- To assess the safety of this strategy with respect to proportion of patients developing adverse events with special attention to allergie (injection) reactions and infections

- Vaststellen van het aantal PsA en axSpA patiënten in de interventie groep die TNF remmers succesvol kunnen afbouwen, stoppen of met kunnen afbouwen zonder toename van ziekteactiviteit,
- Vaststellen van het verschil in werkzaamheid tussen de afbouwstrategie en standaardbehandel groep met TNF remmers, gemeten door PASDAS en BSA van de huid en/of ASDAS op 3, 6, 9 en 12 maanden follow-up,
- Vaststellen van het verschil in verandering vanaf baseline van de Health Assessment Questionnaire Disability Index (HAQ-DI) and Bath Ankylosing Spondylitis Functional Index (BASFI - alleen axSpA) tussen de afbouwstrategie en standaardbehandel groep met TNF remmers op 3, 6, 9 en 12 maanden follow-up,
- Vaststellen van kosten-effectiviteits ratio van de afbouwstrategie van TNF remmers vergeleken met standaardzorg,
- Vaststellen van het aantal patiënten dat gebruik maakt van een NSAID, corticosteroiden of cs/b/tsDMARD's tussen de afbouwstrategie en standaardbehandel groep op 12 maanden follow-up,
- Vergelijken van het verschil in cumulatieve incidentie van flare tussen de afbouwstrategie en standaardbehandel groep op 12 maanden follow-up,
- Voorspellen welke baseline factoren (inclusief (verandering) in serum drug en antidrug antibody levels) in de afbouwstrategie groep geassocieerd zijn met het succesvol en behouden afbouwen,
- Vaststellen van de veiligheid van deze afbouwstrategie met betrekking tot het aantal patiënten die bijwerkingen ontwikkelen, meer bepaald allergische (injectie) reacties en infecties

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 6, 9, 12 months

3, 6, 9, 12 maanden

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Yes

E.8.1.3

Single blind

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Patiënten ontvangen dezelfde TNF remmers die ze al gebruiken= afbouwstrategiestudie vs standaardzorg

Patients will receive the same TNFi that they already use= dose reduction strategy vs usual care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Yes

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

LVLS

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

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:

187

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

234

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)

No specific plans. If patients, following the dose reduction strategy, have a low disease activity than they can choose to continue. If not, than they can go on with the usual care and further treatment desicions will be made according to local protocol.

Geen specifieke plannen. Als patiënten die de afbouwbehandelstrategie volgen een lage ziekteactiviteit hebben, kunnen zij ervoor kiezen om hiermee door te gaan. Indien dit niet het geval is, zullen ze weer de standaardzorg ontvangen, beslissingen over de behandeling zullen dan volgens het lokale protocol gemaakt worden.

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

2018-09-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-17

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