Clinical Trials Register

Summary
EudraCT Number:	2013-003658-26
Sponsor's Protocol Code Number:	unknown
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:	2013-10-18
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

2013-003658-26

A.3

Full title of the trial

Treat-to-target strategy for early RA patients in usual clinical practice:
The COBRA Cohort Study

A.3.1

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

Individualised treatment strategy based on disease activity for early RA patients in usual clinical practice: The COBRA Cohort Study

A.3.2

Name or abbreviated title of the trial where available

COBRA Cohort Study

A.4.1

Sponsor's protocol code number

unknown

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	VU University 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	VU University Medical Center
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Pfizer bv
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	VU University Medical Center
B.5.2	Functional name of contact point	Department of Rheumatology
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.6	E-mail	l.rasch@vumc.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	Methotrexate
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie
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	Methotrexate
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methotrexate
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 25
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.IMP: 2
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	Prednison
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie
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	Prednison
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Prednisone
D.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB10020MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 60
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.IMP: 3
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	Plaquenil
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Synthelabo LTD
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	hydroxycholoquine
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	hydroxychloroquine sulfate
D.3.9.1	CAS number	747-36-4
D.3.9.3	Other descriptive name	HYDROXYCHLOROQUINE SULFATE
D.3.9.4	EV Substance Code	SUB02587MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	400
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.IMP: 4
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	Sulfasalazine
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie
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	Sulfasalazine
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sulfasalazine
D.3.9.3	Other descriptive name	SULFASALAZINE
D.3.9.4	EV Substance Code	SUB10727MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2
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

Early Active Rheumatoid Arthritis

Vroege Reumatoïde artritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

Reuma

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 primary objective of this study is to implement protocolised treatment according to the treat-to-target strategy, aiming at a high percentage of early rheumatoid arthritis patients with a good response to treatment at 26 weeks, in a routine clinical setting.

E.2.2

Secondary objectives of the trial

A secondary objective of this study is to study the psychometric properties of patient reported outcomes in low disease activity and remission.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- RA according to the 2010 classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) (13)
- Age of 18 years and older
- Early RA: a diagnosis of RA of less than 2 years

E.4

Principal exclusion criteria

- Prior treatment DMARDs (except hydroxychloroquine)
- Insulin-dependent Diabetes mellitus
- Uncontrollable non-insuline dependent diabetes mellitus
- Heart failure NYHA class 3-4
- Uncontrollable hypertension
- ALAT/ASAT >3 times normal values
- Reduced renal function (serum creat >125 μmol/l for male and >100 μmol/l for female)
- Contra-indications for methotrexate, sulphasalazine or prednisolone
- Indications of probable tuberculosis
- Increased risk of harm due to contraindications to the study drugs
- Language problems

E.5 End points

E.5.1

Primary end point(s)

- EULAR good response:
The main endpoint of this cohort is the disease activity measured by the percentage of patients that reach an EULAR good response (Table 3). EULAR good response is measured with the Disease Activity Score (DAS) of 44 joints: DAS44. DAS44-score is calculated with the Ritchie articular index, number of swollen joints, Erytrocyt Sedimentatie Rate (ESR), and a general health assessment on a visual analogue scale (VAS) with a range from 0 to 100 mm. The DAS44-score will be measure at each visit. EULAR good response is reached when the DAS44-score is 2.4 or less and has improved 1.2 points or more compared to the previous measurement. If this is not the case, there is moderate or none EULAR response which means intensification of the medication.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 26 weeks

E.5.2

Secondary end point(s)

- Functional ability:
Daily physical functioning of patients is an important parameter in the treatment of patients with RA. In this cohort, we will assess the physical functioning according to the Dutch translation of the Health Assessment Questionnaire (HAQ). This is a validated questionnaire containing twenty questions, which will be filled out at baseline and after 16, 26, 39, and 52 weeks.

- Remission:
According to the ACR/EULAR remission criteria, there will be assessed if the patient is in remission. The ACR/EULAR definitions of remission in RA are:

Boolean-based definition
At any time point, patient must satisfy all of the following:
Tender joint count ≤1
Swollen joint count ≤1
C-reactive protein (CRP) ≤1 mg/dl
Patient global assessment ≤1 (on a 0–10 scale)

Index-based definition
At any time point, patient must have a Simplified Disease Activity Index (SDAI) score of ≤3.3, calculated from tender joint count (using 28 joints), swollen joint count (using 28 joints), patient global assessment (0–10scale), physician global assessment (0–10 scale), and CRP level (mg/dl).

- Radiological progression:
To assess if the treat-to-target therapy given in this cohort is effective on radiological joint damage, x-rays from hands and feet will be made at baseline, and after 16 and 52 weeks. In usual clinical practice, x-rays at baseline and after 52 weeks are routine. In this cohort we will include a x-ray after 16 weeks to be able to follow the radiological progression more closely. In case there are x-rays from less than three months before, these can be used instead of making new x-rays.

- Patient Reported Outcomes (PROs):

*Disease activity:
During the cohort, patients will be asked to filled out the following Patient Reported Outcomes (PROs):
1. How much pain did you had the last 24 hours?
2. How active was your rheumatoid arthritis the last 24 hours?
3. How did you felt in general the last 24 hours due to your joint complaints?
4. Do you suffer from morning stiffness? If yes, how long?
5. Do you think your rheumatoid arthritis is in remission?
For the patients, these questions are translated to Dutch. The first three PROs can be answered using a 100 mm visual analogue scale (VAS). The fourth PRO (about morning stiffness), can be answered by indicating the number of minutes the morning stiffness takes. PRO number 5 can be answered by yes or no. According these questions, patients can assess there own disease activity.

* Rheumatoid Arthritis Impact of Disease-questionnaire (RAID):
The RAID is a validated questionnaire assessing the seven most important domains of impact of RA on the patients.

* Bristol Rheumatoid Arthritis Fatigue-questionnaire (BRAF):
The BRAF is a questionnaire about fatigue in RA patients. The questionnaire contains twenty questions.

* McMaster Toronto Arthritis patient preference-questionnaire (MACTAR):
The MACTAR patient preference disability questionnaire is a semi-structured, valid, and highly responsive instrument to assess change in disease related functional ability of patients with early RA. The patients can define activities that they currently cannot perform, but which they want to be able to perform again. This provides insight into problems that really matter to patients.

* Jenkins Sleeping Scale-questionnaire (JSS):
The JSS is a four item questionnaire about sleeping problems and sleeping disturbance.

* Work Productivity and Activity Impairment-questionnaire (WPAI):
The WPAI is a questionnaire validated to measure impairments in (paid) work and activities in RA patients.

* Appetite:
Patients appetite will be assessed using a 100 mm VAS on which they indicate how much appetite they had the last week. In addition, the Functional Assessment of Anorexia/Cachexia Therapy-questionnaire (FAACT) will be filled out, with 12 questions about appetite and relating aspects.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, and after 4, 16, 26, 39, and 52 weeks

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

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

E.8.1.1

Randomised

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

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 last visit of the last patient undergoing the trial

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:

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

120

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)

At the end of the trial, the treating rheumatologist is at liberty to make an own treatment decision.

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

2013-10-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-11-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-18

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