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Clinical Trial Results:
A Double Blind, Randomized, Placebo Controlled, Multi-Center Trial of Anti-TNFα Chimeric Monoclonal Antibody (Infliximab, Remicade®) in Combination with Methotrexate in Patients with Very Early Inflammatory Arthritis

Summary
EudraCT number	2006-002787-26
Trial protocol	AT NL DE ES GR GB
Global end of trial date	31 Aug 2014

Results information
Results version number	v1(current)
This version publication date	01 Nov 2018
First version publication date	01 Nov 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

DINORA

ISRCTN number

ISRCTN21272423

US NCT number

-

WHO universal trial number (UTN)

-

Sponsor organisation name

Medical University of Vienna

Sponsor organisation address

Spitalgasse 23, Vienna, Austria, 1090

Public contact

Internal Medicine III, Rheumatology, Medical University of Vienna, 043 14040043010, josef.smolen@wienkav.at

Scientific contact

Internal Medicine III, Rheumatology, Medical University of Vienna, +43 14040043010, josef.smolen@wienkav.at

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

23 Feb 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

31 Aug 2014

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of the study is to demonstrate that patients with very early arthritis have a higher probability of achieving a state of clinical remission at end of infliximab therapy if treated with infliximab plus MTX when compared to MTX monotherapy or supportive treatment only.

Protection of trial subjects

Personal data pseudonymized.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

01 May 2007

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

Netherlands: 28

Country: Number of subjects enrolled

Austria: 29

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Greece: 3

Country: Number of subjects enrolled

Italy: 6

Worldwide total number of subjects

90

EEA total number of subjects

90

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

70

From 65 to 84 years

20

85 years and over

0

Subject disposition

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Recruitment details

Patients were eligible if they had symptom duration of 2 to 16 weeks with synovial swelling in at least 2 joints (66 joint count) of which a minimum of one joint must have been a metacarpophalangeal, proximal interpahalangeal or a metatarsophalangeal (MTP) joint. However, two MTP-joints were considered not sufficient for inclusion.

Screening details

Two screening visits for symptom duration which must have been 2 weeks at least (subjects did not receive study treatment before 12 weeks of symptom duration) and 16 weeks at most. The 16 weeks included an observation period of at least 2 weeks, as reported by the subject.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

A “double-dummy-like” administration of study medication was pursued. Every patient was treated with tablets containing methotrexate or placebo and with infusions containing infliximab or placebo. The study medication code was kept blinded in patients who discontinued prematurely.

Are arms mutually exclusive

Yes

IFX+MTX

Arm description

Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

Arm type

Experimental

Investigational medicinal product name

Anti-TNFα chimeric monoclonal antibody infliximab (IFX)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ifliximab is a chimeric IgG1 monoclonal antibody manufactured from a recombinant cell line cultured by continuous perfusion. Infliximab (IFX) was administered by intravenous infusions at a dose of 3 mg/kg at 0, 2 and 6 weeks, and at 5 mg/kg every 8 weeks thereafter.

Investigational medicinal product name

Methotrexate (MTX)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate (MTX) was dosed orally according to a rapid dose escalation scheme: start at 10 mg/week and increased to 25 mg/week in three steps with 2-week intervals except in cases of intolerance.

MTX monotherapy

Arm description

Methotrexate (MTX) monotherapy

Arm type

Experimental

Investigational medicinal product name

Methotrexate (MTX)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate (MTX) was dosed orally according to a rapid dose escalation scheme: start at 10 mg/week and increased to 25 mg/week in three steps with 2-week intervals except in cases of intolerance.

Placebo

Arm description

Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Intravenous use

Dosage and administration details

A “double-dummy-like” administration of study medication was pursued. Every patient was treated with tablets containing methotrexate (MTX) or placebo and with infusions containing infliximab (IFX) or placebo.

Number of subjects in period 1	IFX+MTX	MTX monotherapy	Placebo
Started	38	36	16
Completed	14	11	7
Not completed	24	25	9
Consent withdrawn by subject	6	9	1
Adverse event, non-fatal	2	1	1
Accidental unblinding	-	-	1
Unknown	3	2	-
Lost to follow-up	1	2	-
Unable to comply with protocol	-	2	-
Lack of efficacy	12	9	6

Baseline characteristics

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Reporting group title

IFX+MTX

Reporting group description

Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

Reporting group title

MTX monotherapy

Reporting group description

Methotrexate (MTX) monotherapy

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group values	IFX+MTX	MTX monotherapy	Placebo	Total
Number of subjects	38	36	16	90
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (standard deviation)	52.1 ( 14.1 )	52.9 ( 14 )	54.4 ( 11.2 )	-
Gender categorical
Units: Subjects
Female	26	28	9	63
Male	12	8	7	27

End points

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Reporting group title

IFX+MTX

Reporting group description

Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

Reporting group title

MTX monotherapy

Reporting group description

Methotrexate (MTX) monotherapy

Reporting group title

Placebo

Reporting group description

Placebo

Primary: Clinical remission

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End point title

Clinical remission

End point description

End point type

Primary

End point timeframe

At week 54

End point values	IFX+MTX	MTX monotherapy	Placebo
Number of subjects analysed	38 ^[1]	36 ^[2]	16 ^[3]
Units: Number of patients in clinical remission
Clinical remission	12	5	0
No clinical remission	26	31	16

Notes
[1] - Intention to treat
[2] - Intention to treat
[3] - Intention to treat

Primary endpoint

Comparison groups

IFX+MTX v MTX monotherapy v Placebo

Number of subjects included in analysis

90

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Chi-squared

Confidence interval

Adverse events

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Timeframe for reporting adverse events

During study period

Assessment type

Non-systematic

Dictionary name

Conducted by Janssen

Dictionary version

NA

Reporting group title

IFX+MTX

Reporting group description

Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

Reporting group title

MTX monotherapy

Reporting group description

Methotrexate (MTX) monotherapy

Reporting group title

Placebo

Reporting group description

Placebo

Serious adverse events	IFX+MTX	MTX monotherapy	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 38 (15.79%)	3 / 36 (8.33%)	3 / 16 (18.75%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haematuria, followed by a diagnosis of bladder cancer
subjects affected / exposed	0 / 38 (0.00%)	1 / 36 (2.78%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive episode one hour after the last infusion with study drug
subjects affected / exposed	0 / 38 (0.00%)	1 / 36 (2.78%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction more than half a year after last study drug
subjects affected / exposed	0 / 38 (0.00%)	1 / 36 (2.78%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Social circumstances
Fainted during blood collection, prior to administration of study drug
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Biliary pancreatitis in a time after the study medication
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Significantly raised transaminase levels
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Significant flare of disease activity
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MTX pneumonitis (opportunistic) infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 36 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 38 (0.00%)	0 / 36 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.03%

Non-serious adverse events	IFX+MTX	MTX monotherapy	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 38 (89.47%)	32 / 36 (88.89%)	13 / 16 (81.25%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms
subjects affected / exposed	0 / 38 (0.00%)	1 / 36 (2.78%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Vascular disorders
Diseases of ciculatory system
subjects affected / exposed	6 / 38 (15.79%)	7 / 36 (19.44%)	3 / 16 (18.75%)
occurrences all number	8	10	6
Pregnancy, puerperium and perinatal conditions
Diseases of genitourinary system (pregnancy, childbirth and puerperium)
subjects affected / exposed	2 / 38 (5.26%)	2 / 36 (5.56%)	0 / 16 (0.00%)
occurrences all number	2	4	0
General disorders and administration site conditions
Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified
subjects affected / exposed	11 / 38 (28.95%)	11 / 36 (30.56%)	5 / 16 (31.25%)
occurrences all number	21	22	6
Social circumstances
External causes of morbidity
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Respiratory, thoracic and mediastinal disorders
Diseases of respiratory system
subjects affected / exposed	23 / 38 (60.53%)	16 / 36 (44.44%)	4 / 16 (25.00%)
occurrences all number	33	32	5
Injury, poisoning and procedural complications
Injury, poisoning and certain other consequences of external causes
subjects affected / exposed	6 / 38 (15.79%)	3 / 36 (8.33%)	0 / 16 (0.00%)
occurrences all number	10	3	0
Nervous system disorders
Disease of the nervous system
subjects affected / exposed	6 / 38 (15.79%)	9 / 36 (25.00%)	2 / 16 (12.50%)
occurrences all number	9	13	2
Blood and lymphatic system disorders
Disease of blood and blood-forming organs and certain disorders involving the immune mechanism
subjects affected / exposed	1 / 38 (2.63%)	0 / 36 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Eye disorders
Diseases of the eye and adnexa
subjects affected / exposed	1 / 38 (2.63%)	2 / 36 (5.56%)	0 / 16 (0.00%)
occurrences all number	1	3	0
Skin and subcutaneous tissue disorders
Diseases of the skin and subcutaneous tissue
subjects affected / exposed	12 / 38 (31.58%)	8 / 36 (22.22%)	5 / 16 (31.25%)
occurrences all number	18	14	8
Endocrine disorders
Endocrine, nutritional and metabolic diseases
subjects affected / exposed	2 / 38 (5.26%)	5 / 36 (13.89%)	2 / 16 (12.50%)
occurrences all number	2	7	2
Musculoskeletal and connective tissue disorders
Diseases of musculoskeletal system and connective tissue
subjects affected / exposed	15 / 38 (39.47%)	9 / 36 (25.00%)	6 / 16 (37.50%)
occurrences all number	26	16	8
Infections and infestations
Infections
subjects affected / exposed	19 / 38 (50.00%)	9 / 36 (25.00%)	3 / 16 (18.75%)
occurrences all number	30	22	4
Metabolism and nutrition disorders
Diseases of the digestive system
subjects affected / exposed	15 / 38 (39.47%)	17 / 36 (47.22%)	5 / 16 (31.25%)
occurrences all number	29	35	10

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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