Clinical Trials Register

Summary
EudraCT Number:	2006-003768-67
Sponsor's Protocol Code Number:	IM101119
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-02-07
Trial results	Removed from public view

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

Sweden - MPA

A.2

EudraCT number

2006-003768-67

A.3

Full title of the trial

A Phase III Multicenter, Randomized, Double-Blind, placebo-controlled Study to Assess short-term changes in synovitis and structural damage outcomes in subjects with active Rheumatoid Arthritis and inadequate response to Methotrexate, Treated with Abatacept versus Placebo on a Background Therapy with Methotrexate

Revised Protocol 03, incorporating Protocol Amendment 01 (Version 1.0, Date 16-May-2007), Protocol Amendment 03 (Version 1.0, Date 19-Mar-2008), Protocol Amendment 04 (Version 1.0, Date 05-Dec-2008), and Administrative Letter dated 13-Jun-2007.

A.4.1

Sponsor's protocol code number

IM101119

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Orencia
D.2.1.1.2	Name of the Marketing Authorisation holder	Orencia
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Abatacept
D.3.2	Product code	BMS-188667
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Abatacept
D.3.9.1	CAS number	332348-12-6
D.3.9.2	Current sponsor code	BMS-188667
D.3.9.3	Other descriptive name	CTLA4Ig
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Fusion Protein

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

RHEUMATOID ARTHRITIS,NOS

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Level	LLT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis

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 in subjects with active RA and inadequate response to MTX is to assess changes in wrist synovitis as measured by gadolinium-enhanced Magnetic Resonance Imaging (MRI) and using the OMERACT 6 RA MRI score after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX.

E.2.2

Secondary objectives of the trial

1) To assess in subjects with active RA and inadequate response to MTX changes in
bone lesions (i.e. bone edema, bone erosions) in hands/wrists (measured by
gadolinium-enhanced MRI, using the OMERACT 6 RA MRI score) after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX).
2) To assess in subjects with active RA and inadequate response to MTX changes in
biochemical markers of bone, cartilage and synovial tissue metabolism at Days 15, 29 and 113 (4 months) after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX.
3) To assess the safety and tolerability of Abatacept versus placebo in subjects with
active RA and inadequate response to MTX, on a background therapy with MTX over 4 months.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed written informed consent
2) Subjects must meet the criteria of the American Rheumatism Association (1987)
for the diagnosis of rheumatoid arthritis (Protocol Appendix 1).
3) Subjects must have a diagnosis of RA greater than 6 months and no longer than 5
years from the time of initial diagnosis of RA.
4) Subjects must have a disease activity as defined by a DAS28-CRP > 3.2 or a
tender joint count of ≥ 6, a swollen joint count of ≥ 6, and a CRP measurement
greater than the upper limit of normal
5) Subjects must have clinically detectable synovitis (i.e. “synovial swelling”) of at
least one wrist at screening and baseline visit (D1, prior to infusion).
6) Subjects must have at least one erosion present in the hands/wrists and /or feet
(documented by previous plain radiography) or be anti-CCP positive or be
rheumatoid factor (RF) positive.
7) Subjects must have been treated with MTX, on a weekly dose of at least 15 mg or
a maximum tolerated dose (i.e. 10 mg weekly) for at least 3 months before
screening. In addition, the dose of MTX must be stable for at least 28 days prior
to the first study dose (baseline i.e. Day 1).
8) Subjects must be biologic DMARDs naive (i.e. anti-TNFα, anakinra, rituximab or
other investigational biologics).
9) Subjects who consented to have a knee/ankle arthroscopy with tissue and synovial biopsy must have clinically detectable synovitis (i.e. “synovial swelling”) of at
least one knee/ankle at screening and baseline visit (D1).
10) At randomization (Day 1), subjects must have the following disease activity :
a) 6 or more swollen joints (66 joint count) and
b) 6 or more tender joints (68 joint count) and
c) CRP greater than the upper limit of normal (result from screening visit sample
collection).
11) Drug stabilization requirements (except MTX): Informed consent must be
signed before making any changes in RA therapy if those changes are solely for
the purpose of this study.
a) All DMARDs (except MTX) should be discontinued at least 28 days prior to
treatment (Day 1).
-MTX monotherapy: Subjects who are treated only with MTX will not
require washout.
-Combination DMARD therapy: Subjects who are treated with MTX in
combination with another anti-rheumatic treatment (DMARD) will
require washout.
b) In the case of leflunomide, the subject can be washed-out with cholestyramine
according to manufacturer recommendations.
c) Oral corticosteroid treatment must have been reduced to a maximum equivalent dose of 10 mg prednisone daily for 28 days and stabilized for at least 25 out of 28 days, prior to treatment (Baseline i.e. Day 1).
12) Osteoporosis treatment:
Subjects taking treatments for the prevention of glucocorticoid-induced osteoporosis
(Calcium, vitamin D, Bisphosphonates) will be enrolled as long as their dose has been
stable for at least 3 months prior to randomization and remains stable during the entire double-blind period. Other concomitant osteoporosis treatments will not be permitted at randomization.
13) Men and women (not nursing and not pregnant) >= 18 years of age. Women of
childbearing potential are eligible if they are practicing effective contraceptive
measures.

E.4

Principal exclusion criteria

1)WOCBP unwilling or unable to use acceptable method to avoid pregnancy for entire study period & up to 10 weeks after study
2)WOCBP using prohibited contraceptive method
3)Pregnant or breastfeeding women
4)Women with +pregnancy test on enrollment or prior to study drug administration
5)Contraception for male subjects treated with protocol-permitted concomitant
medications during study should follow manufacturer’s recommendation for need to use contraception & permissible/recommended method(s)
6)Subjects who are impaired,incapacitated,or incapable of completing study related assessments
7)Subjects meeting diagnostic criteria for any other rheumatic disease
8)previous treatment with approved/investigational biologic RA therapy (infliximab, etanercept,anakinra,adalimumab,rituximab,Abatacept)
9)Active vasculitis of a major organ system with exception of rheumatoid nodules
10)current symptoms of severe,progressive, or uncontrolled renal, hepatic,hematological,gastrointestinal,pulmonary,cardiac,neurological,or cerebral disease,or other medical conditions that,in opinion of the investigator,might place subject at unacceptable risk for participation
11)Female subjects who have had breast cancer screening suspicious for malignancy & in whom possibility of malignancy cannot be reasonably excluded following additional clinical,laboratory or other diagnostic evaluations (Protocol Section 7.3.2.3)
12)history of cancer within last 5 years (other than nonmelanoma skin cell (NMSC) cancers cured by local resection). Existing NMSC cancers must be removed prior to dosing
13)Known current metabolic bone disorders other than osteoporosis or low bone mass
14)Vitamin D deficiency
15)Clinically significant drug or alcohol abuse
16)Subjects with any serious bacterial infection within last 3 months, unless treated & resolved with antibiotics, or any chronic bacterial infection
17)Subjects at risk for TB. Specifically subjects with:
-History of active TB within last 3 years even if treated
-History of active TB >3 years ago unless there is documentation
that prior anti-TB treatment was appropriate in duration & type
-Current clinical, radiographic or laboratory evidence of active TB
-Latent TB which was not successfully treated
18)Subjects with herpes zoster or CMV that resolved less than 2 months prior to signing ICF
19)Subjects with evidence of active or latent bacterial/viral infections at time of potential enrollment, including subjects with evidence of HIV, HPB or HPC infection detected during screening
20)Subjects with conditions that preclude accurate DXA measurements
including:
-BMI >35 kg/m²
- Advanced scoliosis or spinal degenerative changes (osteoarthritis, sclerosis)
-Less than 3 lumbar vertebrae in range L1-L4 which are evaluable by DXA
interfering conditions include prevalent vertebral fracture, metal implants or spinal
surgery
-History of bilateral distal radius fracture
21)Subject who received live vaccines within 3 months of anticipated
1st dose of study medication or who will have need of live vaccine at any time
following Day 1 of study
22)History of severe or anaphylactic infusion reaction after receiving a biologic
agent, suspected to be associated with an immune response
23)Subjects who have at any time received treatment with Abatacept
24)Subjects who have at any time received treatment with biologic DMARD
(infliximab, etanercept, adalimumab, rituximab, or any investigational biologic)
25)Subjects that received treatment with any investigational drug within
28 days (or< 5 terminal half-lives of elimination) of Day 1 dose
26) Subjects currently receiving treatment with mycophenolate mofetil (CellCept®),
cyclosporine, tacrolimus, D-Penicillamine, Cytoxan®, or immunoadsorption
columns (such as Prosorba columns).
27)Subjects receiving treatment with following bone active agents, or had previous treatment according to following guidelines:
-Oral bisphosphonate, vitamin D, or calcium treatments for prevention of
glucocorticoid-induced osteoporosis if taken for less than 3 months of randomization or bisphosphonate treatment for established osteoporosis
-Any of following treatments within 3 months of randomization: PTH or PTH
fragments (teriparatide), systemic hormone replacement therapy, selective
estrogen receptor modulators (raloxifene, lasofoxifene, bazedoxifene, etc),
tamoxifen,tibolone,calcitonin,anabolic steroids or testosterone,androgen &
once weekly dose of >50,000 IU of Vitamin D
-treatment with fluoride or strontium ranelate
28)Subjects who received intra-articular injection of steroids within 3 months prior to Screening if injected in >1 joint other than a small joint or in any small joint or within 6 months prior to Screening in the target knee/ ankle for subjects who consented to have a knee/ ankle arthroscopy

See Section 5.2 of Protocol for additional Exclusion Criteria

E.5 End points

E.5.1

Primary end point(s)

Imaging assessments:

• MRI assessment of the degree of inflammation and structural damage [i.e. synovitis of the most clinically inflamed wrists and bone edema and erosions of the target wrist and metacarpophalangeal (MCP) joints] at baseline (D1), 4 months (end of double-blind treatment period) and 1 year (end of open-label extension) by gadolinium-enhanced MRI, using a centralized reader blinded to sequence and treatment and using the OMERACT 6 RA MRI score.

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

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

The double-blind phase is followed by an open-label phase of 8 months.

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Information not present in EudraCT

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

LPLV

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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.1.3

Elderly (>=65 years)

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

See Section 4.1 of the protocol

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

2007-03-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-03-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-05-25

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