Clinical Trials Register

Summary
EudraCT Number:	2010-018674-20
Sponsor's Protocol Code Number:	IM101-226
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-08-16
Trial results	View 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

France - ANSM

A.2

EudraCT number

2010-018674-20

A.3

Full title of the trial

A Phase 3b, Randomized, Active Controlled Trial to Evaluate the Efficacy and Safety of
Abatacept SC in Combination with Methotrexate in Inducing Clinical Remission
Compared to Methotrexate Monotherapy in Adults with Very Early RA.

A.4.1

Sponsor's protocol code number

IM101-226

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	No
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	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous 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	125
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.IMP: 2
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	METHOTREXATE HOSPIRA 2,5 mg tablety
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.1	CAS number	59-05-2
D.3.9.3	Other descriptive name	MTX
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	2.5
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)	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	No

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 injection
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral 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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
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 2 co-primary objectives for this study will compare the clinical efficacy of
abatacept in combination with methotrexate to methotrexate alone on the following:
1) The proportion of randomized and treated subjects with DAS28-CRP < 2.6 at
Month 12.
2) The proportion of randomized and treated subjects with DAS28-CRP < 2.6 at
both Month 12 and Month 18.

E.2.2

Secondary objectives of the trial

1) Assess physical function and health-related quality of life using HAQ and SF-36
(V2.0) in the abatacept/MTX combination, abatacept monotherapy, and MTX
monotherapy arms
2) Assess joint damage progression by MRI scoring at Months 6, 12, 18, and 24 in the abatacept/MTX combination, abatacept monotherapy, and MTX monotherapy arms
3) Assess safety and tolerability including immunogenicity in the abatacept/MTX
combination, abatacept monotherapy, and MTX monotherapy arms.
4) Assess the proportion of randomized and treated subjects in the abatacept
monotherapy arm with a) DAS28-CRP < 2.6 at Month 12 and b) subjects with
DAS28-CRP < 2.6 at both Month 12 and Month 18.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1/ Signed Written Informed Consent
a) Subject is willing to participate in the study and signed the informed consent

2/ Target Population
a) Subjects have active clinical synovitis of at least 2 joints, 1 of which must be a
small joint, for at least 8 weeks at the Screening Visit. Distal interphalangeal
joints (DIP)s do not count toward this requirement
b) Subjects have had the onset of persistent symptoms for ≤ 2 years prior to the
Screening Visit.
c) Subjects have a DAS28-CRP ≥ 3.2 at the Screening Visit
d) Subjects are positive for anti-CCP2.
e) Subjects are MTX naive or have minimum exposure to MTX defined as no more
than 10 mg/wk for no more than 4 weeks and no dose for 1 month prior to the
Screening Visit.
f) Subjects are biologic naive and have not received treatment with an approved or
investigational biologic RA therapy (for ex, infliximab, etanercept, anakinra,
adalimumab, rituximab, tocilizumab, golimumab, and certolizumab) prior to
screening.
g) Subjects receiving oral corticosteroid treatment must be at the equivalent of
≤ 10 mg predinisone daily for ≥ 3 months prior to randomization.

3/ Age and Reproductive Status
a) Men and women, ages ≥ 18
b) Men and women of childbearing potential (WOCBP) must be using an acceptable
method of contraception to avoid pregnancy throughout the study for up to
10 weeks (14 weeks for EU) after the last dose of abatacept in such a manner that
the risk of pregnancy is minimized. See Protocol Section 3.3.4 for the definition of WOCBP.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity
25 IU/L or equivalent units of HCG) within 48 hours prior to the start of investigational product.
d) Women must not be breastfeeding
e) Investigators should follow the manufacturer’s recommendations for MTX.
f) Subjects must be able to receive an MRI. See Protocol Section 3.3.4 for contraindications.

E.4

Principal exclusion criteria

1/ Target Disease Exceptions
a) Subjects who meet diagnostic criteria for other rheumatic disease (eg, lupus
erythematosus).

2/ Medical History and Concurrent Diseases
a) Subjects who are impaired, incapacitated, or incapable of completing study
related assessments.
b) Current symptoms of severe, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral
disease. Concomitant medical conditions that, in the opinion of the investigator,
might place the subject at unacceptable risk for participation in this study.
c) Female subjects who had a breast cancer screening study that is suspicious for
malignancy, and in whom the possibility of malignancy cannot be reasonably
excluded following additional clinical, laboratory or other diagnostic evaluations
d) Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell
cancers must be removed prior to dosing. Subjects with carcinoma in situ, treated
with definitive surgical intervention prior to study entry, are allowed.
e) Subjects who have clinically significant drug or alcohol abuse.
f) Subjects with any serious acute bacterial infection (such as pneumonia or
pyelonephritis unless treated and completely resolved with antibiotics).
g) Subjects with severe chronic or recurrent bacterial infections (such as recurrent
pneumonia, chronic bronchiectasis).
h) Subjects at risk for tuberculosis (TB). Specifically, subjects with:
i) Current clinical, radiographic or laboratory evidence of active TB.
ii) A history of active TB within the last 3 years even if it was treated.
iii) A history of active TB greater than 3 years ago unless there is documentation
that the prior anti-TB treatment was appropriate in duration and type.
iv) Latent TB which was not successfully treated. Subjects with a positive TB
screening test indicative of latent TB will not be eligible for the study unless
active TB infection has been ruled out and they have initiated treatment for
latent TB with isoniazid (INH) for at least 4 weeks prior to dosing of study
drug and they have a negative chest x-ray at enrollment. Such subjects should
complete 9 months of INH treatment.
i) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
j) Subjects with evidence (as assessed by the investigator) of active or latent
bacterial or viral infections at the time of potential enrollment, including subjects
with evidence of Human Immunodeficiency Virus (HIV) infection

3/ Physical and Laboratory Test Findings
a) Hepatitis B surface antigen-positive subjects.
b) Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR positive.
c) Subjects with any of the following laboratory values:
i) Hgb < 8.5 g/dL.
ii) WBC < 3,000/mm3 (3 x 109/L)
iii) Platelets < 100,000/mm3 (100 x 109/L).
iv) Serum creatinine > 2 times upper limit of normal.
v) Serum ALT or AST > 2 times upper limit of normal.
vi) Any other laboratory test results that, in the opinion of the investigator, might
place the subject at unacceptable risk for participation in this study.

4/ Allergies and Adverse Drug Reaction
a) None

5/ Prohibited Treatments and/or Therapies
a) Subjects who have had prior exposure to abatacept (CTLA4-Ig)
b) Subjects who have been exposed to any investigational drug within 4 weeks or
5 half-lives, whichever is longer.
c) Subjects currently (or in the last 3 months) receiving treatment with azathioprine,
gold, leflunomide, immunoadsorption columns (such as Prosorba columns),
mycophenylate mofetil (CellCept®), cyclosporin, other calcineurin inhibitors or
D-Penicillamine.
d) Subjects who have received any live vaccines within 3 months of study drug
administration or are scheduled to receive live vaccines.

6/ Sex and Reproductive Status
a) Sexually active fertile men not using effective birth control if their partners are
WOCBP.

7/ Other
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
c) Subjects who are illiterate.

E.5 End points

E.5.1

Primary end point(s)

The co-primary endpoints are:

1) The proportion of randomized and treated subjects in remission (DAS28-CRP < 2.6) at Month 12 in the Treatment Period

2) The proportion of randomized and treated subjects in remission at both Month 12 and Month 18.

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
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	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	16
F.4.2	For a multinational trial
F.4.2.1	In the EEA	48
F.4.2.2	In the whole clinical trial	470

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

2010-09-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-07-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-10-27

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