Clinical Trials Register

Summary
EudraCT Number:	2006-003843-22
Sponsor's Protocol Code Number:	CURE
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2006-08-30
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2006-003843-22

A.3

Full title of the trial

prospeCtive study on intensive early rheumatoid arthritis treatment with adalimUmab: induction of REmission and maintenance - 'CURE'
A Phase IV multicenter, randomized, double-blind study

CURE-ProspeCtive study on intensive early rheumatoid arthritis treatment with adalimUmab: induction of REmission and maintenance. A Phase IV multicenter, randomized, double-blind study

A.4.1

Sponsor's protocol code number

CURE

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	OSPEDALE POLICLINICO S. MATTEO
B.1.3.4	Country	Italy
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
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	HUMIRA*SC 2SIR+F 40MG 0,8ML+2T
D.2.1.1.2	Name of the Marketing Authorisation holder	ABBOTT SpA *
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
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	Adalimumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	40
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
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	METHOTREXATE*100CPR 2,5MG
D.2.1.1.2	Name of the Marketing Authorisation holder	WYETH LEDERLE SpA *
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	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.3.9.1	CAS number	59-05-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
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	DELTACORTENE FORTE*10CPR 25MG
D.2.1.1.2	Name of the Marketing Authorisation holder	BRUNO FARMACEUTICI SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	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.3.9.1	CAS number	53-03-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

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	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

Artrite reumatoide

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10039075
E.1.2	Term	Rheumatoid arthritis and associated conditions
E.1.2	System Organ Class	100000004870

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the proportion of patients who achieve remission at 12 months, as defined by DAS 28 </= 2.6

valutare la proporzione di pazienti che hanno raggiunto la remissione a 12 mesi, come definito da DAS 28</= 2.6

E.2.2

Secondary objectives of the trial

1. to evaluate the proportion of subjects who maintain stable remission at 24 months) after discontinuation of aggressive treatment
2. evaluation of ACR 20, 50, 70 (21) response at month 4, 8, 12 and 24
3. calculation of DAS 28 score at month 4, 8, 12 and 24
4. evaluation of clinical remission (DAS 28) at month 4, 8, 12 and 24
5. evaluation of HAQ at week 0, 4, 8, 12 and 24
6. evaluation of radiographic progression (Modified total Sharp score) (22) at months 12 and 24
7. evaluation of safety of different treatment regimens

dettagliati di seguito

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able and willing to give written informed consent and comply with the requirements of the study protocol.
2. Patients with active rheumatoid arthritis diagnosed for at least 6 weeks, but no more than 1 year, according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis
3. Patients naïve to treatment with MTX and that have received a prednisone dose ≤ 7,5 mg/d and a total prednisone dose ≤250 mg .
4. Swollen joint count (SJC) > 8 (66 joint count), and tender joint count (TJC) > 8 (68 joint count) at screening and baseline.
5. At screening CRP > 1.5 mg/dL (15 mg/L) or ESR ≥ 28 mm/h
6. ≥ 1 joint erosion or RF positivity or anti-CCP positivity
7. Age 18-70 years.
8. Use of NSAIDs is permitted if stable for at least 2 weeks prior to baseline.
9. For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g. hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation.
10. Must be willing to receive oral folate.

pazienti affetti da artrite reumatoide diagnosticata da almeno 6 settimane e non da non piu' di 12 mesi, naive a MTX (eta' 18-70 anni, ...

E.4

Principal exclusion criteria

Exclusions related to RA
1.Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjögren's syndrome or secondary limited cutaneous vasculitis with RA is permitted.
2.Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
3.History of, or current, inflammatory joint disease other than RA (including, but not limited to, gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (including, but not limited to, systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or any overlap syndrome).

Exclusions Related to General Health
1.Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned during the study.
2.Pregnancy or breastfeeding.
3.Significant and/or uncontrolled cardiac or pulmonary disease (including obstructive pulmonary disease).
4.Evidence of significant concomitant disease, including but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders which, in the investigator's opinion, would preclude patient participation.
5.Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
6.Known active infection of any kind, or any major episode of infection requiring hospitalization or treatment with i.v.anti-infectives within 4 weeks of baseline or completion of oral anti-infectives within 2 weeks prior to baseline.
7.History of serious recurrent or chronic infection.
8.History of previously untreated infection with mycobacterium tuberculosis or current treatment for it.
**Latent TB infection is defined as:
- a positive Mantoux Purified Protein Derivative (PPD) skin test using 10 IU of PPD (≥ 5 mm induration, regardless of BCG vaccination status)
- chest radiograph with changes suggestive for TB infection (a chest radiograph will be performed at screening if not performed within 6 weeks prior to screening).
These patients should be treated accordingly to local guidelines before entering the study.
9.History of cancer, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
10.Any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swelling (e.g.Parkinsons disease, cerebral palsy, diabetic neuropathy
11.Any history or presence of congestive heart failure (CHF) (New York Heart Association classification for CHF: Class III or IV).
12.Any history of myocardial infarction within 5 years.
13.Cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormality, such as ischemia.
14.Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.

Exclusions Related to Medications
1.History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of adalimimab or methotrexate.
2.Previous treatment with MTX
3.Intra-articular or parenteral glucocorticoids within 4 weeks prior to baseline.
4.Intolerance or contraindications to glucocorticoids.

Exclusions Related to Laboratory Findings
1.Positive serum human chorionic gonadotropin (hCG) measured prior to the baseline visit.
2.Positive serology for hepatitis B or C indicating active infection.
3.Hemoglobin < 8.0 g/dL.
4.Absolute neutrophil count (ANC) < 1.5 x 103/microL.
5.Liver function abnormality

malattia reumatica autoimmune diversa da AR o significativo interessamento sistemico secondario a AR, classe funzionale ACR IV, ...

E.5 End points

E.5.1

Primary end point(s)

remission induction in the intensively treated group vs control group treated with standard dosage of adalimumab and MTX

induzione di remissione

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

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

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

Information not present in EudraCT

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

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	No
F.1.1	Number of subjects for this age range:	0
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	Yes
F.3.3.2	Women of child-bearing potential using contraception	No
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	220

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

2006-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-07-31

P. End of Trial
P.	End of Trial Status	Ongoing

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