Clinical Trials Register

Summary
EudraCT Number:	2006-004139-31
Sponsor's Protocol Code Number:	M06-810
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-05-17
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2006-004139-31

A.3

Full title of the trial

A Multicenter, Randomized, Double-Period, Double − Blind Study to Determine the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early Rheumatoid Arthritis.

A.3.2

Name or abbreviated title of the trial where available

OPTIMA

A.4.1

Sponsor's protocol code number

M06-810

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	Abbott GmbH & Co. KG
B.1.3.4	Country	Germany
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	Humira
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	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	Adalimumab
D.3.9.2	Current sponsor code	ABT-Humira
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	40
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)	Yes
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.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	Metex®
D.2.1.1.2	Name of the Marketing Authorisation holder	medac Gesellschaft für klinische Spezialpräparate mbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.9.2	Current sponsor code	Methotrexate disodium
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	Injection*
D.8.4	Route of administration of the placebo	Subcutaneous 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	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 objective of this study is to compare the proportion of subjects who achieve low disease activity as defined by both a clinical response (DAS28<3.2) and no radiographic progression (∆mTSS less than/equal to 0.5) at Week 78 (mong those subjects who responded at Weeks 22 and 26, i.e., DAS28<3.2) in subjects treated with adalimumab/MTX (combination therapy) for 78 weeks(Arm 2) and subjects treated with placebo/MTX monotherapy for 78 weeks (Arm 4). Subjects who did not achive a clinical response (DAS28<3.2) at Week 22 or 26 were not allowed to continue on their current treatment and were given open-label combination therapy (adalimumab/MTX) for the remainder of the study under ethical consideration.

E.2.2

Secondary objectives of the trial

This study is also designed to evaluate the maintenance of clinical response in a population of subjects initially treated with combination therapy but subsequently with methotrexate monotherapy (by discontinuing adalimumab (HUMIRA®), the TNF antagonist).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1. High Field MRI substudy: To be performed in the UK, Germany, Austria, Belgium and Greece. Details are provided on page 38 of the protocol.

2. Low Field MRA substudy: To be performed in Germany only. Details are provided on page 38 of the protocol.

E.3

Principal inclusion criteria

1. Subject is ≥ 18 years of age.
2. Subject has a diagnosis of RA as defined by the 1987-revised ACR-classification criteria and have a disease duration of less than 1 year from diagnosis.
3. Subject must meet the following three criteria: a. DAS28 (CRP) > 3.2. (Baseline Visit only) b. At least 6 swollen joints out of 66 assessed. c. At least 8 tender joints out of 68 assessed.
4. Subject must have an ESR ≥ 28 mm/1h(at the Screening and Baseline visits) or
CRP ≥ 1.5 mg/dL(at the Screening visit only).
5. Subject must fulfill at least one of the following three criteria: a. Rheumatoid Factor (RF)positive. b. Have greater than 1 erosion. c. Anti- CCP Antibody positive.
6. Female subject is either not of childbearing potential, defined as postmenopausal (at least 1 year since last menses) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or is of childbearing potential and practicing one of the following methods of birth control throughout the study and for 150 days after study completion:
• Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD)
• Contraceptives (oral, parenteral, patch) for three months prior to study drug administration)
• A vasectomized partner
7. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Baseline.
8. Subject is judged to be in good general health as determined by the principal investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening.
9. Subjects will be evaluated for latent TB infection with a purified protein derivative (PPD) test and chest X-ray. For this protocol, evidence of latent TB infection is defined as an induration (not erythema) of 5 mm or greater, 48-72 hrs after placement. Subjects who demonstrate evidence of latent TB infection, irrespective of Bacille Calmette − Guérin (BCG) vaccination status, and negative CXR findings for active TB and/or suspicious CXR findings will be allowed to participate in the study provided that one of the following conditions are satisfied;
• Prophylactic treatment is initiated at least two weeks prior to administration of study drug; however the course of prophylaxis need not be completed prior to the onset of study drug. Prophylactic treatment will be according to the United States Centers for Disease Control [CDC] recommended preventive therapy for TB or per local guidelines. Prophylactic treatment should be captured on the concomitant medications page in the CRF and in the source documents. See Appendix D for Centers for Disease Control (CDC) recommended preventive therapy for TB.
• Subject has documented prophylactic treatment for TB and so need not repeat this treatment.
10. Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
11. Subjects must be able and willing to self-administer sc injections or have a qualified person available to administer sc injections.

E.4

Principal exclusion criteria

1. Subject has previous exposure to any systemic anti-TNF therapy (e.g., infliximab or etanercept) including adalimumab.
2. Subject has been previously treated with > 2 (DMARDs) or MTX.
3. Subject has been treated with Intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable medical conditions are allowed.
4. Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
5. Subject has a history of acute inflammatory joint disease of different origin other than RA (e.g., mixed connective tissue disease, seronegative spondyloarthropathy, psoriatic arthritis, Reiter's syndrome, fibromyalgia, systemic lupus erythematosus or any arthritide with onset prior to age 17 years).
6. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs (adalimumab, MTX, or matching placebo).
7. Subject has been treated with any investigational drug of a "chemical" nature within two months prior to study entry (screening visit).
8. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study.
9. Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal, liver disease (e.g., fibrosis, cirrhosis, hepatitis), or gastroenteric ulcer.
10. Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
11. Subject has history of cancer or lymphoproliferative disease other than a successfully treated non − metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix.
12. Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the Baseline visit.
13. Subject currently uses or plans to use anti-retroviral therapy at any time during the study.
14. Subject is known to have immune deficiency, history of HIV or is immunocompromised.
15. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or for 150 days after the last dose of study medication.
16. Subject has a history of clinically significant drug or alcohol usage in the last year or cannot maintain an alcohol intake of 30 g a day or less throughout the study. One standard drink is defined as 180 mL/6 oz (approx. 10 g) of wine, 360 mL/12 oz (approx. 15 g) of regular beer, or 45 mL/1.5 oz (approx. 10 g) of spirits.
17. Screening clinical laboratory analyses show any of the following abnormal laboratory results:
• Aspartate transaminase (AST) or alanine transaminase (ALT) >1.5x the upper limit of normal (ULN).
• Serum total bilirubin ≥ 1.5 mg/dL (≥ 26 micromol/L); or
• Creatinine > 1.5 mg/dL (133 micromol/L) in subjects < 65 years old and > upper limit of normal range in subjects ≥ 65.
• Evidence of chronic Hepatitis B or C serology indicative of previous or current infection.
18. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the composite response at Week 78 defined by low disease activity (DAS28<3.2) and no ragigraphic progression from Baseline (Deltam<TSS <=0.5)
The primary efficacy variable will be compared between subjects treated with blinded, MTX monotherapy for 78 weeks (Arm2 versus Arm4)

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

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)

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

Seventy-day follow-up telephone call to be undertaken seventy days post subjects last study medication dose or as soon as aware that the subject has switched to commercial product (if applicable).

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-05-17.

Yes

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

680

F.4.2.2

In the whole clinical trial

1000

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)

Normal treatment.

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

2007-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-07-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-07-01

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