Clinical Trials Register

Summary
EudraCT Number:	2009-010516-15
Sponsor's Protocol Code Number:	3227K1-2000-WW
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-04-21
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

Greece - EOF

A.2

EudraCT number

2009-010516-15

A.3

Full title of the trial

Randomized, Parallel, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of SBI-087 in Seropositive Subjects With Active Rheumatoid Arthritis on a Stable Background of Methotrexate

A.4.1

Sponsor's protocol code number

3227K1-2000-WW

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	Wyeth Research Division of Wyeth Pharmaceuticals Inc.
B.1.3.4	Country	United States
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	SBI-087
D.3.2	Product code	SBI-087
D.3.4	Pharmaceutical form	Powder for 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	n/a
D.3.9.1	CAS number	n/a
D.3.9.2	Current sponsor code	SBI-087
D.3.9.3	Other descriptive name	Anti-CD20 small modular immunopharmaceutical, WYE-400087
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	160
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	humanized Small Modular Immunopharmaceutical (SMIP™) biologic agent directed against the CD20 antigen located on B lymphocytes

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	Powder for solution for 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 (seropositive)

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	10040107
E.1.2	Term	Seropositive 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

To evaluate clinical efficacy and safety of 4 SBI-087 SC dosing regimens versus placebo in seropositive subjects with active RA on a stable background of MTX

E.2.2

Secondary objectives of the trial

Additional safety evaluations, health outcomes assessments, multiple-dose pharmacokinetics, pharmacodynamics, and evaluation of the relationship between B-cell depletion and SBI-087 serum concentration

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

All sub-studies are described in the main clinical trial protocol.

1) Pharmacogenetic Sub-study:
One of the exploratory objectives of this study is to evaluate possible correlations between individual genotypes and clinical response in subjects with RA after administration of SBI-087. Genetic testing may be performed at a later date to determine the association of certain genetic polymorphisms and SBI-087 dose groups that demonstrate efficacy.

2) Pharmacogenomics Sub-study:
One of the exploratory objectives of this study is to evaluate possible correlations between gene expression profiles after administration of SBI-087 and clinical response in subjects with RA. Gene expression profiles before and after administration of SBI-087 will be monitored at specific time points throughout the study by measuring transcript levels of messenger ribonucleic acid (mRNA) in peripheral blood cells. Expression profiling of mRNA may be done to measure the entire expressed genome of all mRNA transcripts or in a gene-specific manner by focusing on select genes of interest.

3) Immunophenotyping Sub-Study:
Exploratory analysis of B-cell subsets will be performed. The degree of depletion and the rate of repopulation of select B-cell populations following B cell depletion therapy have been associated with clinical response and disease relapse. Exploratory endpoints will include the degree to which depletion of memory B cells may predict clinical response, potential relationships between the rate of repopulation of memory B cells and clinical relapse and potential correlations between repopulation of naïve B cells and clinical response. Levels of B cell populations will be quantified prior to and following dosing with SBI-087. In addition, select T-cell populations and NK cell populations will be analysed.

4) Dense Pharmacokinetic Analysis Sub-Study:
Approximately 7 subjects per dose group will participate in the dense pharmacokinetic substudy (total of 35 subjects).

E.3

Principal inclusion criteria

1. Age ≥18 years at the time of the signing of the ICF (or older as required by local regulation or ethics committees).
2. Subjects must be willing and able to comply with all the requirements of the study.
3. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at screening and baseline. WOCBP are defined as women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Women of non-childbearing potential are defined as either postmenopausal (history of amenorrhea for ≥52 weeks) or who are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or tubal ligation (procedure performed ≥1 year before screening). This information must be documented in the subject’s source documents.
4. All WOCBP who have sexual intercourse with a non-surgically sterilized male must agree and commit to the use of hormonal contraception, double-barrier contraception (use of a condom with spermicide), or an intrauterine device throughout the entire study (defined as the time of the signing of the ICF through the conclusion of subject participation). Vasectomized partners must have had their vasectomy more than
6 months before study day 1.
5. All men (unless surgically sterile) who have sexual intercourse with a WOCBP must agree and commit to using a medically acceptable and highly effective method of contraception for the entire study (defined as the time of the signing of the ICF through the conclusion of subject participation). Medically acceptable and highly effective methods of contraception include properly used barrier forms of contraception.
6. Meets the American Rheumatism Association 1987 revised criteria for classification of RA at least 6 months prior to screening.
7. ACR functional class I through III.
8. At screening and baseline active RA as defined by ≥ 5 swollen joints and ≥ 5 tender joints (28 joint count) and either 1 or both of the following at screening:
• C-reactive protein (CRP) ≥10 mg/L
• Erythrocyte sedimentation rate (ESR) ≥28 mm/h

9. Must be seropositive as defined by a documented history of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) positivity. If a documented history of RF or anti-CCP positivity is not available, RF and anti-CCP titers will be obtained at screening.
10. Must be receiving a MTX regimen (up to 25 mg weekly), according to standard medical practice and local regulation, for at least 12 weeks prior to baseline with or without a prior history of anti-TNF agent use. The dose and route of administration of MTX must be stable for at least 8 weeks prior to baseline and anticipated throughout the course of the study.

E.4

Principal exclusion criteria

1. Pregnant women, nursing mothers, or women planning to become pregnant during the study.
2. Any cardiovascular, neurological, metabolic, immunological, hepatic, or renal condition that, in the opinion of the investigator, could be detrimental to subjects participating in this study, including any clinically important deviations from normal clinical laboratory values or important concurrent medical events.
3. Presence of active or suspected latent infection including any underlying diseases including open cutaneous ulcers that could predispose the subject to infection.
4. Severe heart failure (New York Heart Association [NYHA] class IV) or severe, uncontrolled cardiac disease.
5. Subjects with active tuberculosis. A tuberculosis test, interpreted by the investigator according to local standards or country-specific-guidelines, must be performed during the screening visit for subjects with no documentation of tuberculosis test results available within 4 weeks before the screening visit.
6. Subjects with other rheumatic diseases, including but not limited to Lyme disease, psoriatic arthritis, spondyloarthropathy, systemic lupus erythematosus, systemic vasculitis, polymyositis, infectious arthritis, reactive arthritis, overlap syndrome and primary Sjögren's syndrome.
7. Cancer or history of cancer other than adequately treated cutaneous basal cell carcinoma or squamous cell carcinoma of the skin or in situ cervical cancer, with no evidence of recurrence.
8. History of alcohol or drug abuse that, in the opinion of the investigator, would interfere with the ability to comply with the study protocol.
9. Documented immunodeficiency disease, including but not limited to subjects with known human immunodeficiency virus (HIV) at the time of screening.
10. Subjects positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HepCAb), history of drug-induced liver injury, documented liver cirrhosis, or documented fibrosis at any time before the screening visit.
11. Any significant laboratory abnormality at screening, including the following:
• Hemoglobin (Hb) <85 g/L
• White blood cells (WBC) <3.50 x 10e9/L
• Platelets <125 x 109/L or ≥1000 x 10e9/L
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x the upper limit of normal (ULN)
• Serum creatinine (SCr) >177 μmol/L

12. Clinically significant finding on chest x-ray. Chest x-ray must be obtained during the screening period, unless a radiograph was obtained within 24 weeks prior to the baseline visit.
13. Prior use of B-cell depleting agents (e.g., rituximab).
14. Receipt of abatacept and/or tocilizumab.
15. Receipt of live attenuated vaccine ≤8 weeks prior to the screening visit.
16. Known hypersensitivity to mouse immunoglobulin, mouse/human chimeric immunoglobulin, or other biopharmaceutical proteins.
17. Hypersensitivity to corticosteroids and/or acetaminophen/paracetamol and/or diphenhydramine (or equivalent).
18. Receipt of the following within 24 weeks before the baseline visit:
• Any investigational drug, including biologics
• Any cytotoxic or immunosuppressive agent, including cyclophosphamide or chlorambucil
• Intravenous immunoglobulin (IVIG)
• Prosorba column (extracorporeal immunoadsorption protein A column)
• Leflunomide
• Intra-articular (IA) hyaluronic acid injections

19. Receipt of the following within 12 weeks before the baseline visit:
• Any disease-modifying antirheumatic drug (DMARD; including biologic DMARDs), other than MTX, not listed under the other exclusion criteria
• Golimumab
• Any surgical joint intervention (open or arthroscopic)

20. Receipt of the following within 10 weeks before the baseline visit:
• Adalimumab
• Infliximab

21. Receipt of the following within 4 weeks before the baseline visit:
• Etanercept
• Hydroxychloroquine
• Sulfasalazine

22. Receipt of the following within 2 weeks before the baseline visit:
• More than 10 mg/day of oral prednisone or equivalent, or a change in the dose of prednisone or its equivalent, or having IA corticosteroid injection or bolus intramuscular (IM) or IV treatment with corticosteroids (≥20 mg of prednisone or equivalent)
• More than 1 nonsteroidal anti-inflammatory drug (NSAID), or a change in the dose of the NSAID, or an NSAID dose greater than the maximum recommended dose (aspirin at doses of up to 325 mg for cardiac protection daily is permitted)

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the ACR20 response at week 16 for the modified intent-to-treat (mITT) population.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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)

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

Yes

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

Last subject last visit

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

125

F.4.2.2

In the whole clinical trial

200

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 for rheumatoid arthritis

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

2010-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-07-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-07-25

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