Clinical Trials Register

Summary
EudraCT Number:	2016-002344-16
Sponsor's Protocol Code Number:	RR16/209
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-11-29
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

UK - MHRA

A.2

EudraCT number

2016-002344-16

A.3

Full title of the trial

Targeted treatment early with etanercept (biosimilar) plus methotrexate or methotrexate with T2T care for DMARD-naïve early RA patients. A prospective, longitudinal cohort study with an embedded pilot randomised controlled trial to assess treatment rationalisation based on naïve CD4+ T-cell stratification.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Targeted treatment early with etanercept and methotrexate or methotrexate with treat to target (standard) care for treatment-naive early rheumatoid arthritis patients, based on baseline naive T-cell frequency.

A.3.2

Name or abbreviated title of the trial where available

TEEMS

A.4.1

Sponsor's protocol code number

RR16/209

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	University of Leeds
B.1.3.4	Country	United Kingdom
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	Benepali
D.2.1.1.2	Name of the Marketing Authorisation holder	Samsung Bioepis
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Benepali
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
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	ETANERCEPT
D.3.9.1	CAS number	185243-69-0
D.3.9.4	EV Substance Code	AS1
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	50
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)	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid Arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis - The most common form of inflammatory arthritis. It is a condition where your body’s immune system causes joints to become swollen and damaged.

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Overall Aim: To determine whether a patient's baseline naive T-cell frequency can guide treatment decisions for treatment-naive early RA patients. Specifically, can we rationalise the use of MTX and offer more targeted treatment for patients with a poor prognosis based on their naive T-cells?

Primary Objective:

To determine whether the proportion of patients achieving clinical remission after first-line treatment with methotrexate and standard treat to target care differs according to naive CD4+ T-cell frequency (normal/abnormal) at baseline.

E.2.2

Secondary objectives of the trial

1. To determine the proportion of patients that achieve clinical remission for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving etanercept + methotrexate compared to methotrexate with T2T care.

2. To determine whether the proportion of patients that achieve ultrasound remission (absence of inflammation on ultrasound) with first-line treatment with MTX and T2T care differs according to naïve T-cell frequency (normal/abnormal) at baseline.

3. To determine the proportion of patients that achieve ultrasound remission for patients with abnormal baseline naïve T-cell frequencies receiving etanercept + MTX compared to MTX with T2T care.

4. To determine the proportion of patients who normalize their T-cell frequency for patients with abnormal baseline naïve T-cells receiving MTX with T2T care or etanercept + MTX.

5. To determine whether patient reported outcomes differ between patients with normal or abnormal baseline naive T-cells.

6. To determine whether the prop

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject has a diagnosis of RA as defined by the new ACR/EULAR 2010 classification criteria
2. Newly diagnosed (within 12 weeks)
3. Active disease at screening (DAS28ESR ≥3.2)
4. Anti-citrillunated peptide protein antibody positive (ACPA)
5. Male & female subjects ≥18 years old.
6. DMARD-naïve
7. No use of intra-muscular/Intra-articular or oral corticosteroids 4 weeks prior to screening.
8. All male and female subjects biologically capable of having children must agree to use a reliable method of contraception for the duration of the study and 24 weeks after the end of the study period. Acceptable methods of contraception are surgical sterilisation, oral, implantable or injectable hormonal methods, intrauterine devices or barrier contraceptives.
9. Patients must have the capacity and be willing to provide written informed consent and comply with the requirements of the protocol.
10. Subjects deemed to be in good health with respect to clinical examination and screening blood tests, including full blood count (FBC), urea and electrolytes (U&E), and liver functions tests (LFT)- See below exclusion criteria

E.4

Principal exclusion criteria

1. Use of any additional investigational medications or products within 4 weeks of screening.
2. Use of intramuscular, intra-articular or oral corticosteroids within 4 weeks prior to screening.
3. Pregnant/lactating women or planning pregnancy within 24 weeks of last protocol treatment
4. Planned surgery within the study period (requiring omission of study medication > 28 days).
5. The presence of other comorbidities, which the physician deems as significant to interfere with evaluation (musculoskeletal condition such as osteoarthritis & fibromyalgia).
6. Diagnosis of another inflammatory arthritis or conective tissue disease e.g. psoriatic arthritis or Ankylosing spondylitis, primary Sjogren’s syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis.
7. Patients with any ongoing or active infection or any major episode of severe infection requiring hospitalization or treatment with IV antibiotics within the preceding 4 weeks of screening and/or orally administered antibiotics in the preceding 2 weeks of screening.
8. Any contraindication to conventional DMARD’s and anti-TNF therapy
9. In receipt of a live vaccination within 4 weeks prior to screening
10.Patients with abnormal liver function at the time of screening or abnormal blood tests as shown by:  
o Aminotransferase (AST)/alanine aminotransferase (ALT) >3x upper limit of normal (ULN), OR Bilirubin >51µmol/L  
o Serum Creatinine >175 mmol/L, eGFR below 30ml/L/min/1.73m2
o Neutrophils <2000 x 10*6/L  
o Platelets <125 x 109/L
 o Haemoglobin <90 g/L for males and <85 g/L for females  

E.5 End points

E.5.1

Primary end point(s)

The difference in the proportions of patients in clinical remission (DAS28 ≤2.6) at 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

E.5.2

Secondary end point(s)

• The difference in the proportions of patients in clinical remission (DAS28 ≤2.6) after 12 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies

• The difference in the proportions of patients in clinical remission (DAS28 ≤2.6) at 12 weeks and 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)

• The differences in the medians of patient-reported outcome measures (EMS, VAS scales, HAQ-DI) after 12 weeks & 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies

• The differences in the medians of patient-reported outcome measures (EMS, VAS scales, HAQ-DI) after 12 weeks & 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care(Arm B) vs. etanercept + methotrexate (Arm C)

• The difference in the proportions of patients in imaging remission (PD=0) after 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) or abnormal (Arm B) naïve CD4+T-cell frequencies

• The difference in the proportions of patients in imaging remission (PD = 0) 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)

• The difference in the proportion of patients with normal naïve CD4+ T-cells at 24 weeks (24 weeks)for patients with abnormal baseline naïve CD4+ T-cells receiving methotrexatewith T2T care (Arm B) vs. etanercept +
methotrexate (Arm C)

• The difference in the proportions of patients achieving sustained clinical remission (DAS28ESR ≤2.6 at both 12 and 24 weeks) (Arm A vs. Arm B and Arm B vs. Arm C)

• The difference in the average (median) cumulative amount of intramuscular corticosteroid use at 24 weeks between study arms (Arm A vs. Arm B and Arm B vs. Arm C). This will include any administered at the 24 week visit.

E.5.2.1

Timepoint(s) of evaluation of this end point

As outlined above

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

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Remission Induction

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Information not present in EudraCT

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

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

When all patients have completed 24 weeks of follow-up of the trial, any safety data are resolved and procedures are signed off and all analyses of laboratory samples are complete.

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