Clinical Trials Register

Summary
EudraCT Number:	2014-000555-93
Sponsor's Protocol Code Number:	ARIAA
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-25
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

Czechia - SUKL

A.2

EudraCT number

2014-000555-93

A.3

Full title of the trial

Abatacept reversing subclinical Inflammation as measured by MRI in ACPA positive Arthralgia

Abatacept v léčbě známek zánětu prokázaných při MRI u ACPA pozitivních pacientů s artralgií

A.3.1

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

Abatacept reversing subclinical Inflammation as measured by MRI in ACPA positive Arthralgia

Abatacept v léčbě známek zánětu prokázaných při MRI u ACPA pozitivních pacientů s artralgií

A.4.1

Sponsor's protocol code number

ARIAA

A.5.4

Other Identifiers

Name:

clinicaltrials.gov

Number:

NCT02778906

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 Hospital Erlangen
B.1.3.4	Country	Germany
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	Bristol Myers Squibb
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Erlangen - Medizinische Klinik 3
B.5.2	Functional name of contact point	Lead Clinical Physician
B.5.3	Address:
B.5.3.1	Street Address	Ulmenweg 18
B.5.3.2	Town/ city	Erlangen
B.5.3.3	Post code	91054
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049913185 32093
B.5.5	Fax number	0049913185 35784

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.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	ABATACEPT
D.3.9.1	CAS number	332348-12-6
D.3.9.4	EV Substance Code	SUB20635
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Fusion protein

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 in pre-filled syringe
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

Patients with ACPA (anti citrullinated peptide antibodies) positive arthralgia and OMERACT RAMRIS synovitis (synovialitis or tenosynovitis) or osteitis but without clinical arthritis, defined by joint swelling

Pacienti s artralgiemi s pozitivitou ACPA protilátek (protilátky proti citrulinovaným proteinům) a synovitidou (synovialitidou a tenosynovitidou) podle OMERACT RAMRIS skóre anebo osteitidou bez známek klinické artritidy definované jako kloubní otok

E.1.1.1

Medical condition in easily understood language

Pre clinical phase of RA with joint pain and detection of characteristic antibodies and inflammatory signs detected by MRI (magnetic resonance imaging) but without joint swelling

Pre-klinická fáze RA s bolestivostí kloubů a přítomností charakteristických protilátek a zánětlivých známek zjištěných pomocí MRI (magnetická rezonance), bez otoků kloubů

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003239
E.1.2	Term	Arthralgia
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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 explore whether subclinical MRI inflammatory lesions are reduced in a higher proportion of ACPA positive arthralgia patients treated with abatacept s.c. 125mg/week than placebo after 6 months.

Zjistit podíl pacientů se zlepšením subklinického zánětu charakterizovaného jako regrese synovitidy (synovialitidy anebo tenosynovitidy) anebo osteitidy na MRI dominantní ruky po 6 měsících léčby abataceptem anebo placebem.

E.2.2

Secondary objectives of the trial

To describe the evolution of clinical and radiological parameters (MRI and HR-pQCT) in patients with ACPA positive arthralgia treated with abatacept s.c. or placebo for 6 months.

Popsat vývoj klinických a radiologických paramentrů (MRI a HR-pQCT) u pacientů s ACPA pozitivní artralgií léčených abataceptem s.c. či placebem po 6 měsíců

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

Intestinal microbiota-analysis of patients with CCP+ pre-RA and its modulation through a T-cell mediated immunemodulatory therapy.

Analýza střevního mikrobiomu u CCP+ pacientů v preklinické fázi RA a jeho změna zprostředkovaná T buňkami vlivem imunomodulační terapie

E.3

Principal inclusion criteria

- Females and males aged ≥18 years at time of consent
- ACPA (with or without RF)
- Joint pain (hand, feet, knee, shoulder or elbow) present for at least 6 weeks prior to inclusion or in past history
- Presence of synovitis (synovialitis or tenosynovitis) or osteitis in MRI of the dominant hand at baseline
- Must understand and voluntarily sign an informed consent form including written consent for data protection

- Ženy a muži s ≥ 18 let v době informovaného souhlasu
- ACPA (bez/s revmatoidní faktory)
- Bolest kloubů (ruce, nohy, koleno, rameno) po dobu minimálně 6 týdnů před zařazením anebo anamnesticky
- Přítomnost synovitidy (synovialitidy anebo tenosynovitidy) anebo osteitidy na MRI dominantní ruky na začátku (baseline)
- Musí porozumět a dobrovolně podepsat informovaný souhlas včetně informovaného souhlasu o ochraně dat

E.4

Principal exclusion criteria

- Presence of arthritis in hand, feet, knee, shoulder or elbow joints defined as swelling
- Current treatment with glucocorticoids conventional or biologic DMARDs
- Any other autoimmune or inflammatory disease such as SLE, PSS, MCTD, SpA, Behcet disease, vasculitis or autoimmune hepatitis.
- Any malignancy in the last 5 years
- Chronic infection such as latent TB, (TB not adequately treated according to guidelines), or hepatitis B or C infection
- Immunocompromised patients or patients known to be HIV positive
- Uncontrolled severe concomitant disease
- Pregnant or lactating females
- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

- Přítomnost artritidy rukou, nohou, kolene, ramene nebo lokte definovaného jako otok
- Konkomitantní terapie glukokortikoidy, konvenčními nebo biologickými DMARDs
- Jiné autoimunitní nebo zánětlivé onemocnění jako SLE, PSS, MCTD, SpA, Behcetova choroba, vaskulitida nebo autoimunitní hepatitida
- Jakákoliv malignita v posledních 5 letech
- Chronické onemocnění např. latentní tuberkulóza, tuberkulóza neadekvátně léčena podle doporučení, hepatitida B nebo C
- Imunokompromitovaní nebo HIV pozitivní pacienti
- Špatně kompenzované jiné přidružené onemocnění
- Těhotné nebo kojící ženy
- Jakýkoliv stav, včetně laboratorních abnormalit, který by představoval pro subjekt nepřijatelné riziko, pokud se zúčastnil studie nebo by znemožnil interpretaci studijních dat

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with an improvement of synovitis (synovialitis or tenosynovitis) or osteitis in the MRI of the dominant hand as measured using the OMERACT-RAMRIS score and the tenosynovitis score (change > 0 in the sum of RAMRIS osteitis and synovitis score and tenosynovitis score).

Podíl pacientů se zlepšením akutního zánětu charakterizovaného jako regrese synovitidy (synovialitidy anebo tenosynovitidy) anebo osteitidy na MRI dominantní ruky po 6 měsících léčby abataceptem anebo placebem.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 6 months of treatment with abatacept or placebo

Po 6 měsících léčby abataceptem nebo placebem

E.5.2

Secondary end point(s)

1) RAMRIS synovitis, erosion and osteitis scores in the dominant hand
2)Tenosynovitis score in the dominant hand
3) Proportion of patients with new or persistent arthralgia
4) Time to disappearance of arthralgia
5) Proportion of patients with clinical arthritis defined by joint swelling
6) Proportion of patients with RA (ACR/EULAR 2010 criteria)
7) Proportion of patients with radiological progress in HR-pQCT analysis comparing baseline image with end of study image.
8) TJC 68 and SJC 66
9) DAS28
10) VAS pain, VAS patient global, VAS physician global
11) Duration of joint stiffness
12) HAQ-DI
13) RAID score
14) SF-36 score
15) Bone mineral density (BMD), bone volume per tissue volume (BV/TV), cortical width and cortical porosity in the micro-CT of the distal radius and metacarpal heads
16) Gut microbiota composition for patients in the gut microbiota substudy

1) RAMRIS (Rheumatoid Arthritis Magnetic Resonance Imaging Score) skóre pro hodnocení synovitidy, erozí a osteitidy dominantní ruky
2) Skóre tenosynovitidy dominantní ruky
3) Podíl pacientů s novými nebo přetrvávajícími artralgiemi
4) Doba do kompletního ústupu artralgií
5) Podíl pacientů s klinicky průkaznou artritidou definovanou jako otok kloubu
6) Podíl pacientů s RA splňujících ACR/EULAR 2010 kritéria
7) Podíl pacientů s radiologickou progresí dle HR-pQCT (High-Resolution peripheral Quantitative Computed Tomography) srovnávající vstupní a výstupní výsledek na konci studie
8) Počet bolestivých kloubů z počtu 68 (Tender Joint Count 68, TJC 68), počet oteklých kloubů z počtu 66 (Swollen Joint Count 66, SJC 66)
9) Aktivita onemocnění podle skóre DAS28 (Disease Activity Score) hodnotící 28 kloubů
10) Vizuální analogová škála (VAS) bolesti, VAS globálního hodnocení pacientem, VAS globálního hodnocení lékařem
11) Délka trvání ztuhlosti kloubů
12) Index disability HAQ-DI (Health Assessment Questionnaire- Disability Index)
13) RAID (Rheumatoid Arthritis Impact of Disease) skóre
14) SF-36 (The Short Form 36 Health Survey questionnaire) skóre
15) Kostní hustota (Bone Mineral Density, BMD), objem kosti vzhledem na objem tkáně (bone volume per tissue volume, BV/TV), šíře kortikalis a porozita kortikalis distálního radia a hlaviček metakarpů dle mikro-CT
16) Složení střevní mikrobioty u pacientů v podstudii střevní mikrobioty

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2, 4, 5, 11, 12, 13: After 6, 12, and 18 months
3: In the first 6 months
6, 14: At the end of study (after18 months)
7, 8, 9, 10: After 3, 6, 9, 12, 15 and 18 months
16: After 6 and 12 months

1, 2, 4, 5, 11, 12, 13: po 6, 12, and 18 měsících
3: v prvních 6 měsících
6, 14: na konci studie (po 18 měsících)
7, 8, 9, 10: po 3, 6, 9, 12, 15 a 18 měsících
16: po 6 a 12 měsících

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)

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)

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

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

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

Brazil

Czech Republic

Germany

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

LVLS

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

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.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.4.2.2

In the whole clinical trial

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)

none

žádné

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

2018-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-30

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

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