Clinical Trials Register

Summary
EudraCT Number:	2016-002061-54
Sponsor's Protocol Code Number:	Re-IMPROVE
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-11-15
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002061-54

A.3

Full title of the trial

"Switch between originator infliximab (Remicade®) and biosimilar infliximab (Remsima®) in the treatment of rheumatoid arthritis, spondyloarthritis and chronic inflammatory bowel diseases.
Evaluation of immunogenicity and clinical response"

“Switch tra Infliximab originator (Remicade®) ed Infliximab biosimilare (Remsima®) nel trattamento dell’artrite reumatoide, delle spondiloartriti e delle malattie infiammatorie croniche dell’intestino.
Valutazione dell’immunogenicità e della risposta clinica”

A.3.1

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

Switch between originator infliximab (Remicade®) and biosimilar infliximab (Remsima®) in the treatment of rheumatoid arthritis, spondyloarthritis and chronic inflammatory bowel diseases.

Switch tra Infliximab originator (Remicade®) ed Infliximab biosimilare (Remsima®) nel trattamento dell’artrite reumatoide, delle spondiloartriti e delle malattie infiammatorie croniche dell’intestino.

A.3.2

Name or abbreviated title of the trial where available

Switch between originator infliximab (Remicade®) and biosimilar infliximab (Remsima®)

“Switch tra Infliximab originator (Remicade®) ed Infliximab biosimilare (Remsima®)

A.4.1

Sponsor's protocol code number

Re-IMPROVE

A.5.4

Other Identifiers

Name:

Re-IMPROVE

Number:

Re-IMPROVE

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	UNIVERSITÀ CATTOLICA DEL SACRO CUORE- POLICLINICO A. GEMELLI
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	Celltrion Healthcare Co. Ltd
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Policlinico Universitario "A. Gemelli"
B.5.2	Functional name of contact point	U.O. Complessa di Reumatologia - Un
B.5.3	Address:
B.5.3.1	Street Address	Via Giuseppe Moscati, 31
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0635034654
B.5.5	Fax number	0635034523
B.5.6	E-mail	reumatologia@rm.unicatt.it

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	REMSIMA - 100 MG POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLANCONCINO (VETRO) - 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	CELLTRION HEALTHCARE HUNGARY KFT
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.3.1	Product name	Remsima
D.3.2	Product code	42942019
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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	Biosimilare

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid arthritis, seronegative spondylo arthritis,
Crohn's Disease, Ulcerative Colitis

Artrite Reumatoide, Spondiloartrite sieronegativa, Morbo di Crohn, Colite Ulcerosa

E.1.1.1

Medical condition in easily understood language

Rheumatoid arthritis, seronegative spondylo arthritis,
Crohn's Disease, Ulcerative Colitis

Artrite Reumatoide, Spondiloartrite sieronegativa,
Morbo di Crohn, Colite Ulcerosa

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	10002556
E.1.2	Term	Ankylosing spondylitis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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	10011401
E.1.2	Term	Crohn's disease
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

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	10075634
E.1.2	Term	Acute haemorrhagic ulcerative colitis
E.1.2	System Organ Class	10017947 - Gastrointestinal 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 demonstrate that the switch from Infliximab RMP (Remicade®) to Infliximab biosimilar (Remsima®), in patients who consent their study participation, does not determine, after 40 weeks of treatment (T3), an increase of the percentage of patients ADA positive≥ 20% in comparison with that measured at T0.

Dimostrare che lo switch da Infliximab RMP (Remicade®) ad Infliximab biosimilare (Remsima®), nei pazienti che accettano di partecipare allo studio, non determina dopo 40 settimane di trattamento (T3) un incremento nella percentuale di pazienti ADA positivi superiore al 20% rispetto alla stessa percentuale rilevata al T0.

E.2.2

Secondary objectives of the trial

The following subpopulations are defined: RA+AS for rheumatic disease, CD+UC for bowel disease.
The objectives are:
To assess the rate of change in the proportion of patients ADA+ before vs after the switch in subpopulations and in the overall study population.
To assess for each pathology the therapeutic equivalence of Infliximab RMP and Infliximab biosimilar, through Clinical Indices and laboratory parameters measured at T-1 and T0 and after the switch at T1, T2 and T3 .
To assess the equivalence of sieric level of ADAs at T0 and T3, in subpopulations and in the overall study population.
To assess the equivalence of sieric level of Infliximab among values measured before vs after the switch.
To assess the safety and tolerability of Infiximab biosimilar with respect to rate of AE and changes in vital signs and hematochemical parameters in subpopulations and in the overall study population.

Si definiscono le seguenti sottopopolazioni: AR+AS per patologia reumatica, MC+CU per patologie intestinali.
Gli obiettivi sono:
Valutare nella popolazione globale di studio e nelle sottopopolazioni la variazione nella percentuale di pazienti ADA+ prime e dopo lo switch.
Valutare per singola patologia l’equivalenza terapeutica di Infliximab RMP e Infliximab biosimilare, mediante indici clinici e parametri di laboratorio specifici per patologia, a T-1 e T0 e ai tempi T1, T2 e T3, dopo lo switch.
Valutare, nella popolazione globale e nelle sottopopolazioni, la sostanziale equivalenza del livello sierico di ADAs a T0 e T3.
Valutare, nella popolazione globale e nelle sottopopolazioni, la sostanziale equivalenza dei livelli sierici di Infliximab.
Valutare, nella popolazione globale e nelle sottopopolazioni, la sicurezza e tollerabilità dell’Infliximab biosimilare in termini di incidenza di EA e andamento dei segni vitali e parametri ematochimici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. age ≥18 years
2. diagnosis of
a. Rheumatoid Arthritis according to ACR criteria (1987 e 2010) OR
b. Sieronegative spondiloarthritis (Ankylosing Spondylitis or Sponsiloarthritis (Psoriasic Arthritis) according to ASAS criteria 2009 OR
c. Inflammatory Disease confirmed by endoscopic and histological criteria
3. Treatment with Infliximab RMP (Remicade®) for at least 6 months with stable dosage at least in the last two infusions.
4. Stable clinical response at the time of inclusion in the study (T-1) [stability is defined as reduction ≥30% of the disease activity scores in comparison with the start of treatment with Infliximab RMP (Remicade®)]
5. In case of concomitant therapy with immunosuppressive drugs (azatioprine/6 mercaptopurine, methotrexate o leflunomide), their dosage should be stable at least in the last 2 months.
6. In case of concomitant systemic therapy with steroids their dosage should be stable at least in the last 2 months and ≤7.5 mg/die of prednisone (or equivalent)
7. Any concomitant drug for diseases other than those under study should be at a stable dosage for at least 4 weeks before the study inclusion.

1. età≥18 anni
2. pazienti con diagnosi di:
a. Artrite Reumatoide secondo i criteri dell’ American College of Rheumatology (1987 e 2010)
oppure
b. Spondiloartrite sieronegativa (Spondilite anchilosante o Spondiloartrite/Artrite psoriasica) secondo i criteri ASAS 2009
oppure
c. IBD confermata da criteri endoscopici ed istologici
3. pazienti in trattamento con Infliximab RMP (Remicade®) da almeno 6 mesi con dosaggio stabile almeno nelle ultime 2 infusioni
4. pazienti con malattia in fase stabile di risposta clinica al momento dell’inclusione nel presente studio (T-1) [viene definita fase stabile una riduzione ≥30% degli score di attività di malattia rispetto all’inizio del trattamento con Infliximab RMP (Remicade®)]
5. nel caso di pazienti in trattamento concomitante con farmaci immunosoppressori (azatioprina/6 mercaptopurina, metotrexato o leflunomide) questi farmaci devono essere a dosaggio stabile almeno negli ultimi 2 mesi
6. nel caso di pazienti in trattamento con steroidi sistemici questi devono essere a dosaggio stabile almeno negli ultimi 2 mesi e ≤7.5 mg/die di prednisone (o equivalente)
7. qualsiasi farmaco concomitante per patologie differenti da quelle in studio deve essere a dosaggio stabile da almeno 4 settimane prima dell’ingresso nello studio.

E.4

Principal exclusion criteria

1. Active Infectious diseases
2. Severe comorbidities (known malignancy except for basal cell carcinoma, congestive heart failure NYHA grade III/IV, liver and/or hepatobiliary disease, renal disease)
3. Pregnancy or breast feeding
4. Any underlying condition which, in the opinion of the Investigator, might contrarindicate the switch to Remsima®

1. malattie infettive in fase attiva
2. gravi co-morbidità (neoplasie con esclusione del carcinoma basocellulare cutaneo, insufficienza cardiaca congestizia di grado III/IV secondo la NYHA, malattie epatiche e/o epato-biliari, malattie renali)
3. gravidanza o allattamento
4. qualunque condizione che a giudizio del medico sperimentatore possa controindicare lo switch da infliximab a Remsima®.

E.5 End points

E.5.1

Primary end point(s)

Sieric level of Anti Drug Antibody measured by ELISA test (LISA-TRACKER Duo Infliximab).

Per la determinazione quantitativa dei livelli sierici di ADAs sarà utilizzato un test immuno-enzimatico (ELISA) denominato LISA-TRACKER Duo Infliximab (Diametra, THERADIAG).

E.5.1.1

Timepoint(s) of evaluation of this end point

T0 (Switch) and T3

T0 (Switch) e T3

E.5.2

Secondary end point(s)

Indices of disease activity:
Rheumatoid Arthritis: DAS 28 and CDAI; Spondyloarthritis: BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), ASDAS (Ankylosing Spondylitis Disease Activity Index), LEI (Leeds Enthesitis Index) and only for Psoriatic Arthritis DAPSA (Disease Activity Psoriatic Arthritis), PSAID12 (Psoriatic Arthritis Impact of Disease); Crohn’s Disease: HBI (Harvey Bradshow Index); Ulcerative Colitis pMAYO (partial MAYO).
Indices of quality of life/functional status:
Rheumatoid Arthritis: HAQ (Health Assessment Questionnaire); Spondyloarthritis: BASFI: (Bath Ankylosing Spondylitis Functional Index); Crohn’s Disease and Ulcerative Colitis: IBDQ (Inflammatory Bowel Disease Questionnaire).
Sieric level of infliximab and Anti Drug Antibody measured by ELISA test (LISA-TRACKER Duo Infliximab).

Ematochemical parameters (hemocrome + formula, ERS and CRP, GPT, GGT and GOT, ALP, creatinine only for patients with rheumatological diseases).
Vital signs (blood pressure, body temperature, heart rate)
Physical examination
Adverse events
Anti-Drug Antibodies

Le variabili di efficacia sono rappresentate dagli indici di attività di malattia e di qualità della vita/stato funzionale specifici per la patologia di inclusione, livelli sierici di infliximab e ADAs.
Indici di attività di malattia:
1. Artrite reumatoide: DAS 28 e CDAI
2. Spondiloartriti: BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), ASDAS (Ankylosing Spondylitis Disease Activity Index), LEI (Leeds Enthesitis Index), e solo per pazienti con spondiloartrite psoriasica: DAPSA (Disease Activity Psoriatic Arthritis), PSAID12 (Psoriatic Arthritis Impact of Disease)
3. Malattia di Crohn: HBI (Harvey Bradshow Index)
4. Colite ulcerosa: pMAYO (partial MAYO)
Indici di qualità della vita e stato funzionale:
1. Artrite Reumatoide: HAQ (Health Assessment Questionnaire)
2. Spondiloartriti: BASFI: (Bath Ankylosing Spondylitis Functional Index)
3. Malattia Di Crohn e Colite Ulcerosa: IBDQ (Inflammatory Bowel Disease Questionnaire)
Livelli sierici:
Per la determinazione quantitativa dei livelli sierici di principio attivo e di ADAs sarà utilizzato un test immuno-enzimatico (ELISA) denominato LISA-TRACKER Duo Infliximab (Diametra, THERADIAG).

La valutazione di sicurezza sarà effettuata attraverso esami ematochimici, rilevazione dei segni vitali e degli eventi avversi. Gli ADA oltre a rappresentare un parametro per la valutazione dell’efficacia (vedi sopra) rappresentano anche un parametro in termini di tollerabilità.
1. Esami ematochimici : Emocromo con formula, VES e PCR, ALT, GGT saranno misurati in occasione di tutte le visite dello studio. In aggiunta, per i soli pazienti di Reumatologia, verranno misurati AST, Fosfatasi Alcalina, Creatinina
2. Segni vitali: Pressione arteriosa, temperatura corporea e frequenza cardiaca misurate come da pratica clinica in occasione di tutte le visite dello studio
3. esame obiettivo generale: anormalità alla visita di inclusione saranno registrate in anamnesi mentre quelle rilevate in corso di studio e non prima evidenziate saranno registrate come eventi avversi.
4. eventi avversi

E.5.2.1

Timepoint(s) of evaluation of this end point

T-1, T0 (Switch), T1, T2 and T3

T-1, T0 (Switch), T1, T2 e T3

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

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

Yes

E.6.13.1

Other scope of the trial description

Equivalence in terms of immunogenicity and clinical response in real world

Equivalenza in termini di immunogenicità e risposta clinica in pratica clinica

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

cross over a singolo braccio

single-arm cross over study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

125

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

125

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

F.3.3.1

Women of childbearing potential not using contraception

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

250

F.4.2.2

In the whole clinical trial

250

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)

The treatment and the patient care will be according to the local clinical practice.

Il trattamento e l'assistenza proseguiranno come per pratica clinica di ciascun centro.

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

2016-10-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials