Clinical Trials Register

Summary
EudraCT Number:	2013-001569-17
Sponsor's Protocol Code Number:	ML28699
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-04
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-001569-17

A.3

Full title of the trial

A national, open-label, single-arm, phase IIIB study to evaluate the efficacy of weekly tocilizumab subcutaneous, administered as monotherapy or in combination with methotrexate and/or other DMARDS in rheumatoid arthritis (RA) patients.

STUDIO NAZIONALE, IN APERTO, A SINGOLO BRACCIO, DI FASE IIIB, PER VALUTARE L’EFFICACIA DI TOCILIZUMAB SOTTOCUTE, SOMMINISTRATO UNA VOLTA A SETTIMANA IN MONOTERAPIA O IN COMBINAZIONE CON METOTREXATO E/O CON ALTRI DMARD IN PAZIENTI CON ARTRITE REUMATOIDE (AR).

A.3.1

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

A national, open-label, single-arm, phase IIIB study to evaluate the efficacy of weekly tocilizumab subcutaneous, administered as monotherapy or in combination with other non-biological medicinal products in rheumatoid arthritis (RA) patients.

STUDIO NAZIONALE, IN APERTO, A SINGOLO BRACCIO, DI FASE IIIB, PER VALUTARE L’EFFICACIA DI TOCILIZUMAB SOTTOCUTE, SOMMINISTRATO UNA VOLTA A SETTIMANA IN MONOTERAPIA O IN COMBINAZIONE CON ALTRI FARMACI NON BIOLOGICI IN PAZIENTI CON ARTRITE REUMATOIDE (AR).

A.4.1

Sponsor's protocol code number

ML28699

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	Roche S.p.A.
B.1.3.4	Country	Italy
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	Roche S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Roche S.p.A.
B.5.2	Functional name of contact point	CLINICAL OPERATIONS
B.5.3	Address:
B.5.3.1	Street Address	VIALE G.B. STUCCHI 110
B.5.3.2	Town/ city	MONZA
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390392475070
B.5.5	Fax number	00390392475084
B.5.6	E-mail	ITALY.INFO_CTA@ROCHE.COM

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	tocilizumab SC
D.3.2	Product code	Ro 487-7533/F10-04
D.3.4	Pharmaceutical form	Solution for injection
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	TOCILIZUMAB
D.3.9.1	CAS number	375823-41-9
D.3.9.2	Current sponsor code	RO4877533
D.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.9.4	EV Substance Code	SUB20313
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	180
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid Arthritis

Artrite Reumatoide

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

Artrite Reumatoide

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of subcutaneous (SC) tocilizumab (TCZ) administered in monotherapy or in combination with methotrexate (MTX) and/or other non-biological disease modifying antirheumatic drugs (DMARDs) using Clinical Disease Activity Index (CDAI) over time up to 24, including onset of action at Week 2.

Valutare l’efficacia di tocilizumab (TCZ) sottocute (SC) somministrato in monoterapia o in combinazione con metotrexato (MTX) e/o con altri farmaci antireumatici modificanti la malattia (disease modifying antirheumatic drugs, DMARD) non biologici, utilizzando la variazione del Clinical Disease Activity Index (CDAI) nel tempo fino alla settimana 24, ivi compresa l’insorgenza di azione alla settimana 2.

E.2.2

Secondary objectives of the trial

To assess the efficacy of SC TCZ monotherapy or in combination with MTX and/or other non-biological DMARDs in CDAI remission (defined as a CDAI ≤2.8 during any two consecutive visits, not including the baseline visit), up to Week 52.
To evaluate the safety and tolerability of SC TCZ monotherapy or in combination with MTX and/or other non-biological DMARDs comprising adverse events (AEs), physical examination, vital signs and clinical laboratory assessments, including immunogenicity, in patients with active rheumatoid arthritis (RA) at week 24 and 52. [...]
The complete list of secondary Objectives can be found in the protocol.

Valutare l’efficacia di TCZ SC in monoterapia o in combinazione con MTX e/o con altri DMARD non biologici in termini di remissione secondo il CDAI (definita come riscontro di un valore CDAI ≤2,8 in occasione di due visite consecutive qualsiasi, esclusa la visita basale), fino alla settimana 52.
Valutare alla settimana 24 e alla settimana 52, la sicurezza e la tollerabilità di TCZ SC in monoterapia o in combinazione con MTX e/o con altri DMARD non biologici utilizzando come parametri gli eventi avversi (EA), l’esame obiettivo, i segni vitali e le valutazioni cliniche di laboratorio, ivi comprese le analisi di immunogenicità, nei pazienti con artrite reumatoide (AR) attiva.
[...]
L'elenco completo degli obiettivi secondari si può trovare nel protocollo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Able and willing to give written informed consent and comply with the requirements of the study protocol.
Patients at least 18 years of age.
Patients with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria.
Oral corticosteroids (≤10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs; up to the maximum recommended dose) are permitted if on a stable dose regimen for ≥4 weeks prior to baseline.
Permitted non-biologic DMARDs are allowed if at a stable dose for at least 4 weeks prior to baseline.
Receiving treatment on an outpatient basis, not including TCZ.
Females of childbearing potential and males with female partners of childbearing potential may participate in this study only if using a reliable means of contraception (e.g., physical barrier, contraceptive pill or patch, spermicide and barrier, or intrauterine device) during the study. Females of childbearing potential must use a reliable means of contraception for at least 3 months following the last dose of TCZ.
If female of childbearing potential, the patient must have a negative pregnancy test at Screening and baseline visits.
Patients with moderate to severe RA (CDAI ≥ 10 and DAS28 ≥ 3.2) at screening.
Patients who are Tumor Necrosis Factor (TNF)-Inadequate Responder (IR), MTX-IR, DMARD-IR. The time between the last dose of TNF inhibitor and the randomization in the study should depend on the approved dosing interval as reported in the SmPC and Prescribing Information (PI).

1. Capacità e volontà di fornire il consenso informato scritto e di attenersi ai requisiti del protocollo dello studio.
2. Pazienti di età pari o superiore a 18 anni.
3. Pazienti con diagnosi di AR attiva secondo i criteri ACR rivisti (1987) o i criteri EULAR/ACR (2010).
4. Utilizzo di corticosteroidi orali (≤10 mg/die di prednisone o equivalente) e farmaci antinfiammatori non steroidei (FANS; fino alla massima dose raccomandata) è permesso se utilizzati ad un regime di dosaggio stabile per ≥4 settimane prima della visita basale.
5. Utilizzo di DMARD non biologici è ammesso se utilizzati a una dose stabile per almeno 4 settimane prima della visita basale.
6. Pazienti che ricevono un trattamento in regime ambulatoriale che non includa TCZ.
7. Le donne in età fertile e gli uomini con una partner in età fertile possono partecipare a questo studio solo se utilizzano un metodo di contraccezione affidabile (es. metodi meccanici di barriera, pillola contraccettiva o cerotto, spermicida e metodo di barriera o dispositivo intrauterino) nel corso dello studio. Le donne in età fertile devono utilizzare un metodo di contraccezione efficace per almeno 3 mesi dopo l’ultima dose di TCZ.
8. Le donne in età fertile devono avere un test di gravidanza negativo alla visita di screening e alla visita basale.
9. Pazienti con AR da moderata a severa (CDAI ≥10 e DAS28 ≥3,2) allo screening.
10. Pazienti che hanno avuto una risposta inadeguata (IR) a farmaci antagonisti del tumor necrosis factor (TNF), al MTX e ai DMARD. Il tempo intercorrente fra l’ultima dose assunta dell’inibitore del TNF e la randomizzazione nello studio verrà deciso in base all’intervallo approvato come riportato nella scheda tecnica del prodotto (SmPC) e nelle informazioni di prescrizione (PI).

E.4

Principal exclusion criteria

Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 12 months following baseline.
13. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies.
14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal (GI) disease.
15. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforation.
16. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
17. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening.
18. Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for TB with no recurrence in 3 years are permitted.
19. Current liver disease as determined by the Investigator.
20. Positive hepatitis B surface antigen or hepatitis C antibody.
21. Primary or secondary immunodeficiency (history of or currently active).
22. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years.
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjögren’s syndrome with RA is permitted.
3. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
4. Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16.
5. Prior history of or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, and arthropathy of inflammatory bowel disease).
· Excluded Previous or Concomitant Therapy:
6. Exposure to TCZ (either intravenous [IV] or SC) at any time prior to baseline.
7. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
8. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20.
9. Treatment with IV gamma globulin, plasmapheresis within 6 months of baseline.
10. Intraarticular or parenteral corticosteroids within 4 weeks prior to baseline.
11. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
12. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
23. Pregnant women or nursing (breast feeding) mothers.
24. Patients with reproductive potential not willing to use an effective method of contraception.
25. History of alcohol, drug, or chemical abuse within 1 year prior to Screening.
26. Neuropathies or other conditions that might interfere with pain evaluation.
· Laboratory Exclusion Criteria (at Screening):
27. Serum creatinine >1.4 mg/dL (124 μmol/L) in female patients and >1.6 mg/dL (141 μmol/L) in male patients.
28. Alanine aminotransferase or aspartate aminotransferase >1.5 times upper limit of normal (ULN).
29. Total bilirubin >ULN.
30. Platelet count <100 x 109/L (100,000/mm3).
31. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
32. White blood cells <3.0 x 109/L (3000/mm3).
33. Absolute neutrophil count <2.0 x 109/L (2000/mm3).
34. Absolute lymphocyte count <0.5 x 109/L (500/mm3).

1. Intervento di chirurgia maggiore (ivi compresa chirurgia articolare) nelle 8 settimane precedenti lo screening o programmazione di un intervento di chirurgia maggiore nei 12 mesi successivi alla visita basale.
2. Malattia reumatica autoimmune diversa dall’AR, ivi compresi lupus eritematoso sistemico, malattia mista del tessuto connettivo, sclerodermia, polimiosite o interessamento sistemico significativo secondario all’AR (es. vasculite, fibrosi polmonare o sindrome di Felty). È ammessa la sindrome di Sjögren secondaria associata ad AR.
3. Classe funzionale IV definita in base alla Classificazione ACR dello Stato Funzionale nell’AR.
4. Diagnosi di artrite idiopatica giovanile o AR giovanile e/o AR prima dei 16 anni di età.
5. Pregressa o attuale malattia infiammatoria delle articolazioni diversa dall’AR (es. gotta, malattia di Lyme, spondiloartropatia sieronegativa includente artrite reattiva, artrite psoriasica e artropatia associata a malattia infiammatoria intestinale).
Vi sono poi una serie di criteri di esclusione correlati a:
- terapie precedenti o concomitanti;
- alla sicurezza in generale;
- ai parametri di laboratorio (allo screening);
per i quali si prega di far riferimento al protocollo di studio.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

week 24, including onset of action at Week 2.

settimana 24, ivi compresa l’insorgenza di azione alla settimana 2

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

week 52

settimana 52

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

Immunogenity

Immunogenicità

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

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

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

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

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

LVLS

Lo studio terminerà quando l’ultimo paziente completerà l’ultima visita programmata dallo studio, oppure qualora lo Sponsor decidesse di ritirare lo studio.

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

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:

191

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

225

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 study treatment period is at least 52 weeks. At the end of the 52-week treatment period, if deemed as appropriate by the treating physician, patient will continue the study treatment with SC TCZ until SC TCZ commercial availability in Italy.
Following the 52-week treatment period, patient will perform visits every 3 months until SC TCZ commercial availability in Italy.

Non è previsto un trattamento correlato allo studio per i soggetti al termine della loro partecipazione allo studio stesso. Tuttavia al termine delle 52 settimane, se ritenuto appropriato dal medico dello studio, il paziente continuerà il trattamento con TCZ SC fino alla disponibilità commerciale di TCZ SC in Italia. Dopo il periodo di trattamento di 52 settimane, il paziente sarà sottoposto a visita, nell’ambito dello studio, ogni 3 mesi fino alla disponibilità commerciale di TCZ SC in Italia.

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

2013-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-05

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