Clinical Trials Register

Summary
EudraCT Number:	2018-000391-15
Sponsor's Protocol Code Number:	AIFA-2016-02364869
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:	2018-02-27
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000391-15

A.3

Full title of the trial

Multicentric, open-label, prospective study of subcutaneous tocilizumab in adult patients with refractory myositis

Studio multicentrico prospettico in aperto per valutare l’efficacia e la sicurezza di tocilizumab in soggetti con miosite refrattaria

A.3.1

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

Multicentric, prospective open-label study to assess the efficacy and safety of Tocilizumab in subjects with refractory myositis

Studio multicentrico, prospettico in aperto per valutare l’efficacia e la sicurezza di Tocilizumab in soggetti con miosite refrattaria

A.3.2

Name or abbreviated title of the trial where available

ToReMy

A.4.1

Sponsor's protocol code number

AIFA-2016-02364869

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	Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia
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	AIFA (Agenzia Italiana del Farmaco)
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	Presidio Ospedaliero Arcispedale Santa Maria Nuova – AUSL-IRCCS di Reggio Emilia
B.5.2	Functional name of contact point	Struttura Complessa di Reumatologia
B.5.3	Address:
B.5.3.1	Street Address	Viale Risorgimento, 80
B.5.3.2	Town/ city	Reggio Emilia
B.5.3.3	Post code	42123
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390522 295837
B.5.5	Fax number	+390522 295836
B.5.6	E-mail	mariagrazia.catanoso@ausl.re.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	RoActemra 162 mg soluzione iniettabile in siringa preriempita
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	RoActemra 162 mg soluzione iniettabile in siringa preriempita
D.3.2	Product code	NA
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.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.9.4	EV Substance Code	SUB20313
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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

Myositis (dermatomyositis [DM] or polymyositis [PM])

Miositi: Dermatomiosite (DM) e Polimiosite (PM)

E.1.1.1

Medical condition in easily understood language

Chronic inflammatory disorders of striated muscle with variable involvement of internal organs

Patologie infiammatorie croniche del muscolo striato con variabile interessamento degli organi interni

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	10012503
E.1.2	Term	Dermatomyositis
E.1.2	System Organ Class	10040785 - Skin and subcutaneous 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	10028653
E.1.2	Term	Myositis
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	10036102
E.1.2	Term	Polymyositis
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

Evaluate the efficacy of TCZ in patients with refractory myositis

Lo studio si propone di valutare l’efficacia del Tocilizumab nei pazienti con miosite.

E.2.2

Secondary objectives of the trial

Safety assessment

Valutazione della sicurezza

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. age 18 years or older
2. capacity to provide a written informed consent
3. fulfil the Bohan and Peter criteria and 1) have the typical rash of DM (heliotrope rash and/or Gottron sign and/or Gottron papules) or 2) have a myositis-specific autoantibody (MSA) or else 3) have the diagnosis confirmed by muscle biopsy
4. have significant muscle weakness (grade 4 or less of the Medical Research Council scale in at least 2 proximal muscle groups) plus have either an elevated muscle enzyme (CK or aldolase) at least 1.3 the upper limit of normal and/or an MRI of the thigh muscles showing edema in fat-suppressed sequences
5. physician’s global assessment of at least 2 (0-10 cm VAS)
6. a patient’s global assessment of at least 2 (0-10 cm VAS)
7. Health assessment questionnaire (HAQ) disability index of at least 0.25
8. signed informed consent form

1. età di almeno 18 anni
2. capacità di fornire un consenso informato scritto
3. soddisfare i criteri Bohan e Peter per la classificazione delle miositi e 1) avere la tipica eruzione cutanea della DM (eruzione cutanea eliotropa e / o segno di Gottron e / o papule di Gottron) oppure 2) avere un autoanticorpo specifico per miosite (MSA) oppure 3) avere la diagnosi confermata da biopsia muscolare
4. ipostenia muscolare significativa (grado 4 o meno della scala del Medical Research Council in almeno 2 gruppi muscolari prossimali) e almeno un enzima muscolare elevato (CPK o aldolasi) almeno 1,3 al di sopra del limite superiore della normale e / o RMN dei muscoli della coscia mostrante edema muscolare in sequenze a soppressione del grasso
5. valutazione globale del medico di almeno 2 (VAS da 0-10 cm)
6. valutazione globale del paziente di almeno 2
7. Indice di disabilità (HAQ) di almeno 0.25
8. adesione allo studio mediante firma del consenso informato

E.4

Principal exclusion criteria

1. subjects younger than 18 years
2. inability to provide informed consent
3. history of alcohol or recreational drug use within 1 year prior to screening
4. infections, including serious infections requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening;
5. positive HbsAg status or positive anti-HCV antibodies;
6. latent untreated TB
7. current malignancies or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been removed)
8. severe co-morbidities, including immunodeficiency; any comorbidity that in the opinion of the PI may not allow the patients to safely complete the trial
9. initiation of an exercise program for muscle strengthening within 4 weeks of the screening visit and for the whole duration of the trial
10. major surgery 4 weeks prior to study entry or planned major surgery during the study period
11. immunization with a live vaccines within a month before study entry
12. pregnancy and lactation, patients with reproductive potential not willing to use an effective method of contraception
13. previous treatment with TCZ
14. history of severe hypersensitivity reactions to monoclonal antibodies
15. contraindications to having an MRI of the thigh muscles done
16. abnormal laboratory values, including creatinine above the upper limit of normal unless creatinine clearance is above 30 ml/min; white cell count <3,000 mm3, absolute neutrophil count less than 2,000 mm3, absolute lymphocyte count less than 500/mm3, platelet count less than 100,000 and hemoglobin less than 8.5 g/dl.

1. soggetti di età inferiore ai 18 anni
2. incapacità di fornire un consenso informato,
3. anamnesi positiva per alcolismo o uso di droghe entro un anno prima dello screening,
4. infezioni, incluse infezioni gravi che richiedono ospedalizzazione o trattamento con antibiotici endovenosi entro 4 settimane dalla screening,
5. HbsAg positivo o anticorpi anti-HCV positivi,
6. TBC latente non trattata,
7. tumori maligni diagnosticati nei 5 anni precedenti (ad eccezione del basalioma, carcinoma squamoso della cute o del carcinoma in situ della cervice uterina operato),
8. comorbidità di rilievo, tra cui l'immunodeficienza; qualsiasi comorbidità che a giudizio del PI non possa permettere ai pazienti di completare il trial senza rischi,
9. l'inizio di un programma di esercizi per il rafforzamento muscolare entro 4 settimane dalla visita di screening e per tutta la durata dello studio,
10. intervento chirurgico maggiore 4 settimane prima dell'arruolamento nello studio o intervento maggiore pianificato durante il periodo dello studio,
11. immunizzazione con vaccini vivi entro un mese dall’arruolamento nello studio,
12. gravidanza e allattamento, pazienti con potenzialità riproduttiva che non sono disposti ad utilizzare un metodo efficace di contraccezione,
13. trattamento precedente con TCZ,
14. pregresse reazioni di ipersensibilità grave agli anticorpi monoclonali,
15. controindicazioni all'esecuzione di una risonanza magnetica nucleare dei muscoli della coscia,
16. valori di laboratorio anormali, compresa la creatinina al di sopra del limite superiore del normale, a meno che la clearance della creatinina sia superiore a 30 ml / minuto; conta leucocitaria <3.000 mm3, conta neutrofilica assoluta inferiore a 2.000 mm3, conta linfocitaria assoluta inferiore a 500 / mm3, conta piastrinica inferiore a 100.000 ed emoglobina inferiore a 8.5 g / dl.

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients achieving an improvement according to IMACS (International Myositis Assessment and Clinical Studies Group)

percentuale di pazienti che raggiunge un miglioramento secondo l'IMACS (International Myositis Assessment and Clinical Studies Group)

E.5.1.1

Timepoint(s) of evaluation of this end point

Weeks 0, 4, 8, 12, 16, 24, 38 and 52

settimane 0, 4, 8, 12, 16, 24, 38 e 52

E.5.2

Secondary end point(s)

1. time from first treatment to improvement based on IMACS criteria, percentage of patients achieving remission (defined as normal or stable muscle strength with normal levels of muscle enzymes, absence of muscular edema at MRI and absence of active extramuscular manifestations), reduction glucocorticoid dose, significant minimal improvement in cutaneous dermatomyositis, changes in edema at MRI, changes in fatty atrophy at MRI
2. Frequency and type of adverse events

1. tempo dal primo trattamento al miglioramento in base ai criteri IMACS, percentuale di pazienti che raggiungono la remissione (definita come forza muscolare normale o stabile con i normali livelli degli enzimi muscolari, assenza di edema muscolare alla RMN e assenza di manifestazioni extramuscolari attive), riduzione della dose di glucocorticoidi, miglioramento minimo significativo della dermatomiosite cutanea, cambiamenti nell'edema di MRI, variazioni di atrofia grassosa alla RMN;
2. frequenza e il tipo di eventi avversi

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Weeks 0, 4, 8, 12, 16, 24, 38 and 52
2. Week 0, 4, 8, 12, 16, 24, 38 and 52; any adverse event occurring at any time during the whole study

1. settimane 0, 4, 8, 12, 16, 24, 38 e 52
2. settimane 0, 4, 8, 12, 16, 24, 38 e 52; ogni evento avverso verificatosi a qualunque tempo durante l’intero studio

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

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

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

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:

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.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

Nessuno

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

2018-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-27

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

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