Clinical Trials Register

Summary
EudraCT Number:	2018-001931-27
Sponsor's Protocol Code Number:	STARS-trial
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-11
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

2018-001931-27

A.3

Full title of the trial

Comparison of STep-up and step-down therapeutic strategies in childhood ARthritiS

Confronto di strategie terapeutiche step-up e step-down nell'artrite idiopatica giovanile

A.3.1

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

Comparison of therapeutic strategies in childhood ARthritiS

Confronto di strategie terapeutiche nell'artrite idiopatica giovanile

A.3.2

Name or abbreviated title of the trial where available

the STARS trial

A.4.1

Sponsor's protocol code number

STARS-trial

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	IRCCS Istituto Giannina Gaslini
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
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Compagnia di San Paolo
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Pfizer
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	PRINTO
B.5.2	Functional name of contact point	PRINTO
B.5.3	Address:
B.5.3.1	Street Address	Via Gaslini5
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16147
B.5.3.4	Country	Italy
B.5.4	Telephone number	003901056362795
B.5.5	Fax number	00390104211018
B.5.6	E-mail	printo@gaslini.org

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	Reumaflex
D.2.1.1.2	Name of the Marketing Authorisation holder	Alfasigma
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.3.4	Pharmaceutical form	Solution for infusion 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	METHOTREXATE
D.3.9.1	CAS number	59-05-2
D.3.9.2	Current sponsor code	METHOTREXATE
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
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	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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.IMP: 2
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	Enbrel
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
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.3.4	Pharmaceutical form	Powder and solution for 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	ETANERCEPT
D.3.9.1	CAS number	185243-69-0
D.3.9.2	Current sponsor code	ETANERCEPT
D.3.9.4	EV Substance Code	SUB01984MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	up to
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Juvenile idiopathic arthritis (JIA) is an umbrella term that encompasses a heterogeneous group of disorders characterised by prolonged synovial inflammation that may cause destructive damage to joint structures. Permanent changes may also develop in extraarticular organs, particularly the eye (as a complication of chronic anterior uveitis), or may result from side effects of medications.

L’artrite idiopatica giovanile (AIG) è una malattia cronica caratterizzata da infiammazione persistente alle articolazioni; i segni tipici di infiammazione alle articolazioni sono dolore, gonfiore e limitazione dei movimenti. "Idiopatica" significa che non conosciamo la causa della malattia e "giovanile", in questo caso, significa che l’inizio dei sintomi di solito avviene prima dei 16 anni d’età.

E.1.1.1

Medical condition in easily understood language

Juvenile idiopathic arthritis (JIA) is a chronic disease characterized by persistent inflammation of the joints, pain, swelling and limitation of motion.

L’artrite idiopatica giovanile (AIG) è una malattia cronica caratterizzata da infiammazione persistente alle articolazioni, dolore, gonfiore e limitazione dei movimenti.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10059177
E.1.2	Term	Juvenile arthritis
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study is aimed to compare the effectiveness of a conventional therapeutic regimen, based on treatment escalation (Step-up strategy) and driven by the treat-to-target approach, with that of an early aggressive intervention based on a combination of conventional and biological DMARDs (Step-down strategy).
The hypothesis tested in this trial is whether an early aggressive therapy with a 6-month course of an anti-TNF agent in combination with methotrexate or with methotrexate alone in the milder forms of oligoarthritis (Step-down arm) is more effective in inducing clinical remission on medication (i.e. at least 6-month of continuous inactive disease while receiving anti-rheumatic medications) than a conventional therapeutic approach based on treatment escalation (Step-up arm), which efficacy is maximized through the implementation of a treat-to-target approach

Obiettivo dello studio è confrontare l’efficacia nell’indurre uno stato di remissione di malattia persistente di due diverse strategie terapeutiche per l’AIG: l’avvio precoce di un breve ciclo di terapia massimale combinata (Step-down) e una terapia convenzionale basata sulla progressiva intensificazione del trattamento e ottimizzata con un approccio treat-to-target (Step-up).

E.2.2

Secondary objectives of the trial

• Inactive disease
The rate of patients who achieve the JADAS/JIA ACR state of ID at any single point in time throughout the study period will be compared between the 2 arms.
• Time to inactive disease as per JADAS/JIA ACR criteria
Time to achieve the JADAS/JIA ACR state of ID will be calculated as the time difference (in days) between the date of randomization and the date of the visit at which the patient will be observed to be in ID.
• Time to JADAS/JIA ACR clinical remission
Time to achieve the JADAS/JIA ACR state of clinical remission will be calculated as the time difference (in days) between the date of randomization and the date of the visit at which the patient will be observed to be in clinical remission (i.e. persistent inactive disease for at least 6 months).

• malattia inattiva
Il tasso di pazienti che raggiungono lo stato di malattia inattiva JADAS / JIA ACR in un preciso momento nel tempo durante lo studio sarà confrontato tra i 2 bracci.
• Tempo di malattia inattiva secondo i criteri JADAS / JIA ACR
Il tempo necessario per ottenere lo stato di malattia inattiva secondo i criteri JADAS / JIA ACR verrà calcolato come differenza in giorni tra la data di randomizzazione e la data della visita in cui la malattia del paziente verrà definita come inattiva.
• Tempo per la remissione clinica JADAS / JIA ACR
Il tempo necessario per ottenere lo stato di remissione clinica della malattia secondi i criteri JADAS / JIA ACR sarà calcolato come differenza in giorni tra la data di randomizzazione e la data della visita in cui la malattia del paziente sarà definita in remissione clinica (es. persistente malattia inattiva per almeno 6 mesi).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

I. Newly-diagnosed and synthetic or biologic DMARD-naïve children (only treatment with 1 NSAID is allowed and no corticosteroid joint injections prior to randomization ) with a JIA classified according to the following ILAR categories:
i. Oligoarthritis
ii. Rheumatoid factor negative polyarthritis
II. Active arthritis
III. Onset of JIA symptoms no more than 6 months before randomization
IV. Age 2 to 17 years at enrolment.
V. Female of child-bearing potential must have a negative pregnancy test at the beginning of the trial, and then every 3 months. If sexually active, they must agree to use adequate contraception, throughout study participation, and must have no intention of conceiving during the course of the study. Post-pubertal males must have no plans to father a child during the study and agree to use adequate birth control methods if sexually active.
VI. Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff, competence to give written informed consent; to be applied to the parents and/or patients, as appropriate
VII. Duly executed, written, informed consent/assent obtained from the parents/patient.

Bambini appena diagnosticati e mai trattati con farmaci sintetici o biologci DMARD (è consentito solo il trattamento con 1 FANS e nessuna iniezione di corticosteroidi prima della randomizzazione) con una diagnosi di AIG secondo le seguenti categorie ILAR:
io. Oligoartrite
ii. Poliartrite da fattore reumatoide negativo
II. Artrite attiva
III. Inizio dei sintomi AIG non più di 6 mesi prima della randomizzazione
IV. Età da 2 a 17 anni all'arruolamento.
V. I pazienti di sesso femminile in età fertile devono avere un test di gravidanza negativo all'inizio dello studio e successivamente ogni 3 mesi. Se sessualmente attivi, i pazienti devono accettare di utilizzare una contraccezione adeguata, durante la partecipazione allo studio, e non devono avere intenzione di concepire durante il corso dello studio. I maschi post-puberali non devono avere intenzione di concepire un figlio durante lo studio e devono esprimere il proprio consenso ad usare adeguati metodi anticoncezionali se sessualmente attivi.
VI. Capacità di rispettare tutte le procedure dello studio, capacità di comunicare efficacemente con lo staff medico, deve avere le capacità di esprimere il proprio consenso informato in forma scritta; da sottoporre ai genitori e / o ai pazienti, a seconda dei casi
VII. Consenso / assenso informato debitamente compilato e firmato, ottenuto dai genitori / paziente.

E.4

Principal exclusion criteria

I. Classification in one of the following JIA categories: systemic arthritis, RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, undifferentiated arthritis
II. Patients who need systemic treatment for uveitis
III. Tuberculosis related issues: patients are excluded from the study if they have:
a. Active TB or a history of incompletely treated TB
b. PPD or QuantiFERON-TB positive patients (with no active disease) unless it is documented by a specialist that the patient has been adequately treated for TB and can start treatment with a biologic agent, based on the medical judgment of the study investigator and / or an infectious disease specialist.
c. Suspected extrapulmonary TB infection
d. Patients at high risk of contracting TB, such as close contact with individual with active or latent TB
IV. Previous treatment with any synthetic or biologic DMARD
V. Any live attenuated vaccine within 4 weeks prior to the baseline visit, such as varicella-zoster, oral polio, measles, mumps or rubella vaccines and throughout the study. Killed or inactive vaccine may be permitted based on the investigator’s judgment
VI. Prior or current history of malignancy or any other significant concomitant illness(es) as per the treating physician evaluation

I. Classificazione in una delle seguenti categorie AIG: artrite sistemica, poliartrite FR-positivo, artrite psoriatica, artrite assocoata ad entesite, artrite indifferenziata
II. Pazienti che necessitano di un trattamento sistemico per l'uveite
III. Problemi legati alla tubercolosi: i pazienti sono esclusi dallo studio se hanno:
una TB attiva o una storia di TB non completamente guarita
b. Pazienti positivi ai test PPD o QuantiFERON-TB (senza malattia attiva) a meno che non sia documentato da uno specialista che il paziente è stato adeguatamente trattato per la TB e può iniziare il trattamento con un agente biologico, sulla base del giudizio medico dello sperimentatore dello studio e / o di uno specialista in malattie infettive.
c. Sospetta infezione da TB extrapolmonare
d. Pazienti ad alto rischio di contrarre la tubercolosi, come stretto contatto con individui con TB attiva o latente
IV. Trattamento precedente con qualsiasi DMARD sintetico o biologico
V. Qualsiasi vaccino vivo attenuato fatto entro 4 settimane prima della visita basale, come varicella-zoster, poliomielite orale, morbillo, parotite o rosolia e durante lo studio. Il vaccino ucciso o inattivo può essere autorizzato sulla base del giudizio dello sperimentatore
VI. Anamnesi positiva o precedente di neoplasie maligne o di qualsiasi altra malattia concomitante significativa secondo la valutazione del medico curante

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated at 3, 6, 9, 12 months after enrollment.

I pazienti verranno valutati a 3, 6, 9, 12 mesi dopo l’arruolamento.

E.5.2

Secondary end point(s)

• Inactive disease

• Time to inactive disease as per JADAS/JIA ACR criteria

• Time to JADAS/JIA ACR clinical remission

• Time spent in JADAS/JIA ACR inactive disease

• malattia inattiva

• Tempo di malattia inattiva secondo i criteri JADAS / JIA ACR

• Tempo per la remissione clinica JADAS / JIA ACR

• Tempo trascorso in malattia inattiva JADAS / JIA ACR

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated at 3, 6, 9, 12 months after enrollment.

I pazienti verranno valutati a 3, 6, 9, 12 mesi dopo l’arruolamento.

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

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

confronto di strategie terapeutiche

therapeutic strategies are compared

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.8.6 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

Yes

F.1.1

Number of subjects for this age range:

260

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

130

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

130

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

pediatric patients

pazienti pediatrici

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

260

F.4.2

For a multinational trial

F.4.2.1

In the EEA

260

F.4.2.2

In the whole clinical trial

260

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)

After the conclusion of the 12-month observation period of the trial, patients will be followed for up to 5 years for the evaluation of disease course, medication requirements, adverse events, and long-term disease-related morbidity.

Dopo la conclusione del periodo di osservazione di 12 mesi dello studio, i pazienti verranno seguiti per un massimo di 5 anni per la valutazione del decorso della malattia, dei farmaci, degli eventi avversi e della morbilità correlata alla malattia a lungo termine.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	PRINTO - IRCCS Giannina Gaslini
G.4.3.4	Network Country	Italy

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-28

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

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