Clinical Trials Register

Summary
EudraCT Number:	2015-002127-26
Sponsor's Protocol Code Number:	BAFFI_14
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:	2019-03-18
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

2015-002127-26

A.3

Full title of the trial

Randomized, single-blind, controlled study of the anti-BAFF antibody belimumab or methylprednisolone treatment in hyperthyroid Graves' disease (GD) and active orbitopathy (GO)

A.3.1

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

Comparison between treatment with belimumab and methylprednisolone in Graves’hyperthyroidism (GD) and active orbitopathy (GO).

Confronto tra terapia dell’ipertiroidismo di Graves’ (GD) ed orbitopatia basedowiana (GO) attiva con belimumab vs metilprednisolone

A.3.2

Name or abbreviated title of the trial where available

BAFFI_14

A.4.1

Sponsor's protocol code number

BAFFI_14

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	FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO
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	Glaxo Smith&Kline GSK International
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	FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO
B.5.2	Functional name of contact point	U.O.C. ENDOCRINOLOGIA E DIABETOLOGI
B.5.3	Address:
B.5.3.1	Street Address	VIA F.SFORZA N. 35
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20122
B.5.3.4	Country	Italy
B.5.4	Telephone number	0255033498
B.5.5	Fax number	0250320605
B.5.6	E-mail	l.fugazzola@policlinico.mi.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	BENLYSTA - 120 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO (VETRO) 120 MG 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	GLAXO GROUP LIMITED
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	BENLYSTA
D.3.2	Product code	L04AA26
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	SOLU MEDROL - 500 MG/8 ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONE DI POLVERE DA 500 MG+ FIALA SOLVENTE DA 8 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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	SOLU MEDROL
D.3.2	Product code	D07AA01
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	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	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	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.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

GRAVES' ORBITOPATHY

ORBITOPATIA BASEDOWIANA

E.1.1.1

Medical condition in easily understood language

GRAVES' ORBITOPATHY

ORBITOPATIA BASEDOWIANA

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10057889
E.1.2	Term	Graves' ophthalmopathy
E.1.2	System Organ Class	100000004853

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1) efficacy of therapy on the active inflammatory phase of GO and the progression of the eye disease.
2) efficacy of therapy in inducing remission of hyperthyroid GD and in reducing the frequency and the degree of hyperthyroidism relapses at the end of anti-thyroid treatment.

1)efficacia della terapia sull’attività dell’orbitopatia e sulla progressione della malattia oculare
2)efficacia della terapia nell’induzione della remissione dell’ipertiroidismo della malattia di Graves (GD) e nella riduzione della frequenza e del grado di recidive di ipertiroidismo al termine del trattamento.

E.2.2

Secondary objectives of the trial

effects of belimumab on the target tissues of GD (the thyrocytes) and GO (the eye muscles, orbital fat and connective tissue) and on thyroid and orbital infiltrating immune cells.

effetti del belimumab sui tessuti bersaglio della malattia di Graves (GD) (tireociti) e GO (muscolatura orbitale, graddo orbitale e tessuto connettivo) e sulle cellule infiltranti la tiroide e l’orbita.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female,18-75 years old; Smokers and non smokers. Women of childbearing potential should use adequate contraception (See “Important Safety Information-Women of Child Bearing Potential” section for specific methods of contraception) during BENLYSTA treatment and for at least 4 months after the last dose. GO at first diagnosis or at the time of relapse, with detectable TSH receptor antibodies. Patients with moderate-severe active GO (clinical activity score 4/10 o 3/7) untreated or previously treated with i.v steroids withdrawn for at least 3 months. Not submitted to previous B cell depleting therapy. Euthyroid for at least 6-8 weeks, on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism. Patients will also be allowed to stay on propranolol treatment for the control of tachycardia.

Maschi, femmine di 18-75 anni, fumatori e non fumatori. Le donne in età fertile devono utilizzare metodi contraccettivi sicuri (vedi protocollo ““Important Safety Information-Women of Child Bearing Potential” section for specific methods of contraception”) duranet il trattamento con BENLYSTA e per almeno 4 mesi dopo la somministrazione dell’ultima dose). Presenza di GO alla diagnosi o al momento della recidiva con TRAb dosabili. Pazienti con GO attiva di grado moderato-severo (clinical activity score 4/10 o 3/7) non trattata o precedentemente trattata con steroidi e.v. terminati almeno 3 mesi prima dell’arruolamento. Pazienti mai sottoposta ad altre terapia con deplezione B cellulare. Eutirodei per almeno 6-8 settimane sia in terapia tireostatica (tionamidi) per controllare l’ipertiroidismo o in terapia con L-tiroxina sostitutiva per l’ipotiroidismo. Pazienti in terapia con propranololo per il controllo della tachicardia.

E.4

Principal exclusion criteria

Patients with severe Graves’ orbitopathy (severe keratopathy, compression optic neuropathy and inflammatory optic neuropathy).Treatment with any B cell targeted therapy at any time. Previous oral or intravenous corticosteroid treatment in the last three months not exceeding a cumulative dose of 1 gr. Any immunosuppressant whether biologic or not. Plasmapheresis within 90 days prior to Day 0. Treatment with intravenous immunoglobulin. Azathioprine more than 100 mg/day within 30 days before screening. Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with Belimumab (During study). Splenectomy. Subjects at risk of haemorrhage that threatens a vital organ. History of a major organ transplant or hematopoietic stem cell/marrow transplant. History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix. Required management of infections, as follows: currently on any suppressive therapy for a chronic infection, hospitalisation for treatment of infection within 60 days before Day 0, use of parenteral antibiotics within 60 days before Day 0. Pregnancy. Breast feeding. Known coronary artery disease. Significant cardiac arrhythmias. Severe congestive heart failure. Other serious chronic illness. Active infection. History of recurrent clinically significant infection or recurrent bacterial infections. History of sarcoidosis. Primary or secondary immunodeficiency. History of IgE-mediated or non-IgE-mediated hypersensitivity. Known anaphylaxis to mouse-derived proteins. Positive PPD without documentation of treatment for TB infection. Denied consent to HIV testing. Previous orbital radiotherapy, refusal of treatment. Patients with known allergy to paracetamol, difenidramine, hydrocortisone. Patients positive for HBsAg. Patients positive for HBcAb regardless of HBsAb status will undergo HBV DNA which if positive will be excluded. Patients positive at screening Hepatitis C antibody. Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater or equal to 3x upper limit of normal (ULN). Alkaline phosphatase and bilirubin >2xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is<35%). Grade 3 / 4 IgG deficiency and IgA deficiency (IgA < 10mg/dL). Lymphocyte count<500/mm3. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy including a previous anaphylactic reaction to parenteral administration contrast agents, human or murine proteins or monoclonal antibodies. Major depression. Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk. Current drug or alcohol abuse or dependence.

Pazienti con orbitopatia basedowiana severa (compressione nervo ottico). Trattamento con qualunque teraia anti-cellule B in qualunque tempo. Precedente somministrazione orale o endovenosa di corticosteroidi almeno entro i tre mesi precedenti non eccedente una dose cumulativa di 1 gr. qualunque immunosoppressore sia biologico che no. Plasmaferesi nei 90 giorni precedenti. Trattamento con immunoglobuline e.v. Azatioprina a dosaggio superiore a 10 mg/die nei 30 giorni precedenti lo screening. Somministrazione di vaccini vivi nei 30 giorni precedenti la somministrazione o concomitanti con balimumab (durante lo studio). Splenectomia. Sogetti a rischio per emorragie. Storia di trapianti maggiori o midollari staminali. Storia di tumori maligni negli ultimi 5 anni ad eccezione di tmori curati della pelle (basaliomi o K spinocellulare) o carcinomi in situ della cervice uterina. Richiesta di management delle infezioni come segue: ospedalizzazione per tratamento delle infezini nei 60 giorni prima del giorno 0, uso di antibiotici parenterali nei 60 giorni prima del giorno 0. Gravidanza. Allattamento. Patologia coronarica nota. Aritmie cardiache note. Cardiopatia congestizia. Altre patologie critiche. Storia di ifezioni ricorrenti o batteriche ricorrenti. Storia di sarcoidosi. Immunodeficienza primaria o secondaria. Storia di ipersensibilità IgE e non IgE mediata. Anafilassi nota alle proteine derivate del topo. PPD positivo senza documentazione o trattamento per infezione TB. Consenso negato a test per HIV. Pregressa radioterapia orbitale, rifiuto al trattamento. Pazienti con nota allergia al paracetamolo, difenidramina e idrocortisone. Pazienti con positività per HbsAg. Pazienti positivi per HBcAb indipendentemente dallo stato di HbsAb che verranno sottoposti a HBV DNA che risulti positivo. Pazienti positivi allo screening epatici HCV correlata, HIV. Pazienti con AST e ALT> o uguali a 3x limite superiore di norma. Fosfatasi alcalina e bilirubina >2x. Grado 3/4 IgG deficit e IgA deficit (IgA < 10mg/dL). Conta linfocitaria <500/mm3. Storia di sensibilità a qualunque medicina o compinenti o storia di altre allergie includenti reazioni anafilattiche alla somministrazione parenterale di mezzi di contrasto, umani, murini o antcorpi monoclonali. Depressione maggiore. Rischio di suicidio negli ultimi 6 mesi o idee di suicidio negli ultimi 2 mesi. Uso di droghe o abuso di alcool o dipendenza.

E.5 End points

E.5.1

Primary end point(s)

1. Decrease of the clinical activity score (CAS) of 2 points or disease inactivation (CAS<4) in active GO patients at 12, 24, 36 and 48 weeks from belimumab or methylprednisolone administration.
2. Safety of belimumab therapy in patients with GD and GO.

1. Riduzione del clinical activity score (CAS) di 2 punti o inattivazione della malattia (CAS<4) in pazienti con GO attiva a 12, 24, 36 e 48 settimane della somministrazione di belimumab o metilprednisolone. 2. Sicurezza della terapia con belimumab in pazienti con GD e GO.

E.5.1.1

Timepoint(s) of evaluation of this end point

12-24-36-48 weeks

12-24-36-48 settimane

E.5.2

Secondary end point(s)

1. decrease of GO severity by NOSPECS classes 2 or 3 or 4 of at least 1 point;
2. analysis of the rate of response to therapy and of relapse of active disease at 12, 24, 36 and 48 weeks;
3. time (months) to remission of hyperthyroidism and decrease or negativeness of serum TSH receptor antibodies in patients with hyperthyroid GD at ,12, 24, 36 and 48 weeks;
4. quantification of signs of residual motility abnormalities by motility tests and analysis of quality of life (GO-QoL)
5. analysis of intrathyroidal and orbital tissue and lymphocyte BAFF expression after therapy by immunohistochemistry and cytofluorimetry.

1.riduzione della severità della GO espresso come classi NOSPECS 2 o 3 o 4 di almeno 1 punto;
2.analisi del tasso di risposta alla terapia e rischio di recidiva di malattia attiva a 12, 24, 36 e 48 settimane
3.tempo (mesi) per la remissione dell’ipertiroidismo e riduzione o negativizzazione degli anticorpi anti-recettore del TSH in pazienti con ipertiroidismo a 12, 24, 36 e 48 settimane
4.quantificazione dei segni di anomalie della motilità residue mediante test di motilità e analisi della qualità di vita (GO-QoL)
5.analisi dell’espressione di BAFF a livello intratiroideo, nel tessuto orbitale e sui linfociti dopo terapia mediante immunoistochimica e citofluorimetria.

E.5.2.1

Timepoint(s) of evaluation of this end point

12, 24, 36, 48 weeks

12, 24, 36, 48 settimane

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)

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

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)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

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:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-03-18.

Yes

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)

THEY WILL FOLLOWED IN THE ENDOCRINE UNIT AS OUTPUT PATIENTS WITH GRAVES ORBITOPATHY

VERRANNO SEGUITI PRESSO L'AMBULATORIO DI SECONDO LIVELLO DEDICATO ALLA DIAGNOSI E CURA DELL'ORBITOPATIA BASEDOWIANA

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

2015-07-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-13

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

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