Clinical Trials Register

Summary
EudraCT Number:	2017-005050-11
Sponsor's Protocol Code Number:	SeMMIviD
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:	2021-09-06
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

2017-005050-11

A.3

Full title of the trial

Effects of Selenium and cholecalciferol on hyperthyroidism due to Graves' disease treated with methimazole: a randomized, clinical, open label, pilot trial

Studio clinico randomizzato pilota in aperto per valutare l'efficacia dell'associazione Selenio, colecalciferolo e metimazolo nella terapia dell'ipertiroidismo in pazienti con morbo di Basedow e concomitante deficit di Selenio e ipovitaminosi D

A.3.1

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

Selenium and vitamin D in the treatment of thyroid hormone excess

Effetto combinato del trattamento con Selenio e vitamina D in condizioni di eccessiva secrezione di ormoni tiroidei

A.3.2

Name or abbreviated title of the trial where available

SeMMIviD

A.4.1

Sponsor's protocol code number

SeMMIviD

A.5.4

Other Identifiers

Name:

SeMMIviD

Number:

2017-005050-11

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	A.O. OSPEDALE DI CIRCOLO E FONDAZIONE MACCHI
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	fondi del Dipartimento di Medicina e Chirurgia
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	ASST Sette Laghi Varese
B.5.2	Functional name of contact point	SC Endocrinologia, ASST Sette Laghi
B.5.3	Address:
B.5.3.1	Street Address	Viale Borri 57
B.5.3.2	Town/ city	Varese
B.5.3.3	Post code	21100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0332278325
B.5.5	Fax number	0332393308
B.5.6	E-mail	luigi.bartalena@uninsubria.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	DIBASE - 300.000 UI/ML SOLUZIONE INIETTABILE PER USO ORALE E INTRAMUSCOLARE 2 FIALE 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ABIOGEN PHARMA S.P.A.
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	DIBASE
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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.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	DIBASE - 10.000 UI/ML GOCCE ORALI, SOLUZIONE FLACONE CON GONTACOCCE 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ABIOGEN PHARMA S.P.A.
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	DIBASE
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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.IMP: 3
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	TAPAZOLE - 5 MG COMPRESSE BLISTER IN PVC/AL DA 100 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA 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	Tapazole
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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' disease

Morbo di Basedow o Graves'

E.1.1.1

Medical condition in easily understood language

High levels of thyroid hormones due to toxic diffuse goiter in autoimmune disorder

Eccesso di ormoni tiroidei da gozzo diffuso di origine autoimmune

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10020850
E.1.2	Term	Hyperthyroidism
E.1.2	System Organ Class	10014698 - Endocrine 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 test the efficacy of concomitant therapy of Selenium and cholecalciferol in association to the standard therapy with methimazole to treat hyperthyroidism due to Grave's diseas after 180 days from enrollment.

-Valutare l’efficacia della associazione di Selenio e colecalciferolo alla terapia standard con metimazolo in pazienti affetti da morbo di Basedow naïves con deficit documentato di Selenio e vitamina D, sul controllo biochimico e clinico dell’ipertiroidismo dopo 180 giorni di terapia.

E.2.2

Secondary objectives of the trial

-To test the efficacy of concomitant therapy of Selenium and cholecalciferol in association to the standard therapy with metimazole to treat hyperthyroidism due to Grave's diseas after 45 and 240 days from enrollment.
-To test parameters of oxidative metabolism and t reg profile as possible indicator of efficacy
--Mean dose of methimazole
- Ultrasound thyroid morphology/echogenicity

-.valutare l'efficacia della associazione Selenio e colecalciferolo alla terapia standard con metimazolo nel controllo dell'ipertiroidismo da morbo di Basedow dopo 45 e 240 giorni dall'inizio del trattamento.
Valutare la possibilità di utilizzare una dose inferiore di metimazolo nel gruppo di terapia
-Valutare l'andamento del metabolismo ossidativo e del profilo dei T reg come possibili indicatori surrogati dell'efficacia del trattamento
-pattern di ecogenicità tiroideo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Hyperthyroidism due to Basedow disease
-selenium and Vitamin D deficiency
-age 18-70 years; Caucasian race
-no concomitant major cardiovascular, haepatic, haemopoietic disease
-vitamin D malabsorption (intestinal inflammatory chronic diseases, alcoholism, cystic fibrosis)
- II-III grade obesity
- no concomitant supplementation with vitamin D and/or Selenium
-informed consent

-Ipertiroidismo non trattato dovuto a morbo di Basedow.
-Deficit di Selenio
-Ipovitaminosi D
-Etnia caucasica
-Età compresa tra 18 e 70 anni
-Assenza di comorbilità che influenzino lo stress ossidativo (diabete mellito scompensato, cardiopatia ischemica, insufficienza epatica moderata/severa, insufficienza renale moderata/severa, alcolismo cronico)
-Assenza di altre condizioni che influenzino la conta cellulare plasmatica (malattie dell’emopoiesi)
-Assenza di altre condizioni che influenzino l’assorbimento e il metabolismo della vitamina D (malassorbimento intestinale, mucoviscidosi, fibrosi cistica, insufficienza epatica), alcolismo cronico, obesità di II e III grado
-Buone condizioni di salute generale, salvo le manifestazioni dell’ipertiroidismo
-Dieta priva di alimenti arricchiti con Selenio e/o vitamina D
-Firma del modulo del consenso informato

E.4

Principal exclusion criteria

intolerance to methimazole
intolerance to Selenium (actually not known), or to excipients of Syrel
concomitant conditions interfering with vitamin D metabolism (such as primary hyperparathyroidism, a granulomatous disease, kidney stones, some types of kidney disease, digital therapy
-.pregnancy, breastfeeding

-Ipertiroidismo in terapia con antitiroidei di sintesi
- Controindicazioni al metimazolo (ipersensibilità ai farmaci antitiroidei, gravidanza, allattamento)
- Eventuali controindicazioni al Selenio (al momento non ci sono controindicazioni descritte), intolleranza nota a olio di semi di soia (glycinesoja), gelatina alimentare, glicerolo, lievito arrichito di Selenio, silice colloidale anidre, Biperine–pepe nero (pipernigrum frutti), E555, E171, E172 (presenti nell’integratore)
- Eventuali condizioni in cui la vitamina D deve essere prescritta con cautela e sotto stretto monitoraggio: sarcoidosi, insufficienza renale, assunzione di farmaci digitalici
-Dieta con alimenti arricchiti con Selenio o livelli ematici basali nella norma
- Dieta con alimenti arricchiti con vitamina D o livelli di 25-OH vitamina D basali nella norma
- Assunzione di integratori contenenti Selenio o/o altre sostanze anti-ossidanti
-Assunzione di integratori contenenti vitamina D (in ogni sua formulazione)
-Incapacità di acconsentire a partecipare allo studio

E.5 End points

E.5.1

Primary end point(s)

Biochimical and Clinical manifestation of hyperthyroid after 180 days from baseline. A difference of 3 pg/ml in FT4 levels after 180 days between the treatment group and the standard one is expected.
-severity of hyperthyroidism assesed with Clinical Severity Score -Thyroid hormone levels (FT4, FT3, TSH) after 180 days from enrollment -Mean dose of methimazole

Andamento delle manifestazioni cliniche e biochimiche (TSH, FT4, FT3) dell’ipertiroidismo a 180 giorni , ipotizzando di evidenziare come statisticamente significativa una differenza nei livelli di FT4 pari a 3 pg/ml tra il gruppo di studio (terapia con metimazolo + Selenio + colecalciferolo) e quello di controllo (terapia standard) alla visita T2 (fine fase intervento dello studio), ad un livello di significatività alpha=0.05
-Severità dell’ipertiroidismo a 180 giorni, valutata mediante lo score “Clinical Activity Score”
-Dose di metimazolo media nei due gruppi

E.5.1.1

Timepoint(s) of evaluation of this end point

180 days (T2)

180 giorni (T2)

E.5.2

Secondary end point(s)

-clinical manifestation of hyperthyroid after 45 and 240 days from baseline
-thyroid hormone levels (FT4, FT3, TSH) after 45 and 240 days from enrollment
-severity of Graves' disease assessed by Clinical Severity Score
assessed after 45 and 240 days from enrolment
-Glutathione, Malondialdehyde levels baseline, after 180 and 240 days from enrolment
-Lymphocytes typization for Treg baseline and after 180 days from enrollment
- Ultrasound thyroid morphology/echogenicity

-Andamento delle manifestazioni cliniche e biochimiche dell'ipertiroidismo a 45 e a 240 giorni.
-Severità dell’ipertiroidismo a 45 e a 240 giorni, valutata mediante “Clinical Activity Score”.
-Andamento dei parametri di stress ossidativo (Glutatione e Malondialdeide) a 180 e 240 giorni rispetto al basale.
-Andamento della tipizzazione linfocitaria (Treg) con citofluorometria a 180 e a 240 giorni
-Andamento degli anticorpi circolanti diretti contro antigeni tiroidei a 45, 180 e 240 giorni.
-Andamento del volume tiroideo, del pattern di ecogenicità e della vascolarizzazione ghiandolare.

E.5.2.1

Timepoint(s) of evaluation of this end point

day 45 (T0) and day 240 (T3)

45 (T0) e 240 giorni (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

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

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

gruppo di controllo: terapia standard con metimazolo.
gruppo di trattamento: terapia standard con m

control group: standard therapy with methimazole
treatment group: standard therapy + Selenium + chol

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

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.1.1.1

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

regular follw-up at outpatients clinic of Endocrinology, ASST Sette Laghi Varese

i soggetti partecipanti allo studio proseguiranno in regolare follow-up come da pratica clinica presso gli ambulatori della SC Endocrinologia ASST Sette Laghi di Varese

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

2019-03-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-05

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

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