Clinical Trials Register

Summary
EudraCT Number:	2015-001248-12
Sponsor's Protocol Code Number:	THYR69
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:	2020-11-04
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

2015-001248-12

A.3

Full title of the trial

Randomized crossover trial for the evaluation of the possible effects in the intestine of two different pharmaceutical forms of L - Thyroxine in patients with primary acquired hypothyroidism

Studio randomizzato crossover su pazienti con ipotiroidismo acquisito primario per valutare i possibili effetti a livello intestinale di due diverse formulazioni di L-Tiroxina

A.3.1

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

Evaluation of the possible effects in the intestine of two different pharmaceutical forms of L - Thyroxine in patients with primary acquired hypothyroidism

Studio su pazienti con ipotiroidismo acquisito primario per valutare i possibili effetti a livello intestinale di due diverse formulazioni di L-Tiroxina

A.3.2

Name or abbreviated title of the trial where available

Trial for the evaluation of the possible effects in the intestine of two different pharmaceutical fo

Studio su pazienti con ipotiroidismo acquisito primario per valutare i possibili effetti a livello i

A.4.1

Sponsor's protocol code number

THYR69

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 OSPEDALIERO-UNIVERSITARIA MEYER
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	AOU Meyer
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	Azienda Ospedaliero Universitaria Meyer
B.5.2	Functional name of contact point	Clinical Trial Office
B.5.3	Address:
B.5.3.1	Street Address	Viale Pieraccini 24
B.5.3.2	Town/ city	Firenze
B.5.3.3	Post code	50139
B.5.3.4	Country	Italy
B.5.4	Telephone number	0555662425
B.5.5	Fax number	0555662425
B.5.6	E-mail	clinicaltrialoffice@meyer.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	TIROSINT - 50 MICROGRAMMI/1 ML SOLUZIONE ORALE 30 CONTENITORI MONODOSE 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	IBSA FARMACEUTICI 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	TIROSINT
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	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	EUTIROX - 100 MICROGRAMMI COMPRESSE 50 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BRACCO 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	EUTIROX
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

Primary acquired hypothyroidism

Ipotiroidismo primario acquisito

E.1.1.1

Medical condition in easily understood language

Primary Hypothyroidism

Ipotiroidismo primario

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	LLT
E.1.2	Classification code	10000559
E.1.2	Term	Acquired hypothyroidism
E.1.2	System Organ Class	100000004860

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 effect of two different pharmaceutical forms of L-Thyroxine on the gut in terms of inflammatory parameters, gut absorption

Lo scopo dello studio ¿ quello di testare gli effetti della L-T4, in due diverse formulazioni, a livello intestinale attraverso le modifiche dei parametri infiammatori e dell¿assorbimento intestinale

E.2.2

Secondary objectives of the trial

- Evaluate the effect of two different pharmaceutical forms of L-Thyroxine on the gut in terms of modification of gut microbiota
- Evaluate the effect of the disease (congenital Hypothyroidism) on the gut in terms of modification of gut microbiota, inflammatory parameters, gut absorption
- Evaluate the incidence of celiac disease in hypothyroid patients

- Testare gli effetti della L-T4, in due diverse formulazioni, a livello intestinale, attraverso le modifiche del microbiota
- Caratterizzare l¿effetto dell¿ipotiroidismo sul microbiota intestinale, sui parametri infiammatori e dell¿assorbimento intestinale
- Stimare l¿incidenza della celiachia nell¿intera coorte di pazienti ipotiroidei.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Children with primary acquired hypothyroidism that require Levothyroxine therapy (naïve patients, < 18 years)
2. Informed consent from parents and patient

1. Bambini ed adolescenti con ipotiroidismo primario acquisito con necessitante di terapia con L-T4, non trattati in precedenza e con età inferiore ai 18 anni al momento dell’arruolamento.
2. Ottenimento del consenso informato da parte del genitore e assenso del paziente.

E.4

Principal exclusion criteria

1. Age < 3 years
2. Patients with secondary hypothiroidism, euthyroid sick syndrome or thyroid ormone resistant
3. Patients with celiac diasease, type I diabetes or other known autoimmune diseases
4. Patients with genetic diseases or syndromes, such as Down, Williams-Beuren, Turner
5. Assumption of antibiotics, probiotics, prebiotics, or other medications that could affect the gut microbiota in the month before the beginning of the study
6. Gastrointestinal infectious diaseases in the month before the beginning of the study
7. Hypersensitivity to levothyroxine or any of the ingredients contained in the two pharmaceutical formulations
8. Untreated adrenal insufficiency, untreated pituitary insufficiency and untreated thyrotoxicosis.
9. Patients with cardiovascular disease
10. Patients who show with impaired pancreatic function measured using the assay in faecal fat (steatocrit) at the screeening visit

1. Età inferiore a 3 anni di vita, per le difficoltà inerenti alla corretta conduzione dello studio e le loro particolarità fisiologiche e neuroevolutive.
2. Pazienti con ipotiroidismo secondario, con euthyroid sick syndrome o resistenza agli ormoni tiroidei saranno esclusi per i bias legati alle possibili associazioni di comorbilità ed ai farmaci possibilmente già assunti.
3. Pazienti con una diagnosi di malattia celiaca, diabete tipo I o altre malattie autoimmuni già diagnosticate al momento dell’ipotiroidismo.
4. Pazienti con patologie genetiche o sindromi, come la sindrome di Down, la sindrome di Turner, la sindrome di Williams-Beuren, conosciute essere associate ad un rischio maggiore di sviluppare malattia celiaca.
5. Assunzione di antibiotici, probiotici, prebiotici o qualsiasi altro trattamento medico influenzante il microbiota intestinale nel mese precedente l’inizio dello studio.
6. Malattie infettive gastrointestinali nel mese precedente l’inizio dello studio.
7. Ipersensibilità al principio attivo levotiroxina o a uno qualsiasi degli eccipienti contenuti nelle due formulazioni farmaceutiche
8. Insufficienza surrenalica non trattata, insufficienza ipofisaria non trattata e tireotossicosi non trattata.
9. Pazienti con patologie cardiovascolari
10. Pazienti che allo screening mostrano con alterazione della funzione pancreatica valutata mediante l’utilizzo del dosaggio dei grassi fecali (steatocrito).

E.5 End points

E.5.1

Primary end point(s)

Calculate the difference in gut inflammation parameters (calprotectin, osteoprotegerin, S100-A12 protein) and gut absorption parameters among the two groups of patients at T6-T0 and T12-T6

Misurare le differenze tra i due gruppi al tempo T6 - T0 e le differenze intragruppo al tempo T12 – T6 (analisi prima-dopo) nei parametri infiammatori intestinali (livelli di calprotectina, osteoprotegerina, proteina S100-A12) e dei parametri dell’assorbimento intestinale (steatocrito)

E.5.1.1

Timepoint(s) of evaluation of this end point

6-12 months

6-12 mesi

E.5.2

Secondary end point(s)

Qualitative and quantitative (percentage) characterization of gut microbiota before the initiation of the therapy (T0); Difference in gut microbiota among hypothyroid patients (t0) and healthy patients (data from Human Microbiome Project); Estimate the incidence of positive patients to deamidated AGA T6, T12 e a T24 (follow-up); Evaluate gut inflammation (calprotectin, Osteoprotegerin and S100-A12 protein) and gut absorption (Steatocrit) parameters before the initiation of the therapy (T0); Calculate the difference in Shannon Index
(index of diversity), Chao I (Species richness estimator), percentage of different species (OTU, operational taxonomic unit) among the two groups of patients at T6-T0 and T12-T6

Misurare al tempo T0 le caratteristiche del microbiota intestinale che saranno interamente riferibili allo stato di ipotiroidismo, in termini quantitativi (come percentuale) e qualitativi.; Differenze della tipizzazione del microbiota tra i soggetti ipotiroidei al T0 e quelli sani estrapolati dal Human Microbiome Project (HMP).

; Valutare l¿incidenza della positivit¿ degli AGA deaminati a T6, T12 e a T24 (follow-up).

; Misurare al tempo T0 i parametri infiammatori intestinali (livelli di calprotectina, osteoprotegerina, proteina S100-A12) e dei parametri dell¿assorbimento intestinale (steatocrito).; Misurare le differenze tra i due gruppi al tempo T6 - T0 e le differenze intragruppo al tempo T12 ¿ T6 rispetto a T6-T0 (analisi prima-dopo) nella percentuale di microrganismi presenti (Actinobacteria, Firmicutes, Bacteroidetes, proteobacteria. Le differenze saranno calcolate con lo Shannon Index e Chao I che riguardano rispettivamente la biodiversit¿ e la ricchezza delle specie presenti. Saranno assegnate delle OTU, operational taxonomic unit, che permetteranno attraverso l'analisi bioinformatica di conoscere che tipo di batteri sono presenti e in quale percentuale.

E.5.2.1

Timepoint(s) of evaluation of this end point

BASELINE; BASELINE; BASELINE; BASELINE; 6-12 months

TEMPO 0; TEMPO 0; TEMPO 0; TEMPO 0; 6-12 mesi

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

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)

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

Yes

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

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

Yes

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:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

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)

At the end of the study, the patient will continue the therapy with L-Thyroxine with the last assigned pharmaceutical form (solid or liquid). However, he/she will decide to switch to other form.

Alla fine dello studio, il paziente continuer¿ la terapia con la formulazione in uso (rispettivamente formulazione solida o liquida). Verr¿ comunque data (come da pratica clinica) la possibilit¿ al paziente di scegliere la formulazione pi¿ consona alle sue esigenze.

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

2015-10-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-16

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

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