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    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-001248-12
    A.3Full 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.3.1Title 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.3.2Name 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.4.1Sponsor's protocol code numberTHYR69
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAZIENDA OSPEDALIERO-UNIVERSITARIA MEYER
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAOU Meyer
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAzienda Ospedaliero Universitaria Meyer
    B.5.2Functional name of contact pointClinical Trial Office
    B.5.3 Address:
    B.5.3.1Street AddressViale Pieraccini 24
    B.5.3.2Town/ cityFirenze
    B.5.3.3Post code50139
    B.5.3.4CountryItaly
    B.5.4Telephone number0555662425
    B.5.5Fax number0555662425
    B.5.6E-mailclinicaltrialoffice@meyer.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TIROSINT - 50 MICROGRAMMI/1 ML SOLUZIONE ORALE 30 CONTENITORI MONODOSE 1 ML
    D.2.1.1.2Name of the Marketing Authorisation holderIBSA FARMACEUTICI ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTIROSINT
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name EUTIROX - 100 MICROGRAMMI COMPRESSE 50 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderBRACCO S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEUTIROX
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Primary acquired hypothyroidism
    Ipotiroidismo primario acquisito
    E.1.1.1Medical condition in easily understood language
    Primary Hypothyroidism
    Ipotiroidismo primario
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000559
    E.1.2Term Acquired hypothyroidism
    E.1.2System Organ Class 100000004860
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    6-12 months
    6-12 mesi
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 35
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 35
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 70
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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