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    Summary
    EudraCT Number:2016-000687-41
    Sponsor's Protocol Code Number:LEVOLIO
    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:2018-01-03
    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.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-000687-41
    A.3Full title of the trial
    COMBINED SUBSTITUTIVE THERAPY WITH LEVOTHYROXINE AND LIOTHYRONINE IN THYROIDECTOMIZED PATIENTS: EFFECTS ON PERIPHERICAL TISSUES. A PROSPECTIVE RANDOMIZED CONTROLLED DOUBLE BLIND STUDY.
    TERAPIA SOSTITUTIVA COMBINATA CON LEVOTIROXINA E LIOTIRONINA IN PAZIENTI TIROIDECTOMIZZATI: EFFETTI SUI TESSUTI PERIFERICI. STUDIO PROSPETTICO, RANDOMIZZATO CONTROLLATO, IN DOPPIO CIECO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    In patients who have no more thyroid, the combination of two hormones (T3 and T4) normally secreted by thyroid will be studied, in order to evaluate their effects at the periphery. Neither doctors or patients will know if the patient is enrolled in the group treated with both hormones or in the one treated with only T4 plus a placebo.
    Terapia in pazienti a cui è stata tolta la tiroide con combinazione dei due ormoni normalmente prodotti dalla tiroide (T4 e T3), per valutare i loro effetti a livello dei diversi tessuti del corpo. Nè i medici nè i pazienti sapranno se il paziente appartiene al gruppo dei soggetti che assumono entrambi gli ormoni o solo la T4 più una sostanza che non ha nessuna attività.
    A.3.2Name or abbreviated title of the trial where available
    LEVOLIO
    LEVOLIO
    A.4.1Sponsor's protocol code numberLEVOLIO
    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 UNITÀ SANITARIA LOCALE DI MODENA
    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 supportIBSA Institut Biochimique SA
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAZIENDA USL MODENA
    B.5.2Functional name of contact pointUNITA' DI ENDOCRINOLOGIA
    B.5.3 Address:
    B.5.3.1Street AddressVia Giardini 1355
    B.5.3.2Town/ cityModena
    B.5.3.3Post code41121
    B.5.3.4CountryItaly
    B.5.4Telephone number0593961816
    B.5.5Fax number0593961335
    B.5.6E-mailgiulia.brigante@gmail.com
    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 LIOTIR - 20 MCG / ML GOCCE ORALI, SOLUZIONE FLACONE 20 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 nameLIOTIR
    D.3.4Pharmaceutical form Oral drops, 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 TIROSINT - 100 MCG/ML GOCCE ORALI, SOLUZIONE 1 FLACONE 20 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 drops, 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Post-surgical hypothyroidism in substitutive therapy
    Ipotiroidismo post-chirurgico in terapia sostitutiva
    E.1.1.1Medical condition in easily understood language
    Patients without thyroid that need to take thyroid hormones as a therapy
    Soggetti senza tiroide che devono assumere per bocca gli ormoni tiroidei mancanti
    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 10036429
    E.1.2Term Postsurgical hypothyroidism
    E.1.2System Organ Class 100000004863
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In hypothyroid patients, with no residual thyroid function (thyroidectomized), evaluation of peripheral tissues response to combined therapy with levothyroxine (LT4) and liothyronine (LT3), after partial substitution of ongoing LT4 therapy with personalized doses of LT4 and LT3, respecting its circadian rythmicit and the physiological ratio of T3/T4.
    In pazienti ipotiroidei con funzionalità tiroidea residua praticamente assente (tiroidectomizzati), valutare la risposta dei tessuti periferici alla somministrazione combinata di levotiroxina (LT4) e liotironina (LT3), sostituendo parzialmente la terapia in corso basata su solo LT4 con dosi personalizzate di LT4 e LT3, nel rispetto della ritmicità circadiana di quest’ultima e del fisiologico rapporto T3/T4.
    E.2.2Secondary objectives of the trial
    In hypothyroid patients, with no residual thyroid function (thyroidectomized), evaluation of metabolic modifications, quality of life and gene expression in response to combined therapy with levothyroxine (LT4) and liothyronine (LT3), after partial substitution of ongoing LT4 therapy with personalized doses of LT4 and LT3, respecting its circadian rythmicit and the physiological ratio of T3/T4.
    In pazienti ipotiroidei con funzionalità tiroidea residua praticamente assente (tiroidectomizzati), valutare le modificazioni metaboliche, della qualità di vita e dell'espressione di alcuni geni target, in risposta alla somministrazione combinata di levotiroxina (LT4) e liotironina (LT3), sostituendo parzialmente la terapia in corso basata su solo LT4 con dosi personalizzate di LT4 e LT3, nel rispetto della ritmicità circadiana di quest’ultima e del fisiologico rapporto T3/T4.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients older than 18, capable of consent, able to sign a written informed consent, able to understand and fill in an italian questionnaire; residual thyroid function nearly absent (thyroidectomized, with serum tireoglobulin < 0.2 ng/ml and negative anti-tireoglobulin antibodies , in order to avoid methodological measurement interference), well comopensated with LT4 (pills)substitutive therapy, at stable dose for at least 3 months.
    Pazienti di età superiore a 18 anni, capaci di intendere e di volere,in grado di firmare volontariamente un consenso informato, previamente approvato dal Comitato Etico di riferimento, prima dello svolgimento di qualsiasi procedura prevista nella conduzione dello studio; in grado di capire e compilare un questionario in italiano; con funzionalità tiroidea residua presumibilmente assente (sottoposti a tiroidectomia totale, con tireoglobulina sierica < 0.2 ng/ml e anticorpi anti-tireoglobulina negativi, al fine di evitare interferenze nella metodica di dosaggio della tireoglobulina), in buon compenso in corso di terapia sostitutiva con LT4 in compresse, a dose stabile da almeno 3 mesi.
    E.4Principal exclusion criteria
    TSH-suppressive therapy, pregnancy, severe cardiac diseases, pituitary or adrenal untreated insufficiency, severe liver or kidney or bone disease, ongoing therapy with corticosteroids, amiodarone, colestiramine or iron, or with anti-absorptive drugs ongoing or in the previous 12 months, alcohol addiction, epilepsy.
    terapia TSH soppressiva, tireotossicosi, gravidanza, gravi patologie cardiache, insufficienza surrenalica non trattata, insufficienza ipofisaria non trattata, gravi patologie epatiche, renali o del metabolismo osseo; terapia con corticosteroidi, antiriassorbitivi ossei (in atto o nei 12 mesi precedenti), amiodarone, colestiramina o ferro; alcolismo; epilessia
    E.5 End points
    E.5.1Primary end point(s)
    Peripheral tissues response to variations of fT3 and fT4, measured by tissue markers such as TSH, SHBG, total and LDL cholesterol, lipoprotein(a), osteocalcin,urinary N-telopeptide, ferritin, myoglobin, CK, G6PD, ACE.
    risposta tissutale alle variazioni dei livelli periferici di fT3 e fT4, misurabile valutando i livelli di noti marker tissutali di funzionalità tiroidea, quali, oltre al TSH, SHBG, colesterolo totale, colesterolo LDL, lipoproteina(a), osteocalcina, N-telopeptide urinario, ferritina, mioglobina, creatinkinasi, glucosio-6-fosfato deidrogenasi, ACE.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 settimane
    E.5.2Secondary end point(s)
    Metabolic modifications (body weight, BMI, body and bone composition with DEXA); quality of life assessment; variation in the expression of tissue specific miRNA, for example in the muscle, that change in response to different thyroid states; correlation between TSH, fT3 and/or fT4 and SNPs of genes (DIO1 and DIO2) involved in thyroid hormones metabolism.
    Modificazioni dello stato metabolico (peso, BMI, composizione corporea e ossea mediante densitometria ossea (DEXA)); modificazioni della qualità di vita; variazioni dell’espressione di miRNA tessuto-specifici, per esempio muscolari, che può variare a seconda dello stato tiroideo; correlazione tra i livelli di TSH, fT3 e/o fT4 e i polimorfismi di geni (DIO1 e DIO2) coinvolti nel metabolismo degli ormoni tiroidei.
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 settimane
    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 No
    E.6.5Efficacy Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    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 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state260
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 260
    F.4.2.2In 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)
    At the end of the study, the investigator will decide case by case the treatment to be continued, considering the therapy response
    La terapia da proseguire dopo la fine dello studio sarà valutata dal medico sperimentatore, in base alla risposta ottenuta
    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 Decision2016-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-28
    P. End of Trial
    P.End of Trial StatusOngoing
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