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    Summary
    EudraCT Number:2016-001516-38
    Sponsor's Protocol Code Number:MISEM/2016
    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:2021-06-08
    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 number2016-001516-38
    A.3Full title of the trial
    Levothyroxine soft-gel efficacy with variation of intaking time in hypothyroidism replacement therapy
    Valutazione dell¿efficacia della levotiroxina in capsule molli nella terapia sostitutiva dell¿ipotiroidismo al variare del timing di assunzione
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Levothyroxine soft-gel efficacy with variation of intaking time in hypothyroidism replacement therapy
    Valutazione dell¿efficacia della levotiroxina in capsule molli nella terapia sostitutiva dell¿ipotiroidismo al variare del timing di assunzione
    A.3.2Name or abbreviated title of the trial where available
    MISEM/2016
    MISEM/2016
    A.4.1Sponsor's protocol code numberMISEM/2016
    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 SponsorPROF.EFISIO PUXEDDU, SEZIONE MEDICINA INTERNA SCIENZE ENDOCRINE E METABOLICHE, UNIVERSITà DI PERUGIA
    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 supportFondi del Dipartimento di Medicina
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSezione Medicina Interna Scienze Endocrine e Metaboliche
    B.5.2Functional name of contact pointProf. Efisio Puxeddu
    B.5.3 Address:
    B.5.3.1Street AddressPiazza Lucio Severi 1
    B.5.3.2Town/ cityS. Andrea delle Fratte - Perugia
    B.5.3.3Post code06132
    B.5.3.4CountryItaly
    B.5.4Telephone number0755858210
    B.5.5Fax number0755730855
    B.5.6E-mailefisio.puxeddu@unipg.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 TICHE - "88 MICROGRAMMI CAPSULE MOLLI" 100 CAPSULE IN BLISTER PVC-PCTFE/AL
    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.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN00179301
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive namelevothyroxine
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number75 to 200
    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
    patients who underwent total thyroidectomy followed or not by ablative radioiodine therapy for differentiated thyroid carcinoma and then treated with levothyroxine replacement therapy, in disease remission
    pazienti sottoposti a tiroidectomia totale seguita o meno da terapia ablativa con radioiodio per carcinoma differenziato della tiroide, in attuale remissione di malattia
    E.1.1.1Medical condition in easily understood language
    primary hypothyroidism patients
    pazienti in ipotiroidismo primitivo
    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 PT
    E.1.2Classification code 10021114
    E.1.2Term Hypothyroidism
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to demonstrate the noninferiority between soft gel levothyroxine intake in the interval 0-10 minutes with breakfast and its intake (for tablet formulation) 30 minutes before breakfast (at the same dosage used), for thyroid function replacement.
    dimostrare la non inferiorit¿ dell'assunzione della levotiroxina liquida in capsule molli nell¿intervallo di tempo 0-10 minuti con la colazione rispetto all¿assunzione attualmente raccomandata (per la formulazione in compresse) 30 minuti prima di colazione (a parit¿ di dosaggio utilizzato), per il raggiungimento di un¿ottimale sostituzione della funzione tiroidea.
    E.2.2Secondary objectives of the trial
    to verify variation in quality of life related with variation of levothyroxine intaking time.
    verificare eventuali variazioni nella qualit¿ della vita al variare degli intervalli di tempo intercorrenti tra l'assunzione di levotiroxina e la colazione.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    We will enroll adult subjects with primary hypothyroidism, able to express and sign an informed consent, in which replacement therapy has allowed to achieve the therapeutic target ( TSH between 0.8 and 1.6 mcU/ml). We will enroll patients who underwent total thyroidectomy followed or not by ablative radioiodine therapy for differentiated thyroid carcinoma and then treated with levothyroxine replacement therapy, in disease remission. The enrollment of patients who underwent total thyroidectomy allows that all possible variations in thyroid function are related only to the absorption of levothyroxine pharmacologically administered, in the absence of any interference from any residual intrinsic thyroid function. We will include hypothyroid patients, that accept to switch levothyroxine tablets with soft gel levothyroxine.
    We will not include women in pregnancy; it is expected the inclusion of women in childbearing age or during breastfeeding.
    possono essere arruolati soggetti maggiorenni, in grado di esprimere e firmare un consenso informato, in terapia con levotiroxina a dosaggio sostitutivo per ipotiroidismo primitivo, nei quali la terapia sostitutiva abbia consentito il raggiungimento dell’obiettivo terapeutico auspicato (TSH compreso tra 0,8 e 1,6 mcU/ml). Verranno arruolati pazienti sottoposti a tiroidectomia totale seguita o meno da terapia ablativa con radioiodio per carcinoma differenziato della tiroide, in attuale remissione di malattia e quindi in terapia con levotiroxina a dosaggio sostitutivo. L’arruolamento di pazienti sottoposti a tiroidectomia totale fa sì che tutte le eventuali variazioni dei parametri di funzione tiroidea siano relate soltanto all’assorbimento della levotiroxina somministrata farmacologicamente, in assenza di eventuali interferenze dovute ad un’eventuale funzione tiroidea intrinseca residua. Verranno quindi inclusi pazienti già riconosciuti affetti da ipotiroidismo, in terapia sostitutiva con levotiroxina in compresse, che accettano di passare alla levotiroxina in formulazione capsule molli.
    Non è prevista l'inclusione nello studio di donne in gravidanza; è prevista l'inclusione di donne in età fertile o durante l'allattamento.
    E.4Principal exclusion criteria
    We will exclude all the patients on replacement therapy with levothyroxine in tablet form, which have not reached the therapeutic target (TSH levels between 0.8 and 1.6 mcU/ml) and that have had, in the prior 6 months, instability in levothyroxine dose to require frequent dose adjustments. We will also exclude all patients which take any drug at breakfast (or before or immediately after). Any drug eventually assumed is approved from one hour after breakfast. We will exclude patients with gastro-intestinal illnesses [6] or for malabsorption. We will exclude from enrollment patients with intolerance to the active substance or to any of the ingredients contained in the soft capsule, patients with concomitant untreated adrenal insufficiency, untreated hypopituitarism and untreated hyperthyroidism. We will also exclude patients with acute myocardial infarction, acute myocarditis or acute pancardite and patients unable to swallow a capsule. We will exclude the patients who didn't have surgical total thyroidectomy and patients who need suppressive therapy (patients with differentiated thyroid carcinoma in the first period after the initial treatment or patients with thyroid carcinoma with persistence or relapse of disease).
    verranno esclusi tutti i pazienti che sono in terapia sostitutiva con levotiroxina in compresse, ma nei quali non sia stato raggiunto l’obiettivo terapeutico auspicabile in corso di terapia sostitutiva (livelli di TSH compresi tra 0,8 e 1,6 mcU/ml) e che hanno presentato, nei 6 mesi antecedenti, instabilità nel dosaggio di levotiroxina, tale da richiederne frequenti aggiustamenti. Verranno altresì esclusi tutti i pazienti che assumono un qualsiasi farmaco al momento della colazione (o prima o subito dopo). L’assunzione di un eventuale farmaco è approvata a partire da un’ora dopo la colazione. Verranno esclusi i pazienti che presentano anamnesi positiva per malattie gastro-intestinali [6] o per malassorbimento. Saranno esclusi dall'arruolamento pazienti con intolleranza al principio attivo o ad uno qualsiasi degli eccipienti contenuti nella capsula molle, pazienti con concomitante insufficienza adrenocorticale non trattata, ipopituitarismo non trattato e ipertiroidismo non trattato. Saranno altresì esclusi pazienti con infarto miocardico acuto, miocardite acuta o pancardite acuta e pazienti non in grado di deglutire una capsula molle intera. Verranno esclusi i pazienti in terapia sostitutiva per ipotiroidismo, ma non sottoposti ad intervento chirurgico di tiroidectomia totale ed i pazienti che necessitano di terapia TSH-soppressiva (pazienti affetti da carcinoma differenziato della tiroide nel primo periodo dopo il trattamento iniziale o pazienti affetti da carcinoma della tiroide con persistenza o recidiva di malattia).
    E.5 End points
    E.5.1Primary end point(s)
    Group sample sizes of 25 and 25 patients for each group achieve 91% power to detect non-inferiority between soft gel levothyroxine intake in the interval 0-10 minutes with breakfast and its intake (for tablet formulation) 30 minutes before breakfast (at the same dosage used), for thyroid function replacement. Non-inferiority will be evaluated by comparing the levels of TSH measured in the control arm (in which patients will take levothyroxine in soft capsules 30 minutes before breakfast) and TSH levels measured in the experimental arm (in which patients will assume levothyroxine soft capsule in the range 0-10 minutes with breakfast).
    Una dimensione campionaria di 50 pazienti, 25 nel braccio di controllo e 25 nel braccio sperimentale, consente di ottenere un power del 91% per dimostrare la non inferiorità dell'assunzione della levotiroxina liquida in capsule molli nell’intervallo di tempo 0-10 minuti con la colazione rispetto all’assunzione attualmente raccomandata, per la levotiroxina in compresse, 30 minuti prima di colazione. La non inferiorità verrà valutata mediante il confronto tra i livelli di TSH misurati nel braccio di controllo (nel quale i pazienti assumeranno la levotiroxina in capsule molli 30 minuti prima di colazione) ed i livelli di TSH misurati nel braccio sperimentale (nel quale i pazienti assumeranno la levotiroxina in capsule molli nell'intervallo 0-10 minuti con la colazione).
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 mesi
    E.5.2Secondary end point(s)
    there aren't secondary end points
    non sono previsti end point secondari
    E.5.2.1Timepoint(s) of evaluation of this end point
    0
    0
    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 Yes
    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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Stesso farmaco ma in diverso timing di assunzione
    Same drug with different intaking time
    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 years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months9
    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.1.1.1In 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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 Yes
    F.3.3.1Women 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 2021-06-08. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    patients will be follow according to normal clinical practice
    continueranno ad essere seguiti secondo normale pratica clinica
    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 Decision2016-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-16
    P. End of Trial
    P.End of Trial StatusOngoing
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