Clinical Trials Register

Summary
EudraCT Number:	2012-003677-25
Sponsor's Protocol Code Number:	12I/T405
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:	2012-12-28
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

2012-003677-25

A.3

Full title of the trial

Safety and bioavailability of Tirosint
(Levothyroxine Sodium) Oral Solution
administered as single dose with or without water
in hypothyroid patients.

Tollerabilità e biodisponibilità di Tirosint (levotiroxina sodica)
soluzione per uso orale somministrata in dose singola con o senza
acqua a pazienti ipotiroidei.

A.3.1

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

safety of the administration of levothyroxine sodium
oral solution (LT4s) swallowed in fasting conditions with or without
water in hypothyroid patients

sicurezza della soluzione di
levotiroxina dopo somministrazione per via orale di una dose unica
(100 μg) di LT4 soluzione orale assunta con o senza acqua in condizioni di digiuno da pazienti ipotiroidei

A.4.1

Sponsor's protocol code number

12I/T405

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	IBSA INSTITUT BIOCHIMIQUE SA
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	IBSA INSTITUT BIOCHIMIQUE SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IBSA INSTITUT BIOCHIMIQUE SA
B.5.2	Functional name of contact point	Clinical Reserarch Manager
B.5.3	Address:
B.5.3.1	Street Address	Via del Piano
B.5.3.2	Town/ city	Pambio-Noranco
B.5.3.3	Post code	6915
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0041 58 360 10 00
B.5.5	Fax number	0041 58 360 16 55
B.5.6	E-mail	sandra.fantoni@ibsa.ch

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*OS 30FL 1ML 100MCG/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	IBSA FARMACEUTICI ITALIA Srl
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.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEVOTIROXINA
D.3.9.4	EV Substance Code	SUB20658
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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

Both genders thyroidectomized patients, with thyroglobulin (Tg) circulating levels below 5 ng/mL and no evidence of Tg antibodies (Tg-Ab), at stable (at least 3 months) 100 μg/day levothyroxine tablets therapy

Saranno selezionati per lo studio pazienti tiroidectomizzati di entrambi i sessi, con valori di tireoglobulina circolante inferiori a 5 ng/ml e anticorpi antitireoglobulina non rilevabili, in terapia stabile da almeno 3 mesi con LT4 compresse alla dose giornaliera di 100 μg.

E.1.1.1

Medical condition in easily understood language

hypothyroid patients already treated with levothyroxine tablets

pazienti ipotiroidei già in terapia a dose stabile (100 μg/die) con LT4 compresse,

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10021114
E.1.2	Term	Hypothyroidism
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 evaluate the absorption pattern of LT4, on the basis of circulating total T4 (TT4), in hypothyroid patients already treated with levothyroxine tablets, following the administration of levothyroxine sodium oral solution (LT4s) swallowed in fasting conditions with or without water.

Verificare il profilo di assorbimento della LT4 sulla base dei livelli sierici di T4 totale (TT4), in pazienti ipotiroidei già in trattamento con LT4 compresse, a seguito della somministrazione di una dose unica per via orale di LT4 soluzione assunta con o senza acqua in condizioni di digiuno.

E.2.2

Secondary objectives of the trial

To confirm the clinical safety (in terms of vital signs, ECG, adverse events) of the LT4 solution in both administration conditions; to verify the acceptability of the LT4 solution in both administration conditions.

Confermare la tollerabilità clinica (segni vitali, ECG, eventi avversi) di entrambe le modalità di somministrazione; verificare il gradimento delle due modalità di somministrazione.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• written informed consent; • hypothyroid patients of both genders, thyroidectomized in consequence of thyroid cancer or other thyroid diseases; • ≥18 and ≤75 years of age; • Body Mass Index (BMI) > 18.5 and < 32.0 kg/m2 • Tg levels < 5 ng/mL; • nondetectable (<30 IU/mL) anti-thyroglobulin antibodies (Tg- Ab); • substitutive and/or TSH suppressive treatment with LT4 tablets at a stable (at least three months) dosage (100 μg/day); • serum FT4, FT3 and TSH within normal values for the patient; • availability and possibility of taking part in the study; • reasonable assumption of understanding the study and of reliability.

• consenso informato scritto; • pazienti ipotiroidei di entrambi i sessi tiroidectomizzati (in conseguenza di patologie neoplastiche o altre affezioni tiroidee); • età compresa tra i 18 ed i 75 anni; • Indice di Massa Corporea (Body Mass Index: BMI) superiore a 18.5 e inferiore a 32.0 kg/m2 • Tireoglobulina circolante < 5 ng/mL; • anticorpi antitireoglobulina non rilevabili (<30 IU/mL); • terapia sostitutiva/TSH soppressiva con LT4 compresse a dosaggio (100 μg/die) stabile da almeno tre mesi; • valori sierici di FT4, FT3 e TSH entro valori normali per il singolo paziente (i.e. non necessità di variazioni posologiche); • disponibilità e possibilità di partecipazione allo studio; • ragionevole ipotesi di capacità di comprensione degli scopi e delle modalità dello studio, nonchè di affidabilità.

E.4

Principal exclusion criteria

seriously compromised cardiac (heart failure), hepatic, renal and/or respiratory functions; • active arrhythmia or history of arrhythmia, particularly atrial fibrillation • serious metabolic (e.g. uncompensated diabetes mellitus), organs (e.g. cirrhosis of the liver), endocrine or systemic diseases (excluding the basic pathology); • epilepsy; • neoplastic pathology, active or in remission for less than 5 years (excluding the basic thyroid pathology); • terminal condition; • parenteral or assisted enteral feeding;clinically significant illness or surgery within 4 weeks prior to dosing; • presence of any medical condition or other circumstances which would significantly decrease the chance of obtaining reliable data, achieving study objectives or completing the study; • serious psychiatric problems (whether or not receiving treatment) or in any case such as to compromise the patient’s reliability; • non-therapeutic use of psychotropic substances; • alcoholism; • positive test for hepatitis B, hepatitis C, or HIV at screening; • positive pregnancy test; • breast-feeding; • known hypersensitivity to the ingredients of the preparation involved in the study; • use of concomitant medications that might interfere with study evaluations; • regular consumption of soya and soya derivatives • skin lesions at the site of the blood sampling (forearm); • difficult access to the peripheral venous blood vessels; • emesis episode within 24 hours prior to dosing; • participation in other clinical studies during the two months prior to dosing; • donation of blood during the two months prior to dosing; • presumption of poor reliability/cooperation; • any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

• grave compromissione delle funzioni cardiaca, respiratoria, epatica e/o renale; • presenza di aritmia o storia di aritmia, in particolare fibrillazione atriale; • gravi malattie metaboliche (ad esempio diabete mellito scopensato), d’organo (es. cirrosi epatica), endocrine (esclusa la patologia tiroidea di base) o sistemiche; • epilessia; • patologie neoplastiche in atto o in remissione da meno di 5 anni (esclusa la patologia tiroidea di base); • stato terminale; • alimentazione parenterale o assistita; • significative malattie o procedure chirurgiche entro le 4 settimane prima dei trattamenti sperimentali; • presenza di ogni condizione, medica o di altro tipo, che potrbbe ridurre in maniera significativa la possibilità di ottenere dati affidabili, di raggiungere gli scopi dello studio e/o di completare il medesimo; • patologie psichiatriche serie (in trattamento o meno) o in ogni caso di natura tale da compromettere l’affidabilità del soggetto; • uso non terapeutico di sostanze psicoattive; • alcoolismo; • positività dei tests per epatite B/epatite C/infezione da HIV agli accertamenti di screening; • positività del test di gravidanza; • allattamento al seno; • ipersensibilità nota ai componenti della soluzione oggetto di studio; • uso concomitante di farmaci o sostanze potenzialmente in grado di interferire con i parametri di valutazione; • uso regolare di soia e suoi derivati • lesioni cutanee nella sede dei prelievi ematici; • accesso difficoltoso all rete venosa superficiale; • episodi di emesi nelle 24 ore antecedenti l’inizio dello studio; • partecipazione ad altri studi clinici nei due mesi antecedenti lo studio; • donazioni di sangue nei due mesi antecedenti lo studio; • presunzione di scarsa affidabilità/cooperazione; • ogni elemento che, a giudizio dello Sperimentatore, rappresenti una controindicazione alla partecipazione allo studio da parte del paziente.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood samples: -0.1 hours (= 6 minutes) pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 24 hours post-dose

Campioni di sangue: -0.1 hours (= 6 minutes) pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 24 hours post-dose

E.5.2

Secondary end point(s)

Confermare la tollerabilità clinica (segni vitali, ECG, eventi avversi) di entrambe le modalità di somministrazione; verificare il gradimento delle due modalità di somministrazione

E.5.2.1

Timepoint(s) of evaluation of this end point

pre-dose and and 24 hours post-dose

Prima della somministarzione e 24 ore dopo la somministrazione.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

soluzione di LT4 somministrata con acqua [LT4sw] 

LT4 solution administered with water [LT4sw] LT4

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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.8.6 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

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

Number of subjects for this age range:

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

Yes

F.3.3.1

Women 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 2012-12-28.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

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)

Safety will be checked by medical visit 10-15 days after IMO administration

Un controllo con visita medica di sicurezza sarà effettuata dopo 10-15 giorni dall'ultimo trattamento.

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

2013-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-20

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

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