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

    Summary
    EudraCT number
    		 2012-003677-25
    Trial protocol
    		 IT  
    Global end of trial date
    29 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2017
    First version publication date
    26 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12I/T405
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBSA INSTITUT BIOCHIMIQUE SA
    Sponsor organisation address
    Via del Piano P.O. Box 266, Pambio-Noranco, Switzerland, 6915
    Public contact
    R&D Scientific Affairs Administration & Archive Supervisor, IBSA INSTITUT BIOCHIMIQUE SA, +41 (0) 58 360 10 00, gabriella.gaglio@ibsa.ch
    Scientific contact
    R&D Scientific Affair Manager, IBSA INSTITUT BIOCHIMIQUE SA, +41 (0)58 360 10 00, claudia.scarsi@ibsa.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    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.
    Protection of trial subjects
    The patients were treated with two single doses of an already authorized LT4 solution at the therapeutic dose. However, in the hypothesis of an unforeseen increased absorption, an ECG was performed before study start and thereafter at the end of each treatment period. Vital signs were measured before and 24 hours after each dosing. In addition, patients with 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) were excluded from the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    18
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients scheduled for TSH stimulation test were selected or outpatients willing to comply with the protocol procedures. All of the subjects provided their written informed consent prior to the start of the screening visit.

    Pre-assignment
    Screening details
    		 The screening procedures included: demography; medical and medication history; general physical examination; vital signs (blood pressure [BP], heart rate [HR]); ECG; thyroid analyses (FT3; FT4, TSH, Tg, Tg-Ab); urine pregnancy test (in female subjects only), HIV and hepatitis B+C serology.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Levothyroxine oral solution administered with water
    Arm description
    		 100 to 150 mcg of Levothyroxine oral solution was administered with a total amount of 240 mL water.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tirosint® 25-50-100 μg / 1 mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    the content of 1 ampoule of levothyroxine sodium 100 (and 1 of 25 or 50, depending on current therapeutic dose) μg oral solution was squeezed in a glass and was diluted approximately in 140 mL of natural water at room temperature, the solution stirred with a spoon or stick and the patient drank the obtained solution. The glass was then rinsed twice with 50 mL of water, the solution stirred with the same spoon or stick and the patient drank both of the 50 ml solutions. Therefore the total amount of water consumed was 240 mL.

    Arm title
    		 Levothyroxine oral solution administered without water
    Arm description
    		 100 to 150 mcg of Levothyroxine oral solution was administered directly in the mouth without water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tirosint® 25-50-100 μg / 1 mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    the content of 1 ampoule of levothyroxine sodium 100 μg oral solution (and 1 of 25 or 50, depending on current therapeutic dose) was squeezed directly in the mouth.

    Number of subjects in period 1
    		Levothyroxine oral solution administered with water Levothyroxine oral solution administered without water
    Started
    18
    18
    Completed
    18
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levothyroxine oral solution administered with water
    Reporting group description
    		 100 to 150 mcg of Levothyroxine oral solution was administered with a total amount of 240 mL water.

    Reporting group title
    Levothyroxine oral solution administered without water
    Reporting group description
    		 100 to 150 mcg of Levothyroxine oral solution was administered directly in the mouth without water.

    Reporting group values
    		 Levothyroxine oral solution administered with water Levothyroxine oral solution administered without water Total
    Number of subjects
    		 18 18 18
    Age categorical
    Adults (18-64 years)
    Units: Subjects
        Adults (18-64 years)
    		 18 18 18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.6 ± 9.2 51.6 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    		 15 15 15
        Male
    		 3 3 3
    Subject analysis sets

    Subject analysis set title
    PK Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PK set was defined as all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and with evaluable data-sets of PK readouts for the scheduled treatment comparison, with no major deviations that could affect the PK results. This analysis set was used for the statistical analysis of the PK parameters.

    Subject analysis sets values
    		 PK Set
    Number of subjects
    18
    Age categorical
    Adults (18-64 years)
    Units: Subjects
        Adults (18-64 years)
    18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.6 ± 9.2
    Gender categorical
    Units: Subjects
        Female
    15
        Male
    3

    End points

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    End points reporting groups
    Reporting group title
    Levothyroxine oral solution administered with water
    Reporting group description
    		 100 to 150 mcg of Levothyroxine oral solution was administered with a total amount of 240 mL water.

    Reporting group title
    Levothyroxine oral solution administered without water
    Reporting group description
    		 100 to 150 mcg of Levothyroxine oral solution was administered directly in the mouth without water.

    Subject analysis set title
    PK Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PK set was defined as all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and with evaluable data-sets of PK readouts for the scheduled treatment comparison, with no major deviations that could affect the PK results. This analysis set was used for the statistical analysis of the PK parameters.

    Primary: Cmax

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    End point title
    		 Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Serum concentrations of levothyroxine (TT4) were measured at: -0.1 hours (= 6 minutes) pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 24 hours post-dose.
    End point values
    		 Levothyroxine oral solution administered with water Levothyroxine oral solution administered without water
    Number of subjects analysed
    18
    18
    Units: ng/mL
        arithmetic mean (standard deviation)
    103.64 ± 15.95
    100.59 ± 17.34
    Statistical analysis title
    		 90% CI
    Statistical analysis description
    Analysis of variance (ANOVA) was performed for log-transformed unadjusted AUCs and Cmax. The oral solution ingested with water has been used as the reference formulation. The 90% confidence interval for the B/A ratio of the population means (solution without water/solution with water) were calculated.
    Comparison groups
    Levothyroxine oral solution administered with water v Levothyroxine oral solution administered without water
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.01

    Primary: AUC 0-24

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    End point title
    		 AUC 0-24
    End point description
    End point type
    Primary
    End point timeframe
    Serum concentrations of levothyroxine (TT4) were measured at: -0.1 hours (= 6 minutes) pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 24 hours post-dose.
    End point values
    		 Levothyroxine oral solution administered with water Levothyroxine oral solution administered without water
    Number of subjects analysed
    18
    18
    Units: ng/mL*h
        arithmetic mean (standard deviation)
    2268.21 ± 393.9
    2253.6 ± 397.15
    Statistical analysis title
    		 90% CI
    Statistical analysis description
    Analysis of variance (ANOVA) was performed for log-transformed unadjusted AUCs and Cmax. The oral solution ingested with water has been used as the reference formulation. The 90% confidence interval for the B/A ratio of the population means (solution without water/solution with water) was calculated.
    Comparison groups
    Levothyroxine oral solution administered with water v Levothyroxine oral solution administered without water
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.99
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were monitored for any untoward medical occurrences until safety check (10±3 days after the last IMP dosing). All untoward medical events were recorded in the adverse event section of the CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Levothyroxine oral solution administered without water
    Reporting group description
    		 -

    Reporting group title
    Levothyroxine oral solution administered with water
    Reporting group description
    		 -

    Serious adverse events
    		 Levothyroxine oral solution administered without water Levothyroxine oral solution administered with water
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Levothyroxine oral solution administered without water Levothyroxine oral solution administered with water
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    Musculoskeletal and connective tissue disorders
    Wrist fracture
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2013
    Because the target number of 24 patients hadn’t been reached, the recruitment period was extended beyond the date scheduled in the Study Protocol. In order to facilitate the recruitment of eligible patients, additional daily doses of levothyroxine were admitted beside 100 mcg/day, namely 125 and 150 mcg/day, provided that the patients were on stable treatment since at least 3 months on those doses. In order to obtain the daily doses of 125 and 150 mcg/day with the test product, additional strengths of Tirosint oral solution were provided. Since there were more than one dose involved in the study, the statistical analysis had been modified, by adding the grouping by dose of the descriptive statistics and the adjustment of individual PK parameters for the dose in the relevant sections of the study protocol. Following to changes in the Sponsor organigram, the Drug Safety Manager for this study was Chiara Godina. In the Study Protocol Version 2.0 changes resulting from NON-substantial Amendment N. 1 (change in the head of the clinical laboratory) and from NON-substantial Amendment N. 2 (change in the head of the clinical laboratory, and change in the location of the laboratory for TT4 assay) had been included. Moreover few typographical errors in the text had been corrected.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Apr 2014
    In consequence of the delayed patients recruitment times and in agreement with the EMA guidelines, the Sponsor decided to stop the study on 11.06.2014, when 19 patients had been screened and 18 randomized and completed according to the protocol. Post-hoc evaluation of the type II error, showed that the statistical analysis was still conducted with a power >90% both in the PK set (18 subjects) and in the PK Control set (15 subjects).
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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