Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)

Study Overview
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Brief Summary
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This is a multi-center, prospective, parallel-group, open-label, randomized clinical study in one hundred and twenty-six (126) neonates and infants diagnosed with CH. Subjects will be randomized in a 2:1 ratio to Treatment (Tirosint®-SOL) or Control (conventional therapy with levothyroxine sodium crushed tablets).

Detailed Description
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Newly diagnosed neonates will be randomly assigned to start therapy with LT4 at the initial dose recommended by the Standard of Care (SOC). Infants already on LT4 therapy will continue at the same daily dose within the randomly assigned treatment group (dose adjustments are allowed, if needed based on laboratory parameters and clinical response). Once enrolled, subjects will be treated and followed for 12 months (±1.5 months), participating in 7-8 study visits, consisting of 6-7 inclinic and 1-2 (or more if follow-up visits are required) telemedicine (TM) visits. The total number of visits depends on the age at inclusion.

Official Title
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A Randomized Comparative Study Between Liquid (Tirosint®-SOL) and Tablet Formulations of Levothyroxine in Neonates and Infants With Congenital Hypothyroidism

Conditions
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Congenital Hypothyroidism

Intervention / Treatment
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* Drug: Tirosint®-SOL
* Drug: Levothyroxine Sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patient aged 0 to 9 months Primary CH diagnosis with elevated TSH and low T4, requiring treatment with LT4, under either of the following conditions: Neonates newly diagnosed with primary CH and needing to initiate LT4 therapy, or Infants previously diagnosed with primary CH and who are already on LT4 therapy for at least 4 weeks; Provide and comply with the informed consent. Exclusion Criteria: Preterm neonates with a gestational age < 37 weeks; Low birth weight and very low birth weight neonates (weight < 2.5 kg); Neonates in neonatal intensive care units or requiring admission to NICU or neonates/infants hospitalized or requiring hospitalization; CH diagnosis > 4 weeks after delivery (for newly diagnosed neonates only); Diagnosis of primary gastrointestinal disease: Gastroesophageal reflux requiring medical therapy (beyond thickening of formula or position); Anatomic defects (e.g. intestinal atresia, malrotation, tracheoesophageal fistula, pyloric stenosis, Hirschsprung's disease, gastroschisis); Dietary allergy (e.g. cow's milk protein allergy); Malabsorption related to cystic fibrosis, celiac disease and others; Necrotizing enterocolitis requiring surgical resection; Known or suspected adrenal insufficiency (e.g. congenital adrenal hyperplasia, hypopituitarism); Diagnosis of congenital cardiac disease, cardiac insufficiency or risk for cardiac failure; Diagnosis of chromosomopathy; Diagnosis of central hypothyroidism; Hypersensitivity to glycerol; Concomitant anticonvulsant medications, liothyronine, combination of LT4 and liothyronine, thyroid extracts and/or chronic or long-term use of systemic glucocorticoids History of nonadherence with medication or medical visit schedule; or Any condition for which, participation would not be in the best interest of the patient or that could limit protocol specified assessments.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 9 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Tirosint®-SOL (levothyroxine sodium) oral solution (IBSA Pharma Inc.) at the following strengths: 25, 37.5, 44, 50, 62.5, 75, 88, 100 mcg. | Drug: Tirosint®-SOL<br>* Dosage will be according to the USPI and Standard of Care.<br>* Other names: levothyroxine sodium oral solution (liquid);|
| Active Comparator: Control<br>Crushed levothyroxine sodium tablets | Drug: Levothyroxine Sodium<br>* Tablets will be crushed and dissolved in solution. Dosage will be according to the USPI and Standard of Care.<br>* Other names: levothyroxine sodium tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LT4 dose required to maintain TSH in target range (unit: mcg/kg/day) | The LT4 dose is calculated based on the daily LT4 dose (mcg) used in the time period preceding the visit (or the average daily dose on a weekly basis if more than one strength is used over the course of the week) and the body weight (kg) measured during the visit. | Up to 22 months based on age group | 
| Hormonal (TFTs) profile for TSH | TSH (unit mU/L) | Up to 22 months based on age group | 
| Hormonal (TFTs) profile for FT4 | FT4 (unit ng/dL) | Up to 22 months based on age group | 
| Hormonal (TFTs) profile for TT4 | TT4 (unit µg/dL) | Up to 22 months based on age group | 
| Parent/caregiver reports of satisfaction and ease of administration preferences | Parents Satisfaction Questionnaire is a study-specific tool measuring coping and mental well-being and satisfactions. Score: 1-Strongly disagree, 2-Disagree, 3-Neutral, 4-Agree, 5-Strongly agree. The minimum score of 1 is worse outcome and maximum score of 5 is best outcome. | Up to 22 months based on age group | 
| Subject acceptance of the treatment (CareCAT) | Caregiver Administered Children's Acceptance Tool (CareCAT) is a 5-point nominal scale used to assess the acceptance of oral medicines in infants and toddlers who are unable to verbally give their opinion about a medicine (Blume 2018). Scale: 1-Swallows well, 2-Refusal, 3-Spitting Up, 4-Vomiting, 5-Medication not taken. The minimum score of 1 is best outcome and maximum score of 5 is worse outcome. | Up to 22 months based on age group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of dose adjustments | Percent number of subjects (%) who need a dose adjustment in the long-term follow up phase | Up to 22 months based on age group | 
| Growth patterns for length of body | Subject growth measurements in Length (cm) of body | Up to 22 months based on age group | 
| Growth patterns for body weight | Subject growth measurements in Body weight (kg) | Up to 22 months based on age group | 
| Growth patterns for head circumference | Subject growth measurements in Head circumference (cm) | Up to 22 months based on age group |