Randomized Crossover Trial for the Evaluation of the Possible Effects in the Intestine of Two Different Pharmaceutical Forms of L - Thyroxine in Patients With Primary Acquired Hypothyroidism

Study Overview
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Brief Summary
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Thyroid disorders, in particular hypothyroidism, are associated with gastrointestinal impairment, such as celiac disease. A study reported an increased prevalence of celiac disease in a large cohort of children affected by congenital hypothyroidism, underlying the relationship between these two conditions. The hypothesis of our study is that the onset of celiac disorder may be related to the gut concentration of thyroid hormone (TH) in hypothyroidism patients treated with replacement therapy. In fact, TH replacement therapy showed a low bioavailability with a consequent high gut concentration. Two different pharmaceutical formulations (liquid and solid, per os) are available. The liquid one has a better absorption profile and bioavailability than the solid; therefore, it is associated with a low TH intestinal concentration. According to our hypothesis, the solid TH formulation could increase the microbial diversity in the gut instead of the liquid form, due to the high local TH concentration. Based on these findings, the purpose of this study is to evaluate the effect of two different pharmaceutical formulations of TH on the gut in terms of modification of gut microbiota, inflammatory parameters and gut absorption.

Official Title
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Randomized Crossover Trial for the Evaluation of the Possible Effects in the Intestine of Two Different Pharmaceutical Forms of L - Thyroxine in Patients With Primary Acquired Hypothyroidism

Conditions
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Hypothyroidism

Intervention / Treatment
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* Drug: L-Thyroxine (tablet, per os)
* Drug: L-Thyroxine (oral drops, solution)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children with primary acquired hypothyroidism that require Levothyroxine therapy (naïve patients, < 18 years) Informed consent from parents and patient Exclusion Criteria: Age < 3 years Patients with secondary hypothyroidism, euthyroid sick syndrome or thyroid hormone resistant Patients with celiac disease, type I diabetes or other known autoimmune diseases Patients with genetic diseases or syndromes, such as Down, Williams-Beuren, Turner Assumption of antibiotics, probiotics, prebiotics, or other medications that could affect the gut microbiota in the month before the beginning of the study Gastrointestinal infectious diseases in the month before the beginning of the study Hypersensitivity to levothyroxine or any of the ingredients contained in the two pharmaceutical formulations Untreated adrenal insufficiency, untreated pituitary insufficiency and untreated thyrotoxicosis. Patients with cardiovascular disease Patients who show with impaired pancreatic function measured using the assay in faecal fat (steatocrit) at the screening visit

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid L-Thyroxine<br>Patients assume L-Thyroxine (tablet, per os) according to the Summary Product Characteristics for 6 months (then switch to the other formulation). Dosage in children with hypothyroidism: 0-6 months: 10 mcg/kg body weight/die 6-12 months: 8 mcg/kg body weight/die 1- 5 years: 6 mcg/kg body weight/die 5-10 years: 4 mcg/kg body weight/die Dosage in adults: initial dose of 50mcg/die; maintenance dose 100-200 (300) mcg/die (medium dose 2-2,5 mcg/kg body weight/die). Dosage will be adjusted according to TSH level. | Drug: L-Thyroxine (tablet, per os)<br> <br> * Other names: Eutirox;|
| Active Comparator: Liquid L-Thyroxine<br>Patients assume L-Thyroxine (oral drops, solution) according to the Summary Product Characteristics for 6 months (then switch to the other formulation). Dosage in children with acquired hypothyroidism: initial dose: 12,5-50 mcg/die maintenance dose: 100-150 mcg/m2 body surface area Dosage in adults: initial dose: 50 mcg/die; maintenance dose: 100-200 (300) mcg/die (medium dose 2-2,5 mcg/kg body weight/die). Dosage will be adjusted according to TSH level. | Drug: L-Thyroxine (oral drops, solution)<br> <br> * Other names: Tirosint;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects on gut inflammation parameter (Calprotectin) | Calculate the difference in gut inflammation parameter (calprotectin) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 months | 
| Effects on gut absorption parameters | Calculate the difference in gut absorption parameters (Steatocrit) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 months | 
| Effects on gut inflammation parameter (Osteoprotegerin) | Calculate the difference in gut inflammation parameter (osteoprotegerin) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 months | 
| Effects on gut inflammation parameter (S100-A12 protein) | Calculate the difference in gut inflammation parameter (S100-A12 protein) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline gut microbiota characterization | Qualitative and quantitative (percentage) characterization of gut microbiota before the start of the therapy (T0) | baseline | 
| Difference in gut microbiota among hypothyroid and healthy subjects | Difference in gut microbiota among hypothyroid patients (T0) and healthy patients (data from Human Microbiome Project) | baseline | 
| Incidence of deamidated AGA | Estimate the incidence of positive patients to deamidated AGA at T6, T12, T24 (follow-up) | 6-12-24 months | 
| Baseline gut inflammation parameters | Evaluate gut inflammation (calprotectin, Osteoprotegerin and S100-A12 protein) parameters before the start of the therapy (T0) | baseline | 
| Baseline gut absorption parameters | Evaluate gut absorption (Steatocrit) parameters before the start of the therapy (T0) | baseline | 
| Difference in Shannon Index in the gut microbiota among liquid and solid L-Thyroxine formulations | Calculate the difference in Shannon Index (index of diversity) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 moths | 
| Difference in Chao I in gut microbiota among liquid and solid L-Thyroxine formulations | Calculate the difference in Chao I (Species richness estimator) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 moths | 
| Difference in percentage of different species in gut microbiota among liquid and solid L-Thyroxine formulations | Calculate the difference in percentage of different species (OTU, operational taxonomic unit) among the two groups of patients at T6-T0 and T12-T6 | 0-6-12 moths | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypothyroidism, Microbiota, Thyroid hormone, L-Thyroxine, Celiac disease