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

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.

Study Overview

• Status: Unknown
• Conditions: Hypothyroidism
• Intervention / Treatment: Drug: L-Thyroxine (tablet, per os); Drug: L-Thyroxine (oral drops, solution)

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Florence, Italy
    • Recruiting
    • Meyer Children's Hospital
    • Contact: Stefano Stagi, MD; Phone Number: +390555662585; Email: stefano.stagi@meyer.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Solid L-Thyroxine; 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); Other Names: Eutirox
Active Comparator: Liquid L-Thyroxine; 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); Other Names: Tirosint

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital

Publications and helpful links

General Publications

• Stagi S, Manoni C, Cecchi C, Chiarelli F, de Martino M. Increased risk of coeliac disease in patients with congenital hypothyroidism. Horm Res Paediatr. 2011;76(3):186-92. doi: 10.1159/000328723. Epub 2011 Jul 15.
• Smith DW, Klein AM, Henderson JR, Myrianthopoulos NC. Congenital hypothyroidism--signs and symptoms in the newborn period. J Pediatr. 1975 Dec;87(6 Pt 1):958-62. doi: 10.1016/s0022-3476(75)80918-8.
• Robertson HM, Narayanaswamy AK, Pereira O, Copland SA, Herriot R, McKinlay AW, Bevan JS, Abraham P. Factors contributing to high levothyroxine doses in primary hypothyroidism: an interventional audit of a large community database. Thyroid. 2014 Dec;24(12):1765-71. doi: 10.1089/thy.2013.0661.
• Sanchez E, Donat E, Ribes-Koninckx C, Fernandez-Murga ML, Sanz Y. Duodenal-mucosal bacteria associated with celiac disease in children. Appl Environ Microbiol. 2013 Sep;79(18):5472-9. doi: 10.1128/AEM.00869-13. Epub 2013 Jul 8.
• Ianiro G, Mangiola F, Di Rienzo TA, Bibbo S, Franceschi F, Greco AV, Gasbarrini A. Levothyroxine absorption in health and disease, and new therapeutic perspectives. Eur Rev Med Pharmacol Sci. 2014;18(4):451-6.
• Chao T, Wang JR, Hwang B. Congenital hypothyroidism and concomitant anomalies. J Pediatr Endocrinol Metab. 1997 Mar-Apr;10(2):217-21. doi: 10.1515/jpem.1997.10.2.217.
• Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003 Feb 8;361(9356):512-9. doi: 10.1016/S0140-6736(03)12489-0.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Anticipated): May 1, 2018
• Study Completion (Anticipated): May 1, 2019

Study Registration Dates

• First Submitted: September 7, 2016
• First Submitted That Met QC Criteria: September 26, 2016
• First Posted (Estimate): September 28, 2016

Study Record Updates

• Last Update Posted (Estimate): September 28, 2016
• Last Update Submitted That Met QC Criteria: September 26, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Hypothyroidism; Microbiota; Celiac disease; Thyroid hormone; L-Thyroxine
• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hypothyroidism
• Other Study ID Numbers: THYR69; 2015-001248-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No