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

Hypothyroidism Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02917863
• Other study ID #: THYR69
• Secondary ID: 2015-001248-12
• Status: Recruiting
• Phase: Phase 4
• First received: September 7, 2016
• Last updated: September 26, 2016
• Start date: May 2016
• Est. completion date: May 2019

Study information

• Verified date: September 2016
• Source: Meyer Children's Hospital
• Contact: Stefano Stagi, MD
• Phone: +0555662585
• Email: stefano.stagi[@]meyer.it
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: May 2019
• Est. primary completion date: May 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 18 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Hypothyroidism

Intervention

Drug:
• L-Thyroxine (tablet, per os)

• L-Thyroxine (oral drops, solution)

Locations

Country	Name	City	State
Italy	Meyer Children's Hospital	Florence

Sponsors (1)

Lead Sponsor	Collaborator
Meyer Children's Hospital

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Chao T, Wang JR, Hwang B. Congenital hypothyroidism and concomitant anomalies. J Pediatr Endocrinol Metab. 1997 Mar-Apr;10(2):217-21. — View Citation

Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003 Feb 8;361(9356):512-9. Review. — View Citation

Ianiro G, Mangiola F, Di Rienzo TA, Bibbò 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. Review. — View Citation

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. — View Citation

Sánchez E, Donat E, Ribes-Koninckx C, Fernández-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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	Baseline gut microbiota characterization	Qualitative and quantitative (percentage) characterization of gut microbiota before the start of the therapy (T0)	baseline	No
Secondary	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	No
Secondary	Incidence of deamidated AGA	Estimate the incidence of positive patients to deamidated AGA at T6, T12, T24 (follow-up)	6-12-24 months	No
Secondary	Baseline gut inflammation parameters	Evaluate gut inflammation (calprotectin, Osteoprotegerin and S100-A12 protein) parameters before the start of the therapy (T0)	baseline	No
Secondary	Baseline gut absorption parameters	Evaluate gut absorption (Steatocrit) parameters before the start of the therapy (T0)	baseline	No
Secondary	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	No
Secondary	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	No
Secondary	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	No