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

NCT02917863 | Unknown Phase 4

• 2 other identifiers: THYR692015-001248-12
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hypothyroidism

Keywords

Hypothyroidism; Microbiota; Thyroid hormone; L-Thyroxine; Celiac disease

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (8)

• Baseline gut microbiota characterization

  baseline

• Difference in gut microbiota among hypothyroid and healthy subjects

  baseline

• Incidence of deamidated AGA

  6-12-24 months

• Baseline gut inflammation parameters

  baseline

• Baseline gut absorption parameters

  baseline

Study Arms (2)

Solid L-Thyroxine

EXPERIMENTAL

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)

Liquid L-Thyroxine

ACTIVE COMPARATOR

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)

Interventions

L-Thyroxine (tablet, per os) DRUG

Also known as: Eutirox

Solid L-Thyroxine

L-Thyroxine (oral drops, solution) DRUG

Also known as: Tirosint

Liquid L-Thyroxine

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children with primary acquired hypothyroidism that require Levothyroxine therapy (naïve patients, \< 18 years)
• Informed consent from parents and patient

You may not qualify if:

• 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

Sponsors & Collaborators

• Meyer Children's Hospital IRCCS: lead

Study Sites (1)

Meyer Children's Hospital

Florence, Italy

RECRUITING

Related Publications (7)

• 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.

  PMID: 21757873 BACKGROUND

• 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.

  PMID: 1237554 BACKGROUND

• 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.

  PMID: 25203248 BACKGROUND

• 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.

  PMID: 23835180 BACKGROUND

• 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.

  PMID: 24610609 BACKGROUND

• 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.

  PMID: 9364356 BACKGROUND

• 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.

  PMID: 12583961 BACKGROUND

MeSH Terms

Conditions

Hypothyroidism; Celiac Disease

Interventions

Thyroxine; Tablets; Solutions

Condition Hierarchy (Ancestors)

Thyroid Diseases; Endocrine System Diseases; Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Dosage Forms; Pharmaceutical Preparations

Central Study Contacts

Stefano Stagi, MD

CONTACT

+0555662585; stefano.stagi@meyer.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: September 7, 2016
• First Posted: September 28, 2016
• Study Start: May 1, 2016
• Primary Completion: May 1, 2018
• Study Completion: May 1, 2019
• Last Updated: September 28, 2016

Record last verified: 2016-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)