HypothyroidismPhase 4NCT02917863
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
A Phase 4 study testing L-Thyroxine (tablet, per os) and L-Thyroxine (oral drops, solution) in people with Hypothyroidism, run by Meyer Children's Hospital IRCCS at 1 site in Italy.
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. Read more about this study
- Who is it for?
- Ages 3 to 18 years
- Conditions the study is for
- Hypothyroidism
- What is being tested?
- L-Thyroxine (tablet, per os) and L-Thyroxine (oral drops, solution)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 1 siteItaly
- Study dates
- May 2016to May 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Children with primary acquired hypothyroidism that require Levothyroxine therapy (naïve patients, < 18 years)
- Informed consent from parents and patient
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Meyer Children's Hospital
Florence
Stefano Stagi, MD, +390555662585, stefano.stagi@meyer.it
About this study
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
- Being tested
- L-Thyroxine (tablet, per os), L-Thyroxine (oral drops, solution)
- Keywords
- Hypothyroidism, Microbiota, Thyroid hormone, L-Thyroxine, Celiac disease
- Medical subject headings
- Hypothyroidism, Celiac Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-Thyroxine (tablet, per os)Drug
Also called Eutirox
L-Thyroxine (oral drops, solution)Drug
Also called Tirosint
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: L-Thyroxine (oral drops, solution) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: 0-6-12 months
Secondary outcomes (8)
Baseline gut microbiota characterization
Qualitative and quantitative (percentage) characterization of gut microbiota before the start of the therapy (T0)
Measured: 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)
Measured: baseline
Incidence of deamidated AGA
Estimate the incidence of positive patients to deamidated AGA at T6, T12, T24 (follow-up)
Measured: 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)
Measured: baseline
Baseline gut absorption parameters
Evaluate gut absorption (Steatocrit) parameters before the start of the therapy (T0)
Measured: 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
Measured: 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
Measured: 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
Measured: 0-6-12 moths
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Sep 2016 (estimated)
- Study startMay 2016
- Primary completionMay 2018 (estimated)
- Study completionMay 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for HypothyroidismStudies of the same condition, open and under way.
- More trials run by Meyer Children's Hospital IRCCSThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Meyer Children's Hospital IRCCS
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stefano Stagi, Meyer Children's Hospital IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02917863
- Sponsor's protocol ID
- THYR69
- Other IDs
- 2015-001248-12, 2015
- Status last verified
- Sep 2016
- First submitted
- 7 Sep 2016
- Last updated
- 28 Sep 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 21757873Smith 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.
PubMed 1237554Robertson 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.
PubMed 25203248Sanchez 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.
PubMed 23835180Ianiro 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.
PubMed 24610609Chao 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.
PubMed 9364356Guarner 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.
PubMed 12583961
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02917863
- Acronym / sponsor ID
- THYR69
- Conditions
- Hypothyroidism
- Keywords
- Hypothyroidism, Microbiota, Thyroid hormone, L-Thyroxine, Celiac disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- Meyer Children's Hospital IRCCSUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- May 2018 (estimated)
- Study completion
- May 2019 (estimated)
- First posted
- 28 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Solid L-Thyroxine | Experimental | Drug: L-Thyroxine (tablet, per os)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. |
| Liquid L-Thyroxine | Active comparator | Drug: L-Thyroxine (oral drops, solution)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. |
Who may qualify
- Ages
- 3 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- Children with primary acquired hypothyroidism that require Levothyroxine therapy (naïve patients, < 18 years)
- Informed consent from parents and patient
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-Thyroxine (tablet, per os)Also: Eutirox | Drug | Solid L-Thyroxine |
| L-Thyroxine (oral drops, solution)Also: Tirosint | Drug | Liquid L-Thyroxine |
Primary outcome
Effects on gut inflammation parameter (Calprotectin)
Time frame: 0-6-12 months
Calculate the difference in gut inflammation parameter (calprotectin) among the two groups of patients at T6-T0 and T12-T6
Effects on gut absorption parameters
Time frame: 0-6-12 months
Calculate the difference in gut absorption parameters (Steatocrit) among the two groups of patients at T6-T0 and T12-T6
Effects on gut inflammation parameter (Osteoprotegerin)
Time frame: 0-6-12 months
Calculate the difference in gut inflammation parameter (osteoprotegerin) among the two groups of patients at T6-T0 and T12-T6
Effects on gut inflammation parameter (S100-A12 protein)
Time frame: 0-6-12 months
Calculate the difference in gut inflammation parameter (S100-A12 protein) among the two groups of patients at T6-T0 and T12-T6
8 secondary outcomes
Baseline gut microbiota characterization
Time frame: baseline
Difference in gut microbiota among hypothyroid and healthy subjects
Time frame: baseline
Incidence of deamidated AGA
Time frame: 6-12-24 months
Baseline gut inflammation parameters
Time frame: baseline
Baseline gut absorption parameters
Time frame: baseline
Difference in Shannon Index in the gut microbiota among liquid and solid L-Thyroxine formulations
Time frame: 0-6-12 moths
Difference in Chao I in gut microbiota among liquid and solid L-Thyroxine formulations
Time frame: 0-6-12 moths
Difference in percentage of different species in gut microbiota among liquid and solid L-Thyroxine formulations
Time frame: 0-6-12 moths
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2016.
- Background: PubMed 21757873Stagi 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.
- Background: PubMed 1237554Smith 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.
- Background: PubMed 25203248Robertson 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.
- Background: PubMed 23835180Sanchez 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.
- Background: PubMed 24610609Ianiro 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.
- Background: PubMed 9364356Chao 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.
- Background: PubMed 12583961Guarner 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing L-Thyroxine (tablet, per os) and L-Thyroxine (oral drops, solution) in people with Hypothyroidism, run by Meyer Children's Hospital IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Stefano Stagi, MD (+0555662585, stefano.stagi@meyer.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effects on gut inflammation parameter (Calprotectin) (time frame: 0-6-12 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02917863, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2016.