Antithyroid Drug Treatment of Thyrotoxicosis in Young People

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ClinicalTrials.gov Identifier: NCT01436994

Recruitment Status : Completed

First Posted : September 20, 2011

Last Update Posted : September 21, 2016

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Sponsor:

Information provided by (Responsible Party):

Tim Cheetham, Newcastle-upon-Tyne Hospitals NHS Trust

Study Description

Brief Summary:

The investigators aim to establish whether biochemical control during anti-thyroid drug therapy in young people with thyrotoxicosis varies depending upon whether a 'block and replace' or 'dose titration' regimen is used. The investigators will also assess remission rates and the frequency of side-effects in the two treatment groups.

Condition or disease	Intervention/treatment	Phase
Paediatric Thyrotoxicosis	Procedure: Block and Replace Procedure: Dose Titration Drug: carbimazole Drug: propylthiouracil Drug: thyroxine	Phase 3

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Detailed Description:

Thyrotoxicosis is an uncommon disorder in childhood and adolescence with a UK incidence around 1 per 100,000 (0-15 years). Most patients with thyrotoxicosis have Graves' disease which develops because of thyrotropin (TSH) receptor stimulation by autoantibodies. Patients with Hashimoto's thyroiditis can also be thyrotoxic in the early phase of the disease and occasionally thyrotoxicosis develops because of activating mutations of the TSH receptor. Many general paediatricians have experience of managing patients with thyrotoxicosis but national guidelines to assist in patient care have not been produced to date.

There is no ideal therapy for thyrotoxicosis in children and adolescents. The three treatment modalities for thyrotoxicosis - anti-thyroid drugs (ATD), surgery and radioiodine all have significant disadvantages. Particular considerations when managing young people include:

Low remission rates following a course of ATD.
Concerns about the morbidity associated with thyroidectomy.
Inadequate data regarding the long term safety of radioiodine.

Children and adolescents presenting with autoimmune thyrotoxicosis in the UK are usually treated with ATD from diagnosis for 1 - 4 years. Treatment is then stopped and patients who relapse return to ATD or are offered more definitive treatment with surgery or radioiodine. Life-long thyroid hormone replacement will be required if the thyroid gland is removed by surgery or ablated by radioiodine.

Excess thyroid hormone can have a major detrimental impact on cognitive function as well as cardiovascular and skeletal health. The maintenance of a clinically and biochemically euthyroid state is therefore highly desirable. There are two possible approaches when treating patients with ATD.

'Block and replace' (combined) therapy - where thyroid hormone production is prevented by ATD and thyroxine is then added in a replacement dose.
'Dose titration' (adaptive) therapy - where the dose of ATD is adjusted so that hormone production is normalised.

Both strategies are used by adult endocrinologists but it is unclear which of these approaches is the most appropriate in the young person.

Potential advantages of the 'block and replace' regimen include:

Improved stability with fewer episodes of hyper or hypothyroidism.
A reduced number of venepunctures and visits to hospital.
Improved remission rates following a larger anti-thyroid drug dose.

Potential advantages of the dose titration approach include:

Fewer side effects with a lower anti-thyroid drug dose
Improved compliance on one rather than two medications. A meta-analysis conducted primarily in adult patients concluded that 'dose titration' was the most appropriate way to manage thyrotoxicosis because of fewer ATD-related side-effects although a group of authors subsequently highlighted significant limitations of this study.

This study is a prospective, multi-centre trial which aims to establish which regimen - block and replace or dose titration - is the most appropriate medical therapy for thyrotoxicosis during childhood and adolescence.

Primary completion date changed from January 2019 to November 2014
Study completion date changed from January 2019 to November 2015

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	81 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Randomised Study of Two Anti-thyroid Drug Treatment Regimens in Young People
Study Start Date :	July 2004
Actual Primary Completion Date :	December 2014
Actual Study Completion Date :	November 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Medicines Thyroid Diseases

Drug Information available for: Propylthiouracil Carbimazole

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Block and Replace Carbimazole is commenced in a dose of 0.75 mg/kg/day. The intention is to completely prevent endogenous thyroxine production. Thyroxine is then added in a replacement dose as the thyroid hormone levels fall into the lower half of the laboratory normal range. The principal measure of control during the first 6 months will be thyroid hormone levels rather than TSH.	Procedure: Block and Replace The primary objective of treatment is to maintain a euthyroid state with TSH and thyroid hormone levels in the local laboratory normal range. Carbimazole is commenced in a dose of 0.75 mg/kg/day (propylthiouracil - for dose see below) with the aim being to completely preventing endogenous thyroxine production. Thyroxine is then added in a low replacement dose as the thyroid hormone levels fall into the lower half of the laboratory normal range. The principle measure of control during the first 6 months will be thyroid hormone levels rather than TSH. Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil. Other Names: Carbimazole propylthiouracil thyroxine Drug: carbimazole Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry Drug: propylthiouracil 50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry Drug: thyroxine 25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry
Active Comparator: Dose Titration Carbimazole is commenced in a dose of 0.75 mg/kg/day until thyroid hormone levels fall into the local laboratory normal range. The dose is then reduced to 0.25 mg/kg/day with the intention of maintaining the euthyroid state. The principal measure of control during the first 6 months will be thyroid hormone levels rather than TSH. Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil. Drug: Carbimazole 5mg and 20 mg tablets. Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry Drug: propylthiouracil 50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry.	Procedure: Dose Titration The primary objective of treatment is to maintain a euthyroid state with TSH and thyroid hormone levels in the local laboratory normal range. Carbimazole is commenced in a dose of 0.75 mg/kg/day until thyroid hormone levels fall into the local laboratory normal range. The dose is then reduced to 0.25 mg/kg/day with the intention of maintaining a euthyroid state as reflected by a free thyroxine and TSH within the normal range. Most paediatricians in the UK commence thyrotoxic children on carbimazole rather than propylthiouracil. Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. The guidelines detailed above can be used in the knowledge that 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil. Other Names: carbimazole propylthiouracil Drug: carbimazole Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry Drug: propylthiouracil 50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry

Arm

Intervention/treatment

Active Comparator: Block and Replace

Carbimazole is commenced in a dose of 0.75 mg/kg/day. The intention is to completely prevent endogenous thyroxine production. Thyroxine is then added in a replacement dose as the thyroid hormone levels fall into the lower half of the laboratory normal range. The principal measure of control during the first 6 months will be thyroid hormone levels rather than TSH.

Procedure: Block and Replace

The primary objective of treatment is to maintain a euthyroid state with TSH and thyroid hormone levels in the local laboratory normal range. Carbimazole is commenced in a dose of 0.75 mg/kg/day (propylthiouracil - for dose see below) with the aim being to completely preventing endogenous thyroxine production. Thyroxine is then added in a low replacement dose as the thyroid hormone levels fall into the lower half of the laboratory normal range. The principle measure of control during the first 6 months will be thyroid hormone levels rather than TSH. Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil.

Other Names:

Carbimazole
propylthiouracil
thyroxine

Drug: carbimazole

Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry

Drug: propylthiouracil

50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry

Drug: thyroxine

25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry

Active Comparator: Dose Titration

Carbimazole is commenced in a dose of 0.75 mg/kg/day until thyroid hormone levels fall into the local laboratory normal range. The dose is then reduced to 0.25 mg/kg/day with the intention of maintaining the euthyroid state. The principal measure of control during the first 6 months will be thyroid hormone levels rather than TSH.

Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil.

Drug: Carbimazole 5mg and 20 mg tablets. Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry Drug: propylthiouracil 50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry.

Procedure: Dose Titration

The primary objective of treatment is to maintain a euthyroid state with TSH and thyroid hormone levels in the local laboratory normal range.

Carbimazole is commenced in a dose of 0.75 mg/kg/day until thyroid hormone levels fall into the local laboratory normal range. The dose is then reduced to 0.25 mg/kg/day with the intention of maintaining a euthyroid state as reflected by a free thyroxine and TSH within the normal range.

Most paediatricians in the UK commence thyrotoxic children on carbimazole rather than propylthiouracil. Carbimazole is the preferred treatment because of the increased risk of hepatotoxicity with propylthiouracil but patients who are treated with propylthiouracil can also be recruited and randomised. The guidelines detailed above can be used in the knowledge that 1mg of carbimazole is approximately equivalent to 10 mg of propylthiouracil.

Other Names:

carbimazole
propylthiouracil

Drug: carbimazole

Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry

Drug: propylthiouracil

50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry

Outcome Measures

Primary Outcome Measures :

Biochemical control as reflected by the stability of blood thyroid stimulating hormone (TSH) concentrations [ Time Frame: 2.5 years ]
For each patient, TSH will be determined at each visit: the primary outcome variable is obtained by measuring the proportion of TSH concentrations that are outwith the laboratory normal range (in calculating this value, determinations made within six months of diagnosis are ignored).

Secondary Outcome Measures :

Remission rates as defined by patients who are biochemically euthyroid at the end of the 4 year study period. [ Time Frame: 4 years ]
To establish whether the remission rates post therapy in young people with thyrotoxicosis are affected by treatment with a 'block and replace' or 'dose titration' regimen. This will be determined by determining the proportion of individuals who are in remission ie who are biochemically euthyroid off ATD-thyroid drug therapy at the end of the of the study period (4 years). The proportion of subjects in remission following block and replace therapy will therefore be compared with the proportion in remission following dose titration.
The frequency of adverse events on the 2 treatment regimens. [ Time Frame: 3 years ]
This will be reflected by the number of participants with adverse events and by the proportion of patients changing to a different treatment during the study period.
Additional measures of biochemical control. [ Time Frame: 3 years ]
A comparison of the mean and variability of TSH and thyroid hormone concentrations in the 2 treatment groups.

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 16 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

All patients with thyrotoxicosis aged between 2 and 16 years at the time of diagnosis. Thyrotoxicosis will be diagnosed by the paediatrician on the basis of the clinical picture and the biochemistry (suppressed TSH with high thyroid hormone levels).
Child has consented/assented or consent via parent/guardian has been gained prior to any study specific procedures

Exclusion Criteria:

Known toxic adenoma / toxic hyperplasia (germline activating TSHR mutation).
McCune Albright Syndrome.
Previous episodes of Thyrotoxicosis..
Known allergic response to any of the study medication or ingredients as per SmPC.
Previous participation in this study.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01436994

Locations

Show 18 study locations

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United Kingdom
Royal Aberdeen Children's Hospital
Aberdeen, United Kingdom
Birmingham Children's Hospital
Birmingham, United Kingdom
Addebrookes Hospital
Cambridge, United Kingdom
Wales College of Medicine
Cardiff, United Kingdom
University Hospital
Coventry, United Kingdom
Ninewells Hospital
Dundee, United Kingdom
Royal Hospital for Sick Children
Edinburgh, United Kingdom
Royal Hospital for Sick Children
Glasgow, United Kingdom
Hereford Hospital
Hereford, United Kingdom
Crosshouse Hospital
Kilmarnock, United Kingdom
Alder Hey Children's Hospital
Liverpool, United Kingdom
St Bart's Hospital
London, United Kingdom
St George's Hospital
London, United Kingdom
Royal Manchester Children's Hospital
Manchester, United Kingdom
Royal Victoria Infirmary
Newcastle upon Tyne, United Kingdom
Norfolk & Norwich University Hospitals
Norwich, United Kingdom
Oxford Radcliffe Hospitals
Oxford, United Kingdom
Sheffield Children's Hospital
Sheffield, United Kingdom

Sponsors and Collaborators

Newcastle-upon-Tyne Hospitals NHS Trust

Investigators

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Principal Investigator:	Tim Cheetham	Newcastle upon Tyne Hospiatls NHS Foundation Trust

More Information

Additional Information:

British Society for Paediatric Endocrinology and Diabetes supports this study This link exits the ClinicalTrials.gov site

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Responsible Party:	Tim Cheetham, Dr Tim Cheetham, Newcastle-upon-Tyne Hospitals NHS Trust
ClinicalTrials.gov Identifier:	NCT01436994
Other Study ID Numbers:	NUTH 2759
First Posted:	September 20, 2011 Key Record Dates
Last Update Posted:	September 21, 2016
Last Verified:	September 2016

Keywords provided by Tim Cheetham, Newcastle-upon-Tyne Hospitals NHS Trust:


thyrotoxic thyrotoxicosis paediatric endocrinology	block and replace dose titration carbimazole

Additional relevant MeSH terms:

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Thyrotoxicosis Hyperthyroidism Thyroid Diseases Endocrine System Diseases Propylthiouracil Carbimazole	Antimetabolites Molecular Mechanisms of Pharmacological Action Antithyroid Agents Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs

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