Antithyroid Drug Treatment of Thyrotoxicosis in Young People

Sponsor

Newcastle-upon-Tyne Hospitals NHS Trust (Other)

Overall Status

Completed

CT.gov ID

NCT01436994

Collaborator

(none)

Enrollment

Locations

Arms

136

Duration (Months)

4.5

Patients Per Site

Patients Per Site Per Month

Study Details

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

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

Study Type:

Interventional

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 :

Jul 1, 2004

Actual Primary Completion Date :

Dec 1, 2014

Actual Study Completion Date :

Nov 1, 2015

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 [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. [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. [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. [3 years]
A comparison of the mean and variability of TSH and thyroid hormone concentrations in the 2 treatment groups.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	Country
1	Royal Aberdeen Children's Hospital	Aberdeen	United Kingdom
2	Birmingham Children's Hospital	Birmingham	United Kingdom
3	Addebrookes Hospital	Cambridge	United Kingdom
4	Wales College of Medicine	Cardiff	United Kingdom
5	University Hospital	Coventry	United Kingdom
6	Ninewells Hospital	Dundee	United Kingdom
7	Royal Hospital for Sick Children	Edinburgh	United Kingdom
8	Royal Hospital for Sick Children	Glasgow	United Kingdom
9	Hereford Hospital	Hereford	United Kingdom
10	Crosshouse Hospital	Kilmarnock	United Kingdom
11	Alder Hey Children's Hospital	Liverpool	United Kingdom
12	St Bart's Hospital	London	United Kingdom
13	St George's Hospital	London	United Kingdom
14	Royal Manchester Children's Hospital	Manchester	United Kingdom
15	Royal Victoria Infirmary	Newcastle upon Tyne	United Kingdom
16	Norfolk & Norwich University Hospitals	Norwich	United Kingdom
17	Oxford Radcliffe Hospitals	Oxford	United Kingdom
18	Sheffield Children's Hospital	Sheffield	United Kingdom