Antithyroid Drug Treatment of Thyrotoxicosis in Young People

Paediatric Thyrotoxicosis Clinical Trial

Official title:

A Randomised Study of Two Anti-thyroid Drug Treatment Regimens in Young People

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01436994
• Other study ID #: NUTH 2759
• Status: Completed
• Phase: Phase 3
• First received: August 18, 2011
• Last updated: September 20, 2016
• Start date: July 2004
• Est. completion date: November 2015

Study information

• Verified date: September 2016
• Source: Newcastle-upon-Tyne Hospitals NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: National Research Ethics ServiceUnited Kingdom: Research & Development Review by Sponsor (Newcastle NHS)United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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:

1. Low remission rates following a course of ATD.

2. Concerns about the morbidity associated with thyroidectomy.

3. 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 81
• Est. completion date: November 2015
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 16 Years

Eligibility

Inclusion Criteria:

1. 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).

2. Child has consented/assented or consent via parent/guardian has been gained prior to any study specific procedures

Exclusion Criteria:

1. Known toxic adenoma / toxic hyperplasia (germline activating TSHR mutation).

2. McCune Albright Syndrome.

3. Previous episodes of Thyrotoxicosis..

4. Known allergic response to any of the study medication or ingredients as per SmPC.

5. Previous participation in this study.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Paediatric Thyrotoxicosis
• Thyrotoxicosis

Intervention

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.
• 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.

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
• propylthiouracil
50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry
• thyroxine
25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry

Locations

Country	Name	City	State
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

Sponsors (1)

Lead Sponsor	Collaborator
Newcastle-upon-Tyne Hospitals NHS Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Biochemical control as reflected by the stability of blood thyroid stimulating hormone (TSH) concentrations	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).	2.5 years	No
Secondary	Remission rates as defined by patients who are biochemically euthyroid at the end of the 4 year study period.	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.	4 years	No
Secondary	The frequency of adverse events on the 2 treatment regimens.	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.	3 years	No
Secondary	Additional measures of biochemical control.	A comparison of the mean and variability of TSH and thyroid hormone concentrations in the 2 treatment groups.	3 years	No

External Links

•   British Society for Paediatric Endocrinology and Diabetes supports this study