Antithyroid Drug Treatment of Thyrotoxicosis in Young People
Condition: Paediatric Thyrotoxicosis
MeSH terms: Thyrotoxicosis
Study type: Interventional
Phase: Phase 3

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.
    

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:

        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
    

Intervention name(s): Block and Replace; Dose Titration; carbimazole; propylthiouracil; thyroxine
Intervention type(s): Procedure; Procedure; Drug; Drug; Drug
Intervention description(s): 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.; 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.; Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry; 50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry; 25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry
Other intervention name(s): Carbimazole; propylthiouracil; thyroxine; carbimazole; propylthiouracil
Intervention MeSH terms: Propylthiouracil; Carbimazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: thyrotoxic; thyrotoxicosis; paediatric; endocrinology; block and replace; dose titration; carbimazole