Clinical trial NCT01436994: Antithyroid Drug Treatment of Thyrotoxicosis in Young People
Official title: A Randomised Study of Two Anti-thyroid Drug Treatment Regimens in Young People
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Paediatric Thyrotoxicosis
Keywords: thyrotoxic
thyrotoxicosis
paediatric
endocrinology
block and replace
dose titration
carbimazole
Lead sponsor: Newcastle-upon-Tyne Hospitals NHS Trust
Sponsor class: OTHER
First posted: 2011-09-20
Enrollment: 81
Sex: ALL
Minimum age (years): 2
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Biochemical control as reflected by the stability of blood thyroid stimulating hormone (TSH) concentrations
timeFrame: 2.5 years
Secondary outcomes:
measure: Remission rates as defined by patients who are biochemically euthyroid at the end of the 4 year study period.
timeFrame: 4 years
measure: The frequency of adverse events on the 2 treatment regimens.
timeFrame: 3 years
measure: Additional measures of biochemical control.
timeFrame: 3 years
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Cambridge
country: United Kingdom
facility: Addebrookes Hospital
city: Cardiff
country: United Kingdom
facility: Wales College of Medicine
city: Coventry
country: United Kingdom
facility: University Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
city: Hereford
country: United Kingdom
facility: Hereford Hospital
city: Kilmarnock
country: United Kingdom
facility: Crosshouse Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
city: London
country: United Kingdom
facility: St Bart's Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospitals
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospitals
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
Study officials:
affiliation: Newcastle upon Tyne Hospiatls NHS Foundation Trust
name: Tim Cheetham
role: PRINCIPAL_INVESTIGATOR
References: