Paediatric ThyrotoxicosisPhase 3NCT01436994
Antithyroid Drug Treatment of Thyrotoxicosis in Young People
A Phase 3 study testing Block and Replace, Dose Titration and carbimazole in people with Paediatric Thyrotoxicosis, run by Newcastle-upon-Tyne Hospitals NHS Trust at 18 sites in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 2 to 16 years
- Conditions the study is for
- Paediatric Thyrotoxicosis
- What is being tested?
- Block and Replace, Dose Titration and carbimazole
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 81 participants
- Where
- 18 sitesUnited Kingdom
- Study dates
- Jul 2004to Nov 2015
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
18 sites in 1 country.
18 sites in 1 country
United Kingdom18 sites
Royal Aberdeen Children's Hospital
Aberdeen
Birmingham Children's Hospital
Birmingham
Addebrookes Hospital
Cambridge
Wales College of Medicine
Cardiff
University Hospital
Coventry
Ninewells Hospital
Dundee
Royal Hospital for Sick Children
Edinburgh
Royal Hospital for Sick Children
Glasgow
Hereford Hospital
Hereford
Crosshouse Hospital
Kilmarnock
Alder Hey Children's Hospital
Liverpool
St Bart's Hospital
London
St George's Hospital
London
Royal Manchester Children's Hospital
Manchester
Royal Victoria Infirmary
Newcastle upon Tyne
Norfolk & Norwich University Hospitals
Norwich
Oxford Radcliffe Hospitals
Oxford
Sheffield Children's Hospital
Sheffield
About this study
Official title: A Randomised Study of Two Anti-thyroid Drug Treatment Regimens in Young People
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.
Read the 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
- Conditions
- Paediatric Thyrotoxicosis
- Being tested
- Block and Replace, Dose Titration, carbimazole, propylthiouracil, thyroxine
- Keywords
- thyrotoxic, thyrotoxicosis, paediatric, endocrinology, block and replace, dose titration, carbimazole
- Medical subject headings
- Thyrotoxicosis, Bites and Stings
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Block and ReplaceProcedure or surgery
Also called Carbimazole, propylthiouracil, thyroxine
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 TitrationProcedure or surgery
Also called carbimazole, 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.
carbimazoleDrug
Carbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry
propylthiouracilDrug
50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry
thyroxineDrug
25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry
| Study group | Role | What they receive |
|---|---|---|
| Block and Replace | Active comparator | 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. Receives: Procedure: Block and Replace; Drug: carbimazole; Drug: propylthiouracil; Drug: thyroxine |
| Dose Titration | Active comparator | 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. Receives: Procedure: Dose Titration; Drug: carbimazole; Drug: propylthiouracil |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 2.5 years
Secondary outcomes (3)
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.
Measured: 4 years
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.
Measured: 3 years
Additional measures of biochemical control.
A comparison of the mean and variability of TSH and thyroid hormone concentrations in the 2 treatment groups.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2011 (estimated)
- Study startJul 2004
- Primary completionDec 2014
- Study completionNov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Paediatric ThyrotoxicosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- Newcastle-upon-Tyne Hospitals NHS Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tim Cheetham, Newcastle-upon-Tyne Hospitals NHS Trust
- Investigators
- Tim Cheetham, Principal investigator, Newcastle upon Tyne Hospiatls NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01436994
- Sponsor's protocol ID
- NUTH 2759
- Status last verified
- Sep 2016
- First submitted
- 18 Aug 2011
- Last updated
- 21 Sep 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Study of Two Anti-thyroid Drug Treatment Regimens in Young People
- ClinicalTrials.gov ID
- NCT01436994
- Acronym / sponsor ID
- NUTH 2759
- Conditions
- Paediatric Thyrotoxicosis
- Keywords
- thyrotoxic, thyrotoxicosis, paediatric, endocrinology, block and replace, dose titration, carbimazole
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- Newcastle-upon-Tyne Hospitals NHS TrustUniversity, hospital or other
- Study start
- Jul 2004
- Primary completion
- Dec 2014 (actual)
- Study completion
- Nov 2015 (actual)
- First posted
- 20 Sep 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Block and Replace | Active comparator | Procedure: Block and Replace, Drug: carbimazole, Drug: propylthiouracil, Drug: thyroxineCarbimazole 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. |
| Dose Titration | Active comparator | Procedure: Dose Titration, Drug: carbimazole, Drug: propylthiouracilCarbimazole 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. |
Who may qualify
- Ages
- 2 to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Block and ReplaceAlso: Carbimazole, propylthiouracil, thyroxineThe 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. | Procedure or surgery | Block and Replace |
| Dose TitrationAlso: carbimazole, propylthiouracilThe 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. | Procedure or surgery | Dose Titration |
| carbimazoleCarbimazole 5mg and 20 mg tablets Administered as a once or twice daily regimen with total daily dose adjusted according to prevailing biochemistry | Drug | Block and Replace, Dose Titration |
| propylthiouracil50 mg tablets administered once daily with the dose adjusted according to the prevailing biochemistry | Drug | Block and Replace, Dose Titration |
| thyroxine25mcg, 50mcg and 100mcg tabletes administered once daily with the dose adjusted according to the prevailing biochemistry | Drug | Block and Replace |
Primary outcome
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).
3 secondary outcomes
Remission rates as defined by patients who are biochemically euthyroid at the end of the 4 year study period.
Time frame: 4 years
The frequency of adverse events on the 2 treatment regimens.
Time frame: 3 years
Additional measures of biochemical control.
Time frame: 3 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2016.
- British Society for Paediatric Endocrinology and Diabetes supports this studyLink provided by the sponsor.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tim Cheetham principal investigator
Newcastle upon Tyne Hospiatls NHS Foundation Trust
18 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Block and Replace, Dose Titration and carbimazole in people with Paediatric Thyrotoxicosis, run by Newcastle-upon-Tyne Hospitals NHS Trust at 18 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Biochemical control as reflected by the stability of blood thyroid stimulating hormone (TSH) concentrations (time frame: 2.5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2016.