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Trial registered on ANZCTR


Registration number
ACTRN12615000362594
Ethics application status
Approved
Date submitted
1/04/2015
Date registered
21/04/2015
Date last updated
16/05/2019
Date data sharing statement initially provided
16/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Treat-to-Target thyroid-stimulating hormone receptor antibody (TRAb) in Graves’ Disease
Scientific title
Comparing risk of relapse in Graves' disease patients treated with fixed-time carbimazole vs. treatment guided by TRAb titre
Secondary ID [1] 286467 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Graves' disease 294654 0
Condition category
Condition code
Metabolic and Endocrine 294955 294955 0 0
Thyroid disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment with oral carbimazole (variable dose to achieve euthyroidism; 2.5-60 mg daily) with length of treatment based on TRAb (Thyroid stimulating hormone receptor antibody) titre, performed 3-monthly on blood serum testing.

This is a pilot, single blinded randomised controlled trial assessing whether a treat-to-target TRAb approach with anti-thyroid drugs (carbimazole to achieve euthyroidism, continued until 6 months after TRAb resolution) results in lower risk of relapse of hyperthyroidism after treatment cessation, compared with standard therapy (defined below). In addition, this trial will provide estimates of changes in quality of life, health care utilisation, and assess feasibility of recruitment. It will provide data for a sample size calculation for a properly powered randomised controlled trial.
Intervention code [1] 291551 0
Treatment: Drugs
Comparator / control treatment
Standard fixed length (18 months) treatment of Graves' disease with oral carbimazole tablets (variable dose to achieve euthyroidism; 2.5-60 mg daily).
Control group
Active

Outcomes
Primary outcome [1] 294707 0
Relapse of hyperthyroidism (defined as TSH <0.3 mU/L on blood serum assay)
Timepoint [1] 294707 0
12 months after cessation of carbimazole treatment
Secondary outcome [1] 313898 0
Relapse of hyperthyroidism (defined as TSH <0.3 mU/L on blood serum assay)
Timepoint [1] 313898 0
24 months after cessation of carbimazole treatment
Secondary outcome [2] 313899 0
Cumulative exposure to carbimazole (calculated on prescribed daily dose)
Timepoint [2] 313899 0
Within treatment phase with carbimazole
Secondary outcome [3] 313900 0
Adverse effects of carbimazole therapy (including: rash, gastrointestinal intolerance, significant impairment of liver synthetic dysfunction; or agranulocytosis - neutrophil counts < 0.5x10exp9/L)
Timepoint [3] 313900 0
Within treatment phase with carbimazole
Secondary outcome [4] 313901 0
Incidence of new onset Graves’ eye ophthalmopathy by blinded assessment, as defined by the NOSPECS criteria
Timepoint [4] 313901 0
24 months after cessation of carbimazole treatment
Secondary outcome [5] 313902 0
Quality of life (AQOL-6 and ThyPRO)
Timepoint [5] 313902 0
24 months after cessation of carbimazole treatment
Secondary outcome [6] 313903 0
Mortality
Timepoint [6] 313903 0
24 months after cessation of carbimazole treatment
Secondary outcome [7] 313904 0
Health care associated costs, with incremental cost-effectiveness ratio of treating-to-target over standard care from a health service perspective
Timepoint [7] 313904 0
24 months after cessation of carbimazole treatment

Eligibility
Key inclusion criteria
First presentation of Graves’ disease as defined as hyperthyroidism (free T4 and/or free T3 above the upper limit of normal with TSH suppressed below the lower limit of normal - <0.3mU/L) associated with elevated TSH-receptor antibody (TRAb) (>1.5 U/mL)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Greater than three months since first diagnosis of Graves’ disease
- Age less than 18 years
- Current or planned pregnancy within the next three years
- Current breastfeeding
- Clinical or imaging suspicion of thyroid cancer
- TRAb negative status at time of diagnosis,
- Potential participant or treating physician desire primary treatment with surgery or radioiodine therapy
- Concomitant treatment with lithium, corticosteroids, amiodarone, Lugol’s iodine

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Recruitment will occur from the Thyroid Clinic at Royal Brisbane and Women’s Hospital. A total sample size of 50 will be recruited for this pilot trial. Randomisation will occur using a random number generator within Microsoft Excel, producing 50 random numbers. Patients assigned an even number will be allocated to group 1 (TTT group) and odd numbers to group 2 (standard care). Randomisation will occur on a 1:1 basis. Investigators involved in the assessment of outcomes will be blinded to the group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random number generator
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analysis will be performed on an intention-to-treat basis.
Patient characteristics will be summarised and compared between the intervention and control group. The primary outcome will be analysed using Pearson’s Chi-squared (or Fisher’s exact tests, if required) as will other categorical variables. Continuous variables will be compared using t-tests (for normally distributed data) and Wilcoxon rank sum or Kruskal-Wallis (for non-parametric data). Rates of relapse will be analysed using Kaplan-Meier survival methods.
Area under the curve method will be used to calculate quality adjusted life years, using AQOL-6 data, which, along with health care cost data, will be used in Markov modelling to calculate an incremental cost-effectiveness ratio for TTT over standard care. Sensitivity analysis will be used to assess for the amount of uncertainty in the model.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
While this pilot study was recruiting, the American Thyroid Association (ATA) published new treatment guidelines for treating Graves' disease. These guidelines recommended ceasing Graves’ disease therapy only after normalisation of TRAbs (the issue being assessed in this pilot study). The new ATA recommendation was made without any randomised controlled trial evidence (nor any new published observational data), but was labelled as a “strong recommendation; high-quality evidence”. The pilot study investigators recognized the strong potential for equipoise being altered by these new treatment guidelines and the prominence of the ATA in setting thyroid management benchmarks; the likelihood was that the recommendation would be widely adopted as the new “standard of care” for Graves’ disease. Furthermore, any results from any randomised controlled trial would have been generated in several years time when the use of the guidelines are well entrenched. Therefore the study was stopped early.
Date of first participant enrolment
Anticipated
1/06/2015
Actual
16/06/2015
Date of last participant enrolment
Anticipated
31/05/2016
Actual
6/09/2016
Date of last data collection
Anticipated
15/11/2016
Actual
15/11/2016
Sample size
Target
50
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3645 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 9484 0
4029 - Royal Brisbane Hospital

Funding & Sponsors
Funding source category [1] 291033 0
Charities/Societies/Foundations
Name [1] 291033 0
Royal Brisbane & Women's Hospital Foundation
Country [1] 291033 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Royal Brisbane & Women's Hospital Foundation
Address
PO Box 94
Royal Brisbane and Women’s Hospital
Herston, QLD 4029
Country
Australia
Secondary sponsor category [1] 289718 0
None
Name [1] 289718 0
Address [1] 289718 0
Country [1] 289718 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292617 0
Royal Brisbane & Women's Hospital Human Reserach Ethics Committee
Ethics committee address [1] 292617 0
Level 7, Block 7
RBWH
Butterfield St
Herston, QLD, 4029
Ethics committee country [1] 292617 0
Australia
Date submitted for ethics approval [1] 292617 0
Approval date [1] 292617 0
14/01/2015
Ethics approval number [1] 292617 0
HREC/14/QRBW/521

Summary
Brief summary
This is a pilot, single blinded randomised controlled trial assessing whether a treat-to-target TRAb approach with anti-thyroid drugs (carbimazole) results in lower risk of relapse of hyperthyroidism after treatment cessation in Graves' disease patients, compared with standard fixed length care. In addition, this trial will provide estimates of changes in quality of life, health care utilisation, and assess feasibility of recruitment. It will provide data for a sample size calculation for a properly powered randomised controlled trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56250 0
Dr Donald McLeod
Address 56250 0
Department of Endocrinology and Diabetes
Level 1, JMB
RBWH
Herston, QLD 4029
Country 56250 0
Australia
Phone 56250 0
+61736468111
Fax 56250 0
Email 56250 0
[email protected]
Contact person for public queries
Name 56251 0
Donald McLeod
Address 56251 0
Department of Endocrinology and Diabetes
Level 1, JMB
RBWH
Herston, QLD 4029
Country 56251 0
Australia
Phone 56251 0
+61736468111
Fax 56251 0
Email 56251 0
[email protected]
Contact person for scientific queries
Name 56252 0
Donald McLeod
Address 56252 0
Department of Endocrinology and Diabetes
Level 1, JMB
RBWH
Herston, QLD 4029
Country 56252 0
Australia
Phone 56252 0
+61736468111
Fax 56252 0
Email 56252 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Trial stopped early.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.