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Trial registered on ANZCTR


Registration number
ACTRN12622000106730
Ethics application status
Approved
Date submitted
21/12/2021
Date registered
24/01/2022
Date last updated
24/01/2022
Date data sharing statement initially provided
24/01/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Combination T4/T3 trial for hypothyroidism
Scientific title
Combination T4/T3 treatment in individuals with hypothyroidism dissatisfied with T4 monotherapy: a protocol for randomised, blinded, placebo-controlled n-of-1 trials.
Secondary ID [1] 306091 0
None
Universal Trial Number (UTN)
U1111-1266-9575
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypothyroidism 324753 0
Condition category
Condition code
Metabolic and Endocrine 322204 322204 0 0
Thyroid disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 4 n-of-1 trial of four periods of 8 weeks of treatment with either thyroxine and placebo treatment or thyroxine and liothyronine treatment. Each period is separated by a four week period of treatment with thyroxine alone. Each person will have 2 periods of treatment with thyroxine and placebo, and 2 periods of treatment with thyroxine and liothyronine. Thyroxine will be administered in a daily oral dose and liothyronine in a twice daily oral dose, both by capsules. Doses will be individualised for each participant, based on the pre-trial thyroxine dose and subsequently altered during the trial in response to regular (two to four weekly) measurement of thyroid hormone blood levels by an experienced clinician not otherwise involved with the trial. Adherence will be assessed by counting the capsules returned after each treatment period.
Intervention code [1] 322501 0
Treatment: Drugs
Comparator / control treatment
Control treatment is placebo (capsule containing inactive filler such as microcellulose)
Control group
Placebo

Outcomes
Primary outcome [1] 329970 0
The primary outcome is the difference in hypothyroidism-specific quality of life as measured using composite scores from the ThyPRO tool in periods of combination thyroxine and liothyronine compared with ThyPRO scores during thyroxine and placebo treatment.
Timepoint [1] 329970 0
Thypro scores are measured every 2 weeks for 52 weeks.
Secondary outcome [1] 404479 0
Overall quality of life impact as measured using the ThyPRO tool in periods of combination thyroxine and liothyronine compared with overall quality of life impact scores during thyroxine and placebo treatment.
Timepoint [1] 404479 0
Overall quality of life impact scores are measured every 2 weeks for 52 weeks.
Secondary outcome [2] 404484 0
Hypothyroid physical symptoms as measured using the ThyPRO tool in periods of combination thyroxine and liothyronine compared with overall quality of life impact scores during thyroxine and placebo treatment.
Timepoint [2] 404484 0
Hypothyroid physical symptoms are measured every 2 weeks for 52 weeks.
Secondary outcome [3] 404485 0
Each individual component of hypothyroidism-specific quality of life as measured by the ThyPRO tool in periods of combination thyroxine and liothyronine compared with ThyPRO scores during thyroxine and placebo treatment.
Timepoint [3] 404485 0
Thypro scores are measured every 2 weeks for 52 weeks.

Eligibility
Key inclusion criteria
Adults (over age >18y) with confirmed hypothyroidism defined as previous total thyroidectomy, previous radioiodine treatment with TSH > 4 post radioiodine treatment, or confirmed hypothyroidism with at least two TSH measurements >10 mU/L or at least one TSH measurement >20 mU/L.

Individuals with persistent symptoms (>6 months) that are not explained by inadequate treatment of hypothyroidism, low adherence to T4, or other overt co-morbidity and that the individual believes are related to inadequate treatment of hypothyroidism. Eligible individuals will have at symptoms from at least 2 of the following broad groups: tiredness, fatigue, or lethargy (ThyPRO q2); difficult concentrating or thinking, poor memory, or “brain fog” (ThyPRO q3); mood disturbance (ThyPRO q4-6); and bloating or difficulty maintaining weight (ThyPRO 9a). For each broad category, to be eligible individuals must answer “Quite a bit or “Very much” to at least one of the relevant ThyPRO questions.

Thyroxine monotherapy for at least 6 months, with measurements of TSH within the normal range for at least the preceding 3 months. Minor abnormalities of TSH (0.2-0.4 or 4-6 mu/L) will not exclude individuals from participating. The thyroxine dose must have been stable for at least the preceding 3 months.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Individuals who are asymptomatic or have symptoms from only 1 of the 4 broad groups outlined in the inclusion criteria or do not meet the criteria for severity of symptoms outlined in the inclusion criteria.

Individuals with symptoms they attribute to inadequately treated hypothyroidism that do not fall within the categories outlined in the inclusion criteria.

Individuals with poorly controlled hypothyroidism, defined as TSH <0.2 or >6 within the last 3 months.

Individuals with significant co-morbidity, in which their symptoms are more likely to be caused by their co-morbidity than hypothyroidism.

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)
Allocation will involve contacting the holder of the randomisation sequence who is offsite and has no contact with potential participants or other study staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation sequence for each individual will be generated through permuted block randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
N-of-1 trial
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculations are based on whether the individual patient benefits or not from combination thyroxine/liothyronine compared to thyroxine/placebo based on changes in quality of life assessed using ThyPRO. If the change in ThyPRO attributable to combination treatment is the same or exceeds the pre-specified threshold of 10, which is based on the average change in ThyPro score at 6 months in individuals with hypothyroidism starting thyroxine, an individual will be considered to have benefited from combination treatment.

The sample size is determined such that if there is no benefit from combination treatment, the upper limit of a one-sided 95% confidence interval around the observed probability of benefit will not exceed 30%. This approximates the situation where the probability of the observed results being false positive results is <30%.

Using this approach, a sample size of 20, in which there truly is no effect and two results are false positives, has an upper limit of the 95%CI of the observed probability of benefit is 0.28. In practice, if the proportion of participants benefiting is less than around 30-40%, combination treatment is unlikely to be considered a treatment option. Allowing for a drop out of 20%, gives a target sample size of 25.

Data will be analysed using linear mixed-effects models. Treatment will be model as a fixed effect, with participant, and participant*cycle and treatment*participant interactions modelled as random effects, and other potential covariates, eg time of year, included in the model and estimates for individual treatment effects obtained. If the individual effect estimate is the same or exceeds the pre-specified threshold, the participant will be considered to have benefit. The overall proportion of participants benefitting will be determined and 95% CI calculated.

The main secondary analysis will be to determine the overall treatment effect. A similar model to that for the individual model will be constructed but an overall treatment effect will be estimated. All analyses will be conducted using SAS, or R, and P<0.05 will be considered statistically significant. All available data from all participants will be included in analyses.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2022
Actual
Date of last participant enrolment
Anticipated
1/03/2023
Actual
Date of last data collection
Anticipated
1/03/2024
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment outside Australia
Country [1] 24456 0
New Zealand
State/province [1] 24456 0

Funding & Sponsors
Funding source category [1] 310433 0
Government body
Name [1] 310433 0
HRC
Country [1] 310433 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
85 Park Road, Grafton, Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 311588 0
None
Name [1] 311588 0
Address [1] 311588 0
Country [1] 311588 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310072 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 310072 0
Ethics committee country [1] 310072 0
New Zealand
Date submitted for ethics approval [1] 310072 0
03/09/2021
Approval date [1] 310072 0
06/12/2021
Ethics approval number [1] 310072 0
21/STH/221

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116390 0
A/Prof Mark Bolland
Address 116390 0
Department of Medicine
FMHS
University of Auckland
85 Park Road, Grafton, Auckland 1023
Country 116390 0
New Zealand
Phone 116390 0
+64 93737599
Fax 116390 0
Email 116390 0
m.bolland@auckland.ac.nz
Contact person for public queries
Name 116391 0
Mark Bolland
Address 116391 0
Department of Medicine
FMHS
University of Auckland
85 Park Road, Grafton, Auckland 1023
Country 116391 0
New Zealand
Phone 116391 0
+64 93737599
Fax 116391 0
Email 116391 0
m.bolland@auckland.ac.nz
Contact person for scientific queries
Name 116392 0
Mark Bolland
Address 116392 0
Department of Medicine
FMHS
University of Auckland
85 Park Road, Grafton, Auckland 1023
Country 116392 0
New Zealand
Phone 116392 0
+64 93737599
Fax 116392 0
Email 116392 0
m.bolland@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All data from the trial
When will data be available (start and end dates)?
From the time of publication of trial results on pubmed onward
Available to whom?
Researchers on reasonable request
Available for what types of analyses?
All analyses
How or where can data be obtained?
By emailing the lead author (m.bolland@auckland.ac.nz)


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.