Setting: Tehran Thyroid Study (TTS).
At the first visit, fasting blood sample will be obtained to measure serum TSH, TT3, TT4, FT4, FT3, FBS, lipid profile, insulin, HbA1C, HOMA-IR, SHBG, Enolase, LDH and CK, Ferritin and metabolomics. Assessment of demographic data, quality of life, depression, symptoms of thyroid function and physical examination will be done. The specified treatment will be given to both groups for 24 weeks. All tablets will be distributed in similar packages and the same size and color to be ensure of double-blind design. Participants will be evaluated at baseline and 3 follow-ups at first, third and six months after start-up trial. All blood parameters and questionnaire will be filled out at first and last visits. Also the polymorphism related to deiodinase will be measured and compared between responders and non-responders. The normal control group will not take any placebo, and they only be evaluated for all outcomes at the first and last visits.
Participants/Inclusion and exclusion criteria
Inclusion: Patients≥20y with hypothyroidism who attain euthyroidism under LT4 monotherapy.
Exclusion: Pregnancy,end organ failure,cancer,taking methimazole,PTU,Tamoxifen, estrogen,progesterone and corticosteroids.
Intervention groups
1. LT4+SR-T3 2. LT4 monotherapy
Main outcome variables
T3/T4 ratio,TSH,T4,T3
Clinical signs and symptoms of hypothyroidism
Quality of life
Depression
SerumLipid profile,
FBS,HbA1C,HOMA-IR
SHBG,
Enolase,LDH,CK,ECG
heart rate,BP
Ferritin
Metabolomics
Genetic polymorphism
Epigenetic
General information
Reason for update
Acronym
IRCT registration information
IRCT registration number:IRCT20100922004794N12
Registration date:2020-02-27, 1398/12/08
Registration timing:registered_while_recruiting
Last update:2020-02-27, 1398/12/08
Update count:2
Registration date
2020-02-27, 1398/12/08
Registrant information
Name
Fereidoun Azizi
Name of organization / entity
Country
Iran (Islamic Republic of)
Phone
+98 21 2240 9309
Email address
azizi@endocrine.ac.ir
Recruitment status
Recruitment complete
Funding source
Expected recruitment start date
2020-02-20, 1398/12/01
Expected recruitment end date
2021-01-20, 1399/11/01
Actual recruitment start date
empty
Actual recruitment end date
empty
Trial completion date
empty
Scientific title
Formulation of Levothyroxine plus slow-release Liothyronine preparation for treatment of hypothyroidism
Public title
Improvement in treatment of hypothyroidism using slow-release Liothyronine
Purpose
Treatment
Inclusion/Exclusion criteria
Inclusion criteria:
Patients over 20 y. with hypothyroidism caused by any reason e.g. Hashimoto thyroiditis, treated Graves’ patients after radioactive iodine intake, total thyroidectomised patients due to thyroid cancer or congenital hypothyroidism, who take LT4 monotherapy for at least 3 months and attain euthyroid status (TSH=0.5-5 mU/L is optimal).
Exclusion criteria:
Pregnant women, those with end organ failure e.g. chronic kidney and liver disease, congestive heart failure or any kind of cancer, having other cofactors that mimicked symptoms of hypothyroidism, including low Hb, 25[OH] D deficiency, vitamin B12 deficiency, having long-standing psychiatric disorders(e.g majore depressive disorders) and fibromyalgia, because those can mask some of the hypothyroid symptoms (eg, fatigue, arthralgia, depression, cognitive slowing); will be excluded. The patients should avoid taking methimazole, PTU, Tamoxifen and drug containing estrogen, progesterone, and corticosteroids.
Age
From 20 years old to 75 years old
Gender
Both
Phase
3
Groups that have been masked
Participant
Care provider
Investigator
Outcome assessor
Sample size
Target sample size:
200
Randomization (investigator's opinion)
Randomized
Randomization description
Patients will be allocated to intervention and control groups using stratified randomization.
1. The groups with daily intake of LT4+SR-T3 (Intervention Group)
2. The groups with LT4 mono-therapy (Control group)
Four stratifications will be made based on normal or abnormal T3/T4 ratio and gender. At first patients will be assigned to two groups based on normal or abnormal T3/T4 ratio. Then within each group, the patients will be randomly allocated to control or intervention group based on sex stratification. For example if 20 subjects would be included in the male group with normal T3/T4 ratio, 10 non-duplicate random numbers from 1 to 20 will be selected using random number table or Excel software, and these numbers will be allocated to intervention group. 10 remainder subjects will be considered in control group. The process will be repeated for other stratifications e.g. women with normal T3/T4 ratio, women with abnormal T3/T4 ratio and men with abnormal T3/T4 ratio.
The control group which not taking placebo or any other treatment are age- sex matched normal subjects selected from the same study population, will not be entered into randomization.
Blinding (investigator's opinion)
Double blinded
Blinding description
After proper implementation of randomization, the subjects will be assigned to the groups using allocation concealment which helps to keep clinicians, participants and investigators unaware of upcoming assignments. The standard methods of ensuring allocation concealment will be sequentially numbered or coded opaque containers. For single-center clinical trials such as the current trial, we will identify a staff member not involved with the trial who can keep the randomization list. This staff will be instructed to keep the list private, and to only reveal a treatment allocation after receiving information demonstrating that the patient is eligible and has consented to the trial. Both the subjects and the investigators will be kept from knowing who will be assigned to which treatment (double blind) to fulfill this both groups will receive tablets which are identical in physical appearance, taste and smell.
Placebo
Not used
Assignment
Parallel
Other design features
Secondary Ids
empty
Ethics committees
1
Ethics committee
Name of ethics committee
National Institute for Medical Research Development
Street address
No. 21, Besat Ave, Chamran Highway, West Fatemi Ave.
City
Tehran
Province
Tehran
Postal code
1419693111
Approval date
2019-02-02, 1397/11/13
Ethics committee reference number
IR.NIMAD.REC.1398.007
Health conditions studied
1
Description of health condition studied
Hypothyroidism
ICD-10 code
E03.9
ICD-10 code description
Hypothyroidism, unspecified
Primary outcomes
1
Description
T3/T4 ratio
Timepoint
at one , three and six months after intervention
Method of measurement
Serum Total tri-iodothyronine(TT3), total thyroxine (TT4) will be determined on -20ºC stored serum samples by the electrochemiluminescence immunoasaay (ECLIA) method, using Roche Diagnostics kits and Roche/Hitachi Cobas e-411 analyzer (GmbH, Mannheim, Germany).
Secondary outcomes
1
Description
SERUM TSH
Timepoint
Each month after intervention up to 6 months (6 times)
Method of measurement
on -20ºC stored serum samples by the electrochemiluminescence immunoasaay (ECLIA) method, using Roche Diagnostics kits and Roche/Hitachi Cobas e-411 analyzer (GmbH, Mannheim, Germany)
2
Description
FREE T3 AND FREE T4
Timepoint
Baseline and 1, 3 and 6 month after starting intervention
Method of measurement
electrochemiluminescence immunoasaay (ECLIA)
3
Description
clinical signs and symptoms of hypothyroidism
Timepoint
At baseline and 6 months after intervention
Method of measurement
thyroid symptom questionnaires (TSQ), the Billewicz clinical scoring system
4
Description
Quality of life
Timepoint
At baseline and 6 months after intervention
Method of measurement
Quality of Life Questionnaire
5
Description
Depression
Timepoint
At baseline and 6 months after intervention
Method of measurement
Beck questionnaire
6
Description
Serum Lipid Profile
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
7
Description
FBS, Insulin sensitivity (HbA1C, HOMA-IR)
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
8
Description
Sex Hormone Binding Globulin (SHBG)
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
9
Description
Muscle thyroid status (Enolase, LDH and CK),
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
10
Description
Ferritin
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
11
Description
Metabolomics
Timepoint
At baseline and 6 months after intervention
Method of measurement
Laboratory measurements with related kits
12
Description
Cardiac parameters (ECG, resting heart rate, BP)
Timepoint
At baseline and 6 months after intervention for ECG and for BP and HR at 1, 3 and 6 months after intervention
Epigenetic evaluations include: micro RNA and other noncoding RNA, Histone acetylation, Histone Methylation
Timepoint
At baseline and 6 months after intervention
Method of measurement
with related kits
15
Description
Cognitive Function including memory and executive function
Timepoint
At baseline and 6 months after intervention
Method of measurement
with related tests
Intervention groups
1
Description
Two tablets will be formulated by Tavan Institute and Dorsa pharmaceutical Company. One tablet contains LT4 100 µg and the other tablets contains LT4 85 µg plus SR-T3 6µg. The patients will be randomly assigned to intervention and control groups.1. The group with daily intake of LT4+SR-T3. The tablets should be taken at night, 2 hours after dinner. At the first visit, fasting blood sample will be obtained at 8 am and the specified treatment will be started on the same day. Participants will be evaluated at baseline and 3 consequent follow-ups (first, third and six months after start-up trial) up to 24 weeks. At each follow-up visits, venous blood samples will be collected from all participants after a 12-hour fast for measurement of serum TSH, total T3, total T4, free T4 and free T3. At the first and last visit total cholesterol, LDL, HDL, triglycerides, FBS, insulin, HbA1C, HOMA-IR, SHBG, Enolase, LDH and CK, Ferritin, metabolomics and epigenetic related markers will be measured and heart rate, blood pressure and ECG will be evaluated. . All questionnaires (Thyroid symptoms, Beck and QOL) will be filled out at first and last visits. The drug will be continued for 24 weeks. Patients will also be checked at 4 weeks intervals to measure TSH, assess adherence to therapy and adverse effects. Drug dosage would be adjusted to maintain serum TSH concentration within 0.5-3 mU/l.
Category
Treatment - Drugs
2
Description
Control group: The group with daily intake of 100 µg LT4. The patients are advised to take tablets at night, 2 hours after dinner. At the first visit, fasting blood sample will be obtained at 8 am and the specified treatment will be started on the same day. Participants will be evaluated at baseline and 3 consequent follow-ups (first, third and six months after start-up trial) up to 24 weeks. At each follow-up visits, venous blood samples will be collected from all participants after a 12-hour fast for measurement of serum TSH, total T3, total T4, free T4 and free T3. At the first and last visit total cholesterol, LDL, HDL and triglycerides, FBS, insulin, HbA1C, HOMA-IR, SHBG, Enolase, LDH and CK, ECG, Ferritin, metabolomics and epigenetic related markers will be measured and heart rate, blood pressure and ECG will be evaluated. . All questionnaires (Thyroid symptoms, Beck and QOL) will be filled out at first and last visits. The drug will be continued for 24 weeks. Patients will also be checked at 4 weeks intervals to measure TSH, assess adherence to therapy and adverse effects. Drug dosage would be adjusted to maintain serum TSH concentration within 0.5-3 mU/l.
Category
Treatment - Drugs
3
Description
Control group 2: There is also a normal age-sex matched control group which will not take any placebo, and they will only be evaluated for thyroid hormones, other biochemical and physical evaluations and all questioners such as intervention groups at the first and last visits after six months.
Category
Treatment - Drugs
Recruitment centers
1
Recruitment center
Name of recruitment center
Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences