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IRCT20100922004794N12 IRCT 2020-02-27 Dorsa Pharmaceutical Company Improvement in treatment of hypothyroidism using slow-release Liothyronine Formulation of Levothyroxine plus slow-release Liothyronine preparation for treatment of hypothyroidism (Clinical trial Phase 2& 3) 2024-10-06 anticipated 100 Complete https://irct.ir/trial/44220 interventional Randomization: Randomized, Blinding: Double blinded, Placebo: Not used, Assignment: Parallel, Purpose: Treatment, Randomization description: Phase 3: Patients will be allocated to intervention and control groups using simple stratified randomization. 1. The groups with a daily intake of LT4+SR-T3 (Intervention Group) 2. The groups with LT4 mono-therapy (Control group) Participants will be randomized with equal probability (1:1) to receive one of the two treatments. As the size of each group is predicted to be 50 , the allocation sequence is generated with sample randomization and stratification by gender. The sequences will be generated by the software and in Excel format. The patients sequentially entered to study based on this random sequence. Phase 2: After simple randomization, participants will be assigned to a pre-breakfast regimen of SRT3, L-T3, or L-T4 for 4 weeks. The dose of L-T4 is 1.6 μg/kg. This dosage will be adjusted to achieve 1:5 ratio of SR-T3 to LT4 in combination therapy. Patients will be recalled to the endocrine clinic for weekly follow-up visits and blood sampling, 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 that are identical in physical appearance, taste, and smell. The patients in the control group will receive Placebo instead of SR-T3. 2-3 Hypothyroidism. Intervention 1: Tavan Institute and Dorsa Pharmaceutical Company will formulate SR-T3 tablets (15 µg). Iran Hormone Company produces 50, 75, and 100 µg levothyroxine tablets. The patients will be randomly assigned to intervention (with a daily intake of LT4+SR-T3; 1:5 ratio) and control groups. The tablets should be taken in the morning at least half an hour before breakfast. At the first visit, a 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 ( third, sixth, and 12 months after the start-up trial) up to 48 weeks. At each follow-up visit, venous blood samples will be collected from all participants after a 12-hour fast to measure 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, C-telopeptide, N- N-telopeptide and metabolomics will be measured and heart rate, blood pressure will be evaluated. All questionnaires (Thyroid symptoms, Thypro-39 QOL) will be filled out at the first and last visits(6 and 12 months of start-up). The drug will be continued for 48 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 0.5-5 mU/l. Intervention 2: Control group: The group with a daily intake of 100 µg LT4. The patients are advised to take tablets at least 0.5 hours before breakfast. At the first visit, a 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 (third, sixth, and 12 months after the start-up trial) up to 24 weeks. At each follow-up visit, 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, CK, Ferritin, C and N- telopeptides and metabolomics will be measured and heart rate and blood pressure will be evaluated. All questionnaires (Thyroid symptoms, and Thypro-39 QOL) will be filled out at first and last visits. The drug will be continued for 48 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. Intervention 3: 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 12 months. No - There is not a plan to make this available Justification or reason for not sharing IPD is These data are belonged to Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran
public Ladan Mehran
No.23, Erabi St, Yaman Ave., Velenjak
Tehran Iran (Islamic Republic of) 1985717413 +98 21 2243 2500 lmehran@endocrine.ac.ir Shahid Beheshti University of Medical Sciences scientific Fereidoun Azizi
No.23, Erabi St, Yaman Ave., Velenjak
Tehran Iran (Islamic Republic of) 1985717413 +98 21 2243 2500 azizi@endocrine.ac.ir Shahid Beheshti University of Medical Sciences Iran (Islamic Republic of) Iran (Islamic Republic of) Inclusion criteria for Phase 2 and Phase 3 are the same as follows: Patients over 20 y. with hypothyroidism caused by any reason e.g. Hashimoto thyroiditis, treated Graves’ patients after radioactive iodine intake, total thyroidectomized 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). 20 years 75 years Both Exclusion criteria for Phase 2 and Phase 3 are the same as follows: 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 major 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. E03.9 Hypothyroidism, unspecified Treatment - Drugs Treatment - Drugs Treatment - Drugs Tavan Institute and Dorsa Pharmaceutical Company will formulate SR-T3 tablets (15 µg). Iran Hormone Company produces 50, 75, and 100 µg levothyroxine tablets. The patients will be randomly assigned to intervention (with a daily intake of LT4+SR-T3; 1:5 ratio) and control groups. The tablets should be taken in the morning at least half an hour before breakfast. At the first visit, a 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 ( third, sixth, and 12 months after the start-up trial) up to 48 weeks. At each follow-up visit, venous blood samples will be collected from all participants after a 12-hour fast to measure 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, C-telopeptide, N- N-telopeptide and metabolomics will be measured and heart rate, blood pressure will be evaluated. All questionnaires (Thyroid symptoms, Thypro-39 QOL) will be filled out at the first and last visits(6 and 12 months of start-up). The drug will be continued for 48 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 0.5-5 mU/l. Control group: The group with a daily intake of 100 µg LT4. The patients are advised to take tablets at least 0.5 hours before breakfast. At the first visit, a 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 (third, sixth, and 12 months after the start-up trial) up to 24 weeks. At each follow-up visit, 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, CK, Ferritin, C and N- telopeptides and metabolomics will be measured and heart rate and blood pressure will be evaluated. All questionnaires (Thyroid symptoms, and Thypro-39 QOL) will be filled out at first and last visits. The drug will be continued for 48 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. 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 12 months. Quality of Life. Timepoint: At baseline and 6 and 12 months after trial. Method of measurement: Thyroid-specific Patient-Reported Outcome short-form (ThyPRO-39) modeled for hypothyroid subjects. SERUM TSH. Timepoint: At baseline and 3, 6, and 12 months after start-up. 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). Total T4, FREE T4, Total T3, T3/T4 ratio. Timepoint: At baseline and 3, 6, and 12 months after start-up. Method of measurement: electrochemiluminescence immunoasaay (ECLIA), 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). Clinical signs and symptoms of hypothyroidism. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: thyroid symptom questionnaire. Serum Lipid Profile(TG,HDL,LDL, TOTAL CHOLESTROL). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. FBS, Insulin sensitivity (HbA1C, HOMA-IR). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. Sex Hormone Binding Globulin (SHBG). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. Muscle thyroid status (Enolase, LDH and CK),. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. Ferritin. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. Metabolomics. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Laboratory measurements with related kits. Cardiac parameters (resting heart rate, BP). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: With related measures. Thr92Ala polymorphism of the type 2 deiodinase gene (DIO2) (Thr92Ala-DIO2) and polymorphisms in thyroid hormone transporters (e.g. MCT8, MCT10, OATP1C1). Timepoint: at the end of the study. Method of measurement: whole genome sequencing. Cognitive Function including memory and executive function. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: with related tests. C-telopeptide or N-telopeptide. Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: ECLIA. Patient preference. Timepoint: At the end of trial. Method of measurement: With a question. Body composition and Resting Energy Expenditure (REE). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: Indirect calorymetry. Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences Approved 2019-02-02 National Institute for Medical Research Development No. 21, Besat Ave, Chamran Highway, West Fatemi Ave. Tehran Tehran Iran (Islamic Republic of) Approved 2024-08-11 Ethics Human Research Review Committee of the Research Institute for Endocrine Sciences, Shahid Behe No. 24, Aarabi St. Velenjak area Tehran Tehran Iran (Islamic Republic of)