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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: Used, Assignment: Parallel, Purpose: Treatment, Randomization description: Phase 3: Participants will be randomly allocated in a 1:1 ratio to one of two parallel treatment groups: LT4 plus slow-release liothyronine (SR-T3) combination therapy (intervention group). LT4 monotherapy (control group). A computer-generated random allocation sequence will be prepared to assign participants to the two treatment groups with equal probability. The allocation sequence will be kept confidential, and participants will be enrolled sequentially according to the generated randomization sequence. Phase 2: After simple randomization, participants will be assigned to one of three pre-breakfast treatment regimens: SR-T3, L-T3, or L-T4, for 4 weeks. The L-T4 dose will be 1.6 μg/kg, and the corresponding SR-T3 and L-T3 doses will be administered according to the Phase 2 protocol. Participants will attend the endocrine clinic for weekly follow-up visits and blood sampling during the 4-week treatment period, Blinding description: The random allocation sequence will be concealed from investigators and clinical staff involved in participant recruitment and assessment. The allocation sequence will be kept confidential by a designated staff member who will not be involved in participant recruitment, clinical management, or outcome assessment. After eligibility has been confirmed and written informed consent has been obtained, the participant will be assigned the next allocation code according to the randomization sequence. The treatment will be provided using the corresponding coded study medication without revealing the assigned treatment to participants or investigators. Both participants and investigators will remain blinded to treatment allocation. Participants assigned to the LT4 monotherapy group will receive a matching placebo corresponding to SR-T3. Active SR-T3 and placebo tablets will be matched in physical appearance, taste, smell, and packaging to maintain double blinding. 2-3 Hypothyroidism. Intervention 1: Participants randomized to combination therapy will start treatment with LT4 plus slow-release liothyronine (SR-T3) at an initial SR-T3:LT4 dose ratio of approximately 1:5. The absolute starting doses of LT4 and SR-T3 will be individualized according to each participant's thyroid hormone replacement requirement.The 1:5 ratio will represent the initial treatment ratio only and will not be required to remain fixed throughout follow-up. During the dose-adjustment period, LT4 and SR-T3 doses will be individually titrated according to biochemical response in order to maintain serum TSH within approximately 0.5–5.0 mU/L. In participants receiving combination therapy, the serum T3/FT4 ratio and the intended balance between LT4 and SR-T3 exposure will also be considered during dose titration. Consequently, the SR-T3:LT4 dose ratio may change during follow-up.SR-T3 tablets containing 15, 20, and 25 μg and LT4 tablets containing 50, 75, and 100 μg will be available for individualized dose adjustment. Study treatment will be administered once daily in the morning before breakfast and will continue for 48 weeks. After completion of study treatment, participants will return to conventional LT4 replacement and will be followed until biochemical euthyroidism is re-established. Intervention 2: Control group: LT4 monotherapyParticipants randomized to the control group will receive individualized LT4 monotherapy according to their pretrial LT4 replacement requirement and subsequent biochemical response. LT4 dosing will not be restricted to a fixed dose of 100 μg/day.LT4 tablets containing 50, 75, and 100 μg will be available for individualized dose adjustment. During follow-up, the LT4 dose will be adjusted when required to maintain biochemical euthyroidism, with serum TSH maintained within approximately 0.5–5.0 mU/L.Participants will take the assigned study tablets once daily in the morning before breakfast. Treatment will continue for 48 weeks. To maintain double blinding, participants in this group will also receive a matching placebo corresponding to SR-T3. 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) Adults aged 20 to 75 with hypothyroidism of any etiology who have been receiving stable levothyroxine (LT4) monotherapy for at least 3 months prior to randomization. Biochemically euthyroid patients, with serum TSH levels in the approximate range of 0.5 to 5.0 mIU/L. Eligible etiologies include, but are not limited to: Hashimoto's thyroiditis, Hypothyroidism following radioactive iodine treatment for Graves' disease, Hypothyroidism following definitive treatment for thyroid cancer. Prior treated thyroid cancer resulting in hypothyroidism is not considered an exclusion criterion, provided there is no current or active malignancy. 20 years 75 years Both Pregnancy or planning for pregnancy during the study period; Clinically significant cardiovascular disease, including unstable cardiovascular disease, clinically significant cardiac arrhythmia, or congestive heart failure; Clinically significant renal or hepatic impairment; Current or active malignancy; Diseases or conditions that could significantly mimic the symptoms of hypothyroidism or confound their assessment, including anemia, vitamin D deficiency, vitamin B12 deficiency, chronic and clinically significant psychiatric disorders (such as major depressive disorder), and fibromyalgia. Additionally, patients taking methimazole, propylthiouracil, tamoxifen, estrogen- or progesterone-containing medications, or corticosteroids are excluded from the study. E03.9 Hypothyroidism, unspecified Treatment - Drugs Treatment - Other Participants randomized to combination therapy will start treatment with LT4 plus slow-release liothyronine (SR-T3) at an initial SR-T3:LT4 dose ratio of approximately 1:5. The absolute starting doses of LT4 and SR-T3 will be individualized according to each participant's thyroid hormone replacement requirement.The 1:5 ratio will represent the initial treatment ratio only and will not be required to remain fixed throughout follow-up. During the dose-adjustment period, LT4 and SR-T3 doses will be individually titrated according to biochemical response in order to maintain serum TSH within approximately 0.5–5.0 mU/L. In participants receiving combination therapy, the serum T3/FT4 ratio and the intended balance between LT4 and SR-T3 exposure will also be considered during dose titration. Consequently, the SR-T3:LT4 dose ratio may change during follow-up.SR-T3 tablets containing 15, 20, and 25 μg and LT4 tablets containing 50, 75, and 100 μg will be available for individualized dose adjustment. Study treatment will be administered once daily in the morning before breakfast and will continue for 48 weeks. After completion of study treatment, participants will return to conventional LT4 replacement and will be followed until biochemical euthyroidism is re-established. Control group: LT4 monotherapyParticipants randomized to the control group will receive individualized LT4 monotherapy according to their pretrial LT4 replacement requirement and subsequent biochemical response. LT4 dosing will not be restricted to a fixed dose of 100 μg/day.LT4 tablets containing 50, 75, and 100 μg will be available for individualized dose adjustment. During follow-up, the LT4 dose will be adjusted when required to maintain biochemical euthyroidism, with serum TSH maintained within approximately 0.5–5.0 mU/L.Participants will take the assigned study tablets once daily in the morning before breakfast. Treatment will continue for 48 weeks. To maintain double blinding, participants in this group will also receive a matching placebo corresponding to SR-T3. 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, T3/FT4 and FT3/FT4 ratios and proportion of participants with T3/FT4 ratio whithin reference range. Timepoint: At baseline and 3, 6, and 12 months after start-up. Method of measurement: Electrochemiluminescence immunoassay (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, ECG parameters). Timepoint: At baseline, 6 and 12 months after intervention. Method of measurement: With related measures. Pharmacogenetic variants: rs225014، rs12885300، rs225015، rs17606253. Timepoint: at the end of the study. Method of measurement: genotyping. 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: Bioelectrical impedance analysis (BIA). 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 Committee of the National Institute for Medical Research Development (NIMAD) of the Islamic R No. 21, Besat Ave, Chamran Highway, West Fatemi Ave. Tehran Tehran Iran (Islamic Republic of)