Randomized control Clinical Trial to assess the efficacy of the three different combined preparations of levothyroxine plus slow-release liothyronine

To assess and compare the efficacy of treatment of hypothyroidism with LT4 monotherapy with three different combinations of LT4 plus SR-T3

A parallel randomized, double-blind controlled clinical trial, phase 2, 120 samples

Patients will be recalled from a private clinic in Tehran to the Research Institute for Endocrine Sciences. The treatment will be allocated based on the pre-specified double-blinded random allocation while the researchers and patients are blinded to therapy. The drug will be continued for eight weeks. Participants will be evaluated for biochemical assessments and thyroid symptoms at baseline and the end of the study. TSQ will assess treatment satisfaction at the end of the study. Also, in the last visit, blood samples will be obtained six times during 24 hours to assess the pharmacokinetic of slow-release T3.

Patients≥20y with hypothyroidism who attain euthyroidism under LT4 monotherapy. Exclusion criteria: Pregnancy, chronic liver and kidney disease, heart failure, cancer, taking methimazole, PTU, Tamoxifen, estrogen, progesterone, and corticosteroids

1. The group with a daily intake of 75µg LT4 plus 7.5 µg SR-T3( ratio 1:10) 2. The group with a daily intake of 68.5µg LT4 plus 9 µg SR-T3(ratio 1:8) 3. The group with a daily intake of 60µg LT4 plus 12µg SR-T3 (ratio 1:5) 4. The group with LT4 monotherapy (control group)

T3/T4 ratio, TSH, T4, T3, free T4. Clinical signs and symptoms of hypothyroidism(Thyroid symptom questionnaire), serum lipid profile, FBS, LDH, CK, insulin, Metabolomics, T3 Cmax, T3 Tmax ECG heart rate, BP, Thyroid treatment satisfaction questionnaire(THY-TSQ)

Patients will be allocated to three intervention groups and one control group using stratified randomization. Six stratifications will be made based on age and gender. At first, patients will be assigned to three age groups of ≤50y, 51-70y, >70 y. Under each subgroup, patients will be assigned to male and female. Then under each sex subgroup, patients will be randomly assigned to four treatment groups using the random table.

After implementation of randomization and specific coding, 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 only reveal a treatment allocation after receiving information demonstrating that the patient is eligible and has consented to the trial. The subjects and the investigators will be kept from knowing who will be assigned to which treatment (double-blind). Both groups will receive identical tablets in physical appearance, taste, and smell to fulfill this.

These data are belonged to Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran