Treatment of hypothyroidism with levothyroxine plus slow-release liothyronine: a study protocol for a randomized controlled double-blinded clinical trial.

The trial will enroll 100 patients with hypothyroidism who have achieved euthyroidism under LT4 monotherapy for at least 3 months.

• Participants must be aged ≥ 20 years.
• Euthyroidism under LT4 monotherapy must have been achieved and maintained for at least 3 months prior to enrollment.
• Patients will be randomized into two groups of 50 each.
• Expected recruitment start date: 2024-10-06; expected recruitment end date: 2025-10-23.

The intervention arm will receive combination therapy of 75 µg LT4 plus 25 µg slow-release liothyronine (SRT3), compared to LT4 monotherapy in the control arm.

• The slow-release formulation of T3 (SRT3) is hypothesized to restore T3 concentrations more physiologically than immediate-release T3.
• The trial is double-blinded and randomized.
• Treatment duration is 48 weeks.
• The specific doses are 75 µg LT4 + 25 µg SRT3 for the combination group versus LT4 monotherapy for the control group.

Participants will be evaluated at baseline and at three subsequent follow-up time points: 12, 24, and 48 weeks after treatment allocation.

• Body weight, heart rate, blood pressure, ECG, quality of life, resting energy expenditure, and body composition will be evaluated before and after the intervention.
• Serum TSH, total T3, total T4, free T4, free T3, lipid panel, FBS, insulin, HbA1C, HOMA-IR, SHBG, enolase, LDH, CK, ferritin, and metabolomics will be assessed at baseline and compared with values at 24 and 48 weeks.
• Quality of life will be measured using both the ThyPRO-39 and SF-12 instruments.
• Epigenetic-related markers will be measured and compared between responders and non-responders.

The trial addresses the clinical problem of persistent complaints in hypothyroid patients despite achieving normal serum TSH levels on LT4 monotherapy.

• The authors note 'emerging controversies regarding the priority of T4 + T3 combination therapy over standard care with levothyroxine monotherapy.'
• Combination therapy with SRT3 and LT4 is hypothesized to provide better outcomes 'especially in individuals with persistent complaints despite having normal serum TSH levels.'
• The trial targets a specific subgroup of hypothyroid patients with persistent symptoms under LT4 monotherapy.

Genetic polymorphism sequencing is included in the trial design to identify hypothyroid patients who do not respond well to levothyroxine alone.

• Epigenetic-related markers will be measured and compared between responders and non-responders to combination therapy.
• The authors state that 'genetic polymorphism sequencing may identify hypothyroid patients who are not responding well to levothyroxine alone.'
• This component of the study aims to characterize the biological basis of differential treatment response.

The trial is registered with the Iranian Registry of Clinical Trials with registration ID IRCT20100922004794N12.

• Trial ID: 44220.
• IRCT ID: IRCT20100922004794N12.
• Registration date: 2020-02-27.
• The trial is conducted in Iran.