Desiccated Thyroid Extract Combined With Levothyroxine for TSH Suppression Therapy in DTC

Desiccated Thyroid Extract Combined With Levothyroxine for TSH Suppression Therapy in Intermediate-to-High Risk Differentiated Thyroid Cancer After Surgery: A National Multicenter, Open-Label, Randomized Controlled Trial

The global incidence of Differentiated Thyroid Cancer (DTC) is rising. While surgery followed by TSH suppression is the standard of care, achieving target TSH levels with levothyroxine (L-T4) monotherapy remains challenging, with only 25-70% of intermediate/high-risk patients attaining it within 6-8 months. This therapeutic dilemma stems from three key issues: impaired T4-to-T3 conversion due to DIO2 polymorphisms, the non-physiological hormone ratio of T4 monotherapy, and L-T4's narrow therapeutic window. This often results in an "under- versus over-suppression" paradox, increasing risks of recurrence, atrial fibrillation, and osteoporosis. Combining L-T4 with desiccated thyroid extract (DTE; T4:T3 ≈ 4:1) may overcome these limitations by bypassing DIO2 defects and providing a more physiological hormone profile, thereby potentially improving TSH control while mitigating side effects. Supported by the 2023 Chinese guidelines and our promising pilot data (82% cumulative target attainment at a median of 1.4 months), we propose a two-stage national study: a multicenter cohort study followed by a randomized trial, to generate high-level evidence for this combination therapy in high-risk DTC.

This study is a multicenter, open-label, randomized controlled trial. Stage 1 eligibility: (1) Age ≥ 18 years；(2) Histologically proven DTC after initial surgery (± ¹³¹I)；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) On L-T4 monotherapy: TSH above target despite FT4 ≥ 90 % of normal upper limit；(5) Signed informed consent and agreement to follow-up. Stage 2 eligibility: (1) Age 18-70 years (inclusive)；(2) Histologically proven DTC undergoing first-time surgery；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) Signed informed consent and agreement to post-operative follow-up. Exclusion criteria: (1) Non-DTC histology; (2) Hyperthyroidism, toxic adenoma, or toxic nodular goiter; (3) Malabsorptive GI disorders (e.g., H.-pylori gastritis, atrophic gastritis, celiac disease) or history of gastric bypass; (4) Hypersensitivity to levothyroxine or desiccated thyroid; (5) Angina, coronary artery disease, tachyarrhythmia, osteoporosis; (6) Concurrent malignancy; (7) Pregnant, lactating, or planning pregnancy within 12 months; (8) Severe COPD, hepatic or renal insufficiency, uncontrolled hypertension or diabetes, or any condition that could bias outcome assessment; (9) Chronic use of psychotropics, systemic glucocorticoids, amiodarone, chemotherapy, iron, thionamides, PPIs, or other drugs interfering with thyroid hormone; (10) Previous exposure to levothyroxine, desiccated thyroid, or T3 preparations; (11) Participation in another clinical trial that could interfere with this study.

Stage 1 prospectively enrolls patients who underwent initial DTC surgery at participating sites, were classified as intermediate or high recurrence risk, subsequently failed to achieve target TSH suppression on L-T4 monotherapy while having FT4 ≥ 90 % of the normal upper limit. The TSH-suppressive regimen is switched to DTE + L-T4, creating a before-and-after self-control study. Stage 2 screens patients scheduled for initial DTC surgery; eligible participants are randomized 1:1 to experimental arm (DTE + L-T4 combination) and control arm (L-T4). The stage 2 target sample size is 446 patients (223 per arm).

Data collection includes: (1) Baseline characteristics: sex, age, BMI, comorbidities (cardiovascular, endocrine, thyroid, etc.), prior neck irradiation; (2) Pre-operative imaging/labs: laryngoscopy, thyroid US, TSH, FT3, FT4, TT3, TT4; (3) Operative data: procedure type, date, extent of lymph-node dissection; (4) Symptom/QoL: ThyPRO-39 questionnaire; (5) hair-pull test for alopecia; (6) Genetics: DIO2 polymorphism; (6) Post-operative plan: initial TSH-suppression dose, first dosing date, RAI administration; (7) Pathology: histology, TNM stage, molecular results, ATA risk stratum. Follow-up at 1, 3, 6, 9, 12 months post-op and 1 month after every dose adjustment: (1) Vital signs, weight, TSH-suppression details; (2) Imaging/labs: thyroid US, TSH, FT3, FT4, TT3, TT4, Tg, TgAb, calcium, 25-OH-VD; (3) Adverse events: cardiovascular, musculoskeletal, neurologic, GI, allergic reactions; (4) ThyPRO-39 and hair-pull test repeated at each visit.

Inclusion Criteria:

• Stage 1 eligibility: (1) Age ≥ 18 years；(2) Histologically proven DTC after initial surgery (± ¹³¹I)；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) On L-T4 monotherapy: TSH above target despite FT4 ≥ 90 % of normal upper limit；(5) Signed informed consent and agreement to follow-up. Stage 2 eligibility: (1) Age 18-70 years (inclusive)；(2) Histologically proven DTC undergoing first-time surgery；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) Signed informed consent and agreement to post-operative follow-up.

Exclusion Criteria:

• (1) Non-DTC histology; (2) Hyperthyroidism, toxic adenoma, or toxic nodular goiter; (3) Malabsorptive GI disorders (e.g., H.-pylori gastritis, atrophic gastritis, celiac disease) or history of gastric bypass; (4) Hypersensitivity to levothyroxine or desiccated thyroid; (5) Angina, coronary artery disease, tachyarrhythmia, osteoporosis; (6) Concurrent malignancy; (7) Pregnant, lactating, or planning pregnancy within 12 months; (8) Severe COPD, hepatic or renal insufficiency, uncontrolled hypertension or diabetes, or any condition that could bias outcome assessment; (9) Chronic use of psychotropics, systemic glucocorticoids, amiodarone, chemotherapy, iron, thionamides, PPIs, or other drugs interfering with thyroid hormone; (10) Previous exposure to levothyroxine, desiccated thyroid, or T3 preparations; (11) Participation in another clinical trial that could interfere with this study.