Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design
Approximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. H...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1282608/full |
| _version_ | 1797622976376471552 |
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| author | Lakdasa D. Premawardhana Peter Nicholas Taylor Onyebuchi E. Okosieme Mohamed A. Adlan Emmanuel K. Obuobie Colin Mark Dayan |
| author_facet | Lakdasa D. Premawardhana Peter Nicholas Taylor Onyebuchi E. Okosieme Mohamed A. Adlan Emmanuel K. Obuobie Colin Mark Dayan |
| author_sort | Lakdasa D. Premawardhana |
| collection | DOAJ |
| description | Approximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection—(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 μg/day or 100 μg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication. |
| first_indexed | 2024-03-11T09:18:54Z |
| format | Article |
| id | doaj.art-5b4e0c7376114156a627f8af8d144406 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-11T09:18:54Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-5b4e0c7376114156a627f8af8d1444062023-11-16T18:29:35ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-11-011410.3389/fendo.2023.12826081282608Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial designLakdasa D. Premawardhana0Peter Nicholas Taylor1Onyebuchi E. Okosieme2Mohamed A. Adlan3Emmanuel K. Obuobie4Colin Mark Dayan5Thyroid Research Group, Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United KingdomThyroid Research Group, Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United KingdomThyroid Research Group, Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United KingdomSection of Endocrinology, Ysbyty Ystrad Fawr and Royal Gwent Hospitals, Aneurin Bevan University Health Board, Newport, United KingdomSection of Endocrinology, Ysbyty Ystrad Fawr and Royal Gwent Hospitals, Aneurin Bevan University Health Board, Newport, United KingdomThyroid Research Group, Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United KingdomApproximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection—(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 μg/day or 100 μg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.https://www.frontiersin.org/articles/10.3389/fendo.2023.1282608/fullhypothyroidismcombined LT3 and LT4 treatmentdeiodinase 2 polymorphismrandomized controlled trialpoor quality of life (QoL) |
| spellingShingle | Lakdasa D. Premawardhana Peter Nicholas Taylor Onyebuchi E. Okosieme Mohamed A. Adlan Emmanuel K. Obuobie Colin Mark Dayan Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design Frontiers in Endocrinology hypothyroidism combined LT3 and LT4 treatment deiodinase 2 polymorphism randomized controlled trial poor quality of life (QoL) |
| title | Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design |
| title_full | Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design |
| title_fullStr | Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design |
| title_full_unstemmed | Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design |
| title_short | Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design |
| title_sort | designing a combined liothyronine lt3 l thyroxine lt4 trial in symptomatic hypothyroid subjects on lt4 the importance of patient selection choice of lt3 and trial design |
| topic | hypothyroidism combined LT3 and LT4 treatment deiodinase 2 polymorphism randomized controlled trial poor quality of life (QoL) |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1282608/full |
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