Disclosures: Jonklaas reports no relevant financial disclosures. Please see the consensus statement for all other authors’ relevant financial disclosures.
February 23, 2021
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Better trials needed to assess combination therapy for hypothyroidism

Disclosures: Jonklaas reports no relevant financial disclosures. Please see the consensus statement for all other authors’ relevant financial disclosures.
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Three large professional thyroid organizations issued a joint statement calling for new trials of combination therapy to treat hypothyroidism, citing new clinical endpoints and the importance of assessing patient-reported outcomes.

“Even though a large number of trials have already been published, a clear benefit of combination therapy has not been shown,” Jacqueline Jonklaas, MD, PhD, professor of medicine in the division of endocrinology at Georgetown University, told Healio. “Our authors believed that there were sufficient anecdotal data from patients and sufficient new scientific data — both basic science, translational science and clinical science — that the issue deserved to be reconsidered. Additionally, most of the trials already conducted had sufficient non-optimal design features that we thought better-designed trials could be conducted, potentially with different results.”

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Endocrinologists are frequently asked to consult on adult patients with hypothyroidism prescribed levothyroxine who are dissatisfied with their therapy, Jonklaas and colleagues wrote in the statement. However, use of combination therapy with levothyroxine and liothyronine remains “highly controversial,” in part due to conflicting results from clinical trials.

Jacqueline Jonklaas

“Shortcomings of prior trials included being underpowered, not focusing on patients with residual symptoms or with deiodinase or thyroid hormone transporter polymorphisms, short duration of the study, and once-daily dosing liothyronine, rather than twice or even three times daily,” Jonklaas said. “Currently there is no FDA-approved ‘sustained-release’ liothyronine preparation. A potential new extended-release preparation liothyronine is entering phase 1 trials. It goes without saying that when this is approved, new trials will be absolutely indicated.”

Summary, consensus statements

Fourteen clinical trials have shown no consistent benefit of combination therapy with levothyroxine and liothyronine, the researchers noted in the statement. Despite the publication of these trials, combination therapy is widely used, and patients reporting benefit continue to generate patient and physician interest.

“Recent scientific developments may provide insight into this inconsistency and guide future studies,” the researchers wrote.

The American Thyroid Association, British Thyroid Association and European Thyroid Association held a joint conference in November 2019 to review new basic science and clinical evidence regarding combination therapy, with presentations and input from 12 content experts.

After the presentations, researchers developed summary and consensus statements on best practices for the design of future clinical trials of levothyroxine/liothyronine combination therapy. Of 34 consensus statements available for voting, 28 received at least 75% agreement from thyroid groups, with 13 receiving 100% agreement.

Statements with 100% agreement included recommendations to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, to include patients dissatisfied with their current therapy, and to require at least 1.2 µg/kg of levothyroxine daily, as well as twice-daily liothyronine or a slow-release preparation, if available.

Incorporate patient experiences

Researchers also recommended that trials assess patient-reported outcomes as a primary outcome — measured by a tool with relevant content validity and responsiveness — and patient preference as a secondary outcome.

“The key aspects of thyroid-related quality of life are typically tiredness and emotional susceptibility, not classical depression or anxiety, and may be missed using generic patient-reported outcome measures,” the researchers wrote.

Any trial assessing combination therapy should also be randomized, double blind and placebo controlled with a parallel design, they wrote.

“Patient reports regarding combination therapy are mixed,” Jonklaas said. “Some patients feel that there is a night-and-day difference between when they were taking levothyroxine and when they started liothyronine, with improvement in symptoms and increased quality of life. Some patients report benefit from desiccated thyroid extract. However, not all patients experience benefit, and in some individuals, the benefit wears off over time. It is commonly believed that combination therapy should not be continued if patients do not experience benefits, as combination therapy may have more risks, be more complicated, and also be more expensive.”

Jonklaas said that any future research that is considered using current liothyronine preparations should specifically recruit patients with residual symptoms and include those with deiodinase and thyroid hormone transporter polymorphisms.

“They should include patients that are similar to the general hypothyroid population so that trial results will be relevant for them,” Jonklaas said. “Patient-reported outcomes should be the major focus of future trials, and patient preference should be examined. Trials should be adequately powered to achieve statistical significance and so will need to be considerably larger than prior trials, and they also should be longer in duration to assess the durability of the response to combination therapy and to better assess any potential risks.”

For more information:

Jacqueline Jonklaas, MD, PhD, can be reached at jonklaaj@georgetown.edu.

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