Better trials needed to assess combination therapy for hypothyroidism
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.”
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.
“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.
Perspective
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Jonklass and colleagues address a fundamental question in treatment of hypothyroidism: What is the optimal thyroid hormone replacement therapy? As a practicing clinical endocrinologist for the past 29 years, I would like to focus on a different question: Are patients and physicians satisfied with our current understanding of optimal treatment, and will more studies with the current treatment options lead to meaningful results?
The authors review the basic, translational and clinical studies to date in order to provide summary statements on 10 topic areas that relate to levothyroxine/liothyronine combination therapy. With this information, 12 content experts developed 28 consensus statements that required at least 75% approval. Several parameters would be included in an adequately parallel double-blind-designed study, including the use of twice-daily liothyronine or a slow-release form when available, patient-reported data as a primary outcome, and requiring superiority of the combination therapy as an endpoint of the study.
From my perspective, there are a number of patients who are dissatisfied with their thyroid hormone replacement, although in my practice, I would not be able to quantify this number among the group that is quite satisfied with their replacement therapy. There have been levothyroxine-controlled trials that have failed to show any difference between monotherapy and levothyroxine/liothyronine combination therapy, and the authors pointed out the problems with the trials conducted to date. If it is necessary to provide guidance to physicians and patients that levothyroxine/liothyronine treatment is superior to levothyroxine monotherapy, it would seem to me that enhancing the study cohort with dissatisfied patients might bias the results. If the study is adequately powered, then including patients with hypothyroidism of every cause and with any symptoms would be the best course.
In the final analysis, patients and physicians are looking for the optimal treatment for all patients with hypothyroidism, not just dissatisfied patients on thyroid hormone replacement therapy. Although the scientific data from clinical studies like those suggested would be interesting, without the clinical tools like slow-release liothyronine available to attempt to achieve superiority in the use of combination therapy, the time, cost and likely lack of specific superior outcome cannot justify further formal research trials at this time.
For the foreseeable future, most endocrinologists will most likely continue to add liothyronine to levothyroxine in combination therapy to dissatisfied patients on thyroid hormone replacement and clinically and biochemically assess the outcome of this clinical trial for their patient.
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