ICF: LIothyrONiNe Sulphate (T3S) use in hypothyroid subjects on T4 homozygous for the Thr92Ala Deiodinase 2 (D2) polymorphism - the LIONNS-D2 study

甲状腺素是英国第三常见的处方药，每年开出的处方超过3300万张。它被用来治疗甲状腺活动不足，导致疲劳、体重增加和“认知”(记忆)问题等症状。在大多数人中，这些症状随着每天服用左旋甲状腺素(LT4)而改善。然而，尽管接受了治疗，至少有10%-15%的人的致残症状持续存在，导致生活质量(QOL)下降。甲状腺会产生两种激素，甲状腺素(T4)和三碘甲腺原氨酸(T3)。T4荷尔蒙是“不活跃的”，需要在体内转化为“活跃的”T3才能产生效果。在英国，超过95%的人单独接受LT4治疗，与甲状腺功能正常的人相比，LT4在血液中产生不同的T4到T3平衡(T4更多，T3更少)。对一些人来说，这种不同的平衡可能是持续症状的原因。如果是这样的话，LT3和LT4联合治疗可能会有所帮助。对于那些具有不同基因形式的脱碘酶2或D2的人来说，这似乎是一个特别的问题。脱碘酶2或D2激活T4至T3。这种不同的形式被称为Thr92Ala，存在于大约14%的人口中。我们已经表明，服用LT4的患者比其他人群生活质量下降的可能性高22%，而携带Thr92Ala的LT4患者的可能性高200%。然而，到目前为止，将LT3+LT4治疗与单独使用LT4进行比较的研究试验并不总是显示出好处。LT3药片的作用时间只有几个小时，会导致血液中的T3水平不稳定。结果，试验中的T3水平与正常人的水平有很大不同。另一种天然存在的T3被称为T3硫酸盐(T3S)，它提供了一种潜在的“巧妙”解决方案。我们的合作者桑蒂尼教授已经证明，当给患者服用T3时，它会非常缓慢地转换回T3，因此水平非常稳定。90%的人可以恢复正常的甲状腺激素水平平衡，而LT4患者的这一比例不到45%。重要的是，如果体内的甲状腺激素水平升高过高，一种酶就会被激活，从而破坏T3s。这是人体自然控制机制的一部分，这意味着使用T3很可能是非常安全的。重要的是，因为服用T3S时血液中的T3水平非常稳定，所以可以每天进行一次治疗，并在一天中的任何时间进行血液测试，以准确监测水平，使T3S的日常使用非常方便。在这个项目中，一家专业的甲状腺激素制造商将生产用于临床试验的T3。76名正常单独服用LT4的患者将单独服用LT4或LT4+T3s。24周后，所有患者将切换到另一种治疗24周(“交叉”)。我们将使用专门设计的问卷来测量甲状腺相关生活质量(ThyPro)，以及测量甲状腺激素的其他影响，包括身体成分、体重和代谢率，以比较两种治疗方法。研究中的所有患者都将携带Thr92Ala基因差异，因为他们可能受益最大，但未来的研究可能也会显示T4的其他患者也受益。甲状腺激素是由规模较小的“仿制药”公司销售的，这些公司没有大的研究预算，因此如果没有UKRI的资助，这些公司不太可能进行这项研究。如果我们的试验显示有好处，医生很可能想给他们的病人开这种药。我们已经与监管机构MHRA进行了初步磋商，讨论是否有可能将T3视为T3的一种形式，而不是“新的活性物质”。这将意味着，只需要有限的额外证据就可以获得销售T3的许可证。如果是这样的话，在当前研究完成后的2-3年内，患者可以使用T3，如果试验显示有好处，我们已经有一家领先的甲状腺激素公司有兴趣销售T3。

Thyroxine is the third commonest drug prescribed in the UK, with more than 33 million prescriptions issued per year. It is used to treat an underactive thyroid gland which causes symptoms like fatigue, weight gain and "cognitive" (memory) problems. In most people, these symptoms improve with a daily dose of levothyroxine (LT4). However, despite treatment, in at least 10-15% of people disabling symptoms persist causing a poor quality of life (QoL).The thyroid gland produces two hormones, thyroxine (T4) and triiodothyronine (T3). The T4 hormone is "inactive" and needs to be converted to "active" T3 in the body to produce effects. More than 95% of people in the UK are treated with LT4 alone which produces a different balance of T4 to T3 in blood (more T4, less T3) than in people with a normal thyroid. In some people, this different balance may be the cause of persistent symptoms. If so, treatment with a combination of LT3 and LT4 might be help. This seems to be a particular problem in people who have a genetically different form of the enzyme deiodinase 2 or "D2" that activates T4 to T3. This different form is known as Thr92Ala and is present in around 14% of the population. We have already shown that patients on LT4 are 22% more likely to have reduced QoL than the rest of the population and in those on LT4 with Thr92Ala it is 200% more likely. However, up to now research trials comparing LT3+LT4 treatment to LT4 alone have not always shown benefit. LT3 tablets act only for a few hours and cause blood T3 levels that are unstable. As a result, T3 levels in the trials were very different from levels in normal people. An alternative, naturally occurring form of T3 called T3 sulphate (T3S) offers a potentially "ingenious" solution. Our collaborator, Prof Santini has shown that when T3S was given to patients it was converted back into T3 very gradually so that levels were very stable. A normal balance of thyroid hormone levels could be restored in 90% of individuals compared to less than 45% on LT4. Importantly, if thyroid hormone levels in the body rise too high, an enzyme becomes activated that destroys T3S. This is part of a natural control mechanism in the body and means that the use of T3S is likely to be very safe. Importantly, because the level of T3 in the blood is very stable when taking T3S the treatment can be given once a day and a blood test taken at any time of day can be used to accurately monitor the level, making T3S very convenient for everyday use. In this project a specialist thyroid hormone manufacturer will make T3S for use in a clinical trial. 76 patients who are normally on LT4 alone will take either LT4 alone or LT4+T3S. After 24 weeks, all patients will swap to the other treatment for another 24 weeks ("cross-over"). We will use a specially designed questionnaire to measure thyroid related QoL ("ThyPro") as well as measuring other effects of thyroid hormone including body composition, body weight and metabolic rate to compare the two treatments. All patients in the study will carry the Thr92Ala gene difference as they are likely to benefit the most, but future studies may also show benefit in other patients on T4. Thyroid hormones are sold by smaller "generic" drug companies that do not have large research budgets, so the companies are unlikely to do this study without UKRI funding. If our trial shows benefit, doctors are likely to want to prescribe it for their patients. We have had initial consultations with the regulatory authority, MHRA, regarding the possibility to consider T3S as a form of T3 and not a "new active substance". This would mean that only limited additional evidence would be required to obtain a licence to market T3S. If so, T3S could be available to patients within 2-3 years of completion of the current study and we have already had interest from one of the leading thyroid hormone companies in marketing T3S if the trial shows benefit.