ICF: LIothyrONiNe Sulphate (T3S) use in hypothyroid subjects on T4 homozygous for the Thr92Ala Deiodinase 2 (D2) polymorphism - the LIONNS-D2 study
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
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.
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.
Technical Summary
Thyroid hormone is the 3rd most commonly prescribed drug in the UK and is used by over 1.5 million patients daily. Use of the prohormone, thyroxine (LT4) rather than the active hormone (liothyronine, LT3) is currently recommended. However this results in an unphysiological high serum T4/T3 ratio and population based studies show significant increases in psychological morbidity as well as BMI, lipid abnormalities and cardiovascular and all cause mortality. Laboratory studies show that excess LT4 inhibits local generation of T3 within tissues by the deiodinase 2 (D2) enzyme resulting in relative tissue hypothyroidism which may explain excess morbidity. In addition, 14% of the population are homozygous for a polymorphism in the coding region of the D2 gene (Thr92Ala) which appears to substantially increase the excess morbidity associated with LT4 monotherapy.
Rodent studies indicate that combination LT4+LT3 therapy is required to achieve normal tissue thyroid hormone activity. However, currently available LT3 preparations have a short half-life and cannot deliver serum T3 levels that are stable enough to allow accurate dosing and physiological replacement.
T3 sulphate (T3S) is a potential solution. T3S is a natural metabolite of T3 from which T3 can be regenerated. Once daily orally administered T3S results in slow generation of circulating T3 producing stable levels for more than 48 hours permitting physiological replacement. A phase 2a multi-dose study over 11 weeks achieved both T4/T3 ratios and levels of TSH in the reference range in around 90% of individuals as compared to 45% on LT4 alone. We therefore propose to conduct a phase 2b randomised blinded cross-over study in 76 individuals currently on LT4 alone to determine whether combination LT4+T3S therapy is superior to LT4 alone in addressing the unmet clinical need. Subjects homozygous for the D2 Thr92Ala polymorphism will be studied as this appears to enrich for subjects with persistent symptoms.
Rodent studies indicate that combination LT4+LT3 therapy is required to achieve normal tissue thyroid hormone activity. However, currently available LT3 preparations have a short half-life and cannot deliver serum T3 levels that are stable enough to allow accurate dosing and physiological replacement.
T3 sulphate (T3S) is a potential solution. T3S is a natural metabolite of T3 from which T3 can be regenerated. Once daily orally administered T3S results in slow generation of circulating T3 producing stable levels for more than 48 hours permitting physiological replacement. A phase 2a multi-dose study over 11 weeks achieved both T4/T3 ratios and levels of TSH in the reference range in around 90% of individuals as compared to 45% on LT4 alone. We therefore propose to conduct a phase 2b randomised blinded cross-over study in 76 individuals currently on LT4 alone to determine whether combination LT4+T3S therapy is superior to LT4 alone in addressing the unmet clinical need. Subjects homozygous for the D2 Thr92Ala polymorphism will be studied as this appears to enrich for subjects with persistent symptoms.
