BACKGROUND: Eprotirome is a liver-selective thyroid hormone receptor agonist 
that has been shown to lower plasma LDL cholesterol concentrations in previous 
phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the 
long-term safety and efficacy of 50 μg and 100 μg eprotirome in patients with 
familial hypercholesterolaemia.
METHODS: For this randomised, double-blind, placebo-controlled, parallel-group, 
phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 
2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients 
were eligible for enrolment if they were aged 18 years or older, diagnosed with 
heterozygous familial hypercholesterolaemia, and had not reached target LDL 
cholesterol concentrations after at least 8 weeks of statin therapy with or 
without ezetimibe. We used a computer-generated randomisation sequence to 
allocate patients to one of three groups: 50 μg eprotirome, 100 μg eprotirome, 
or placebo. This trial was planned for 52-76 weeks, with primary efficacy 
analysis at 12 weeks, but it was prematurely terminated when another study found 
that eprotirome causes cartilage damage in dogs. Although it was impossible to 
meet the predefined study outcomes, we analysed changes in the concentrations of 
LDL cholesterol and other lipids, liver parameters, thyroid hormone 
concentrations, and adverse effects of treatment with eprotirome versus placebo 
at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks 
of treatment. This study is registered with ClinicalTrials.gov, number 
NCT01410383.
FINDINGS: We enrolled 236 patients, randomly allocating 80 to receive placebo, 
79 to receive 50 μg eprotirome, and 77 to receive 100 μg eprotirome. 69 patients 
reached the 6 week timepoint (23 given placebo, 24 given 50 μg eprotirome, and 
22 given 100 μg eprotirome). Mean LDL cholesterol concentrations increased by 9% 
(95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs 
placebo) in the 50 μg eprotirome group, and decreased by 22% (-32 to -13%; 
p=0.0045 vs placebo) in the 100 μg eprotirome group. We noted statistically 
significant increases between both eprotirome groups and placebo in aspartate 
aminotransferase (AST; p<0.0001), alanine aminotransferase (ALT; p<0.0001), 
conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (p<0.0001). 
Four patients had to discontinue or interrupt study treatment before trial 
termination due to AST increases between the upper limit of normal (ULN) and six 
times ULN, and ALT concentrations between three and seven times ULN. Although we 
detected no changes in serum concentrations of thyroid-stimulating hormone or 
free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in 
the 50 μg eprotirome group and 27% (30 to 23) in the 100 μg eprotirome group 
(p<0.0001 vs placebo for both groups).
INTERPRETATION: Our findings show that eprotirome can lower LDL cholesterol 
concentrations in patients with familial hypercholesterolaemia when added to 
conventional statin treatment with or without ezetimibe, but that it has the 
potential to induce liver injury. These findings, along with findings of 
cartilage damage in dogs, raise serious doubts about selective thyroid hormone 
mimetics as a therapeutic approach to lower LDL cholesterol concentrations.
FUNDING: Karo Bio AB.