title: Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Karo Bio AB.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sjouke
authors.affiliation: Lipid Clinic, Medical Department, Oslo University Hospital, Oslo, Norway.
authors.forename: Gisle
authors.initials: G
authors.lastname: Langslet
authors.affiliation: Center for Preventive Cardiology, General Teaching Hospital, and First Medical Faculty of Charles University in Prague, Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Ceska
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA; South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, SA Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: Karo Bio AB, NOVUM, Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Öhlander
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Ladenson
authors.affiliation: Department of Medicine and Health, Faculty of Health Sciences, Linköping University, Linköping, and Stockholm Heart Center, Stockholm, Sweden.
authors.forename: Anders G
authors.initials: AG
authors.lastname: Olsson
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. Electronic address: j.j.kastelein@amc.uva.nl.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000349:Africa; D000410:Alanine Transaminase / Q000187:drug effects; D000704:Analysis of Variance; D000813:Anilides / Q000009:adverse effects / Q000627:therapeutic use*; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000187:drug effects; D001208:Asia; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology*; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000813:Anilides; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D000410:Alanine Transaminase