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11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial

Keira Markey, James Mitchell, View ORCID ProfileHannah Botfield, View ORCID ProfileRyan S Ottridge, Tim Matthews, Anita Krishnan, View ORCID ProfileRebecca Woolley, View ORCID ProfileConnar Westgate, View ORCID ProfileAndreas Yiangou, View ORCID ProfilePushkar Shah, Caroline Rick, Natalie Ives, View ORCID ProfileAngela E Taylor, Lorna C Gilligan, View ORCID ProfileCarl Jenkinson, View ORCID ProfileWiebke Arlt, View ORCID ProfileWilliam Scotton, Rebecca Fairclough, Rishi Singhal, View ORCID ProfilePaul M Stewart, View ORCID ProfileJeremy W Tomlinson, View ORCID ProfileGareth G Lavery, View ORCID ProfileSusan P Mollan, View ORCID ProfileAlexandra J Sinclair
doi: https://doi.org/10.1101/648410
Keira Markey
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)
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James Mitchell
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UKDepartment of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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Hannah Botfield
Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)
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Ryan S Ottridge
Birmingham Clinical Trials Unit, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
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Tim Matthews
Birmingham Neuro-Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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Anita Krishnan
Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK
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Rebecca Woolley
Birmingham Clinical Trials Unit, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
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Connar Westgate
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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Andreas Yiangou
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UKDepartment of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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Pushkar Shah
Institute of Neurological Sciences, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Glasgow, G51 4TF, UK
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Caroline Rick
Birmingham Clinical Trials Unit, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
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Natalie Ives
Birmingham Clinical Trials Unit, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
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Angela E Taylor
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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Lorna C Gilligan
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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Carl Jenkinson
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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Wiebke Arlt
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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William Scotton
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UKDepartment of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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Rebecca Fairclough
Emerging Innovations Unit, Scientific Partnering and Alliances, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 0SL, UK
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Rishi Singhal
Upper GI Unit and Minimally Invasive Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B9 5SS, UK
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Paul M Stewart
Medical School, University of Leeds, Leeds, LS2 9JT, UK
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Jeremy W Tomlinson
Oxford Centre for Diabetes, Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK
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Gareth G Lavery
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
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Susan P Mollan
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Birmingham Neuro-Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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Alexandra J Sinclair
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom (UK)Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UKDepartment of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK
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  • For correspondence: a.b.sinclair@bham.ac.uk
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Abstract

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension (>25cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m2) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1-1.5; p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: −4.3 cmH2O (SD=5.7); p=0.009) but not in the placebo group (mean change: −0.3 cmH2O (SD=5.9); p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

Footnotes

  • ↵* joint authorship

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625129/

  • Abbreviations

    11β-
    11β-hydroxysteroid dehydrogenase type 1
    HSD1
    inhibitor
    5αTHF
    5α-tetrahydrocortisol
    ACTH
    Adrenocorticotropic hormone
    BBB
    Blood brai barrier
    CP
    Choroid Plexus
    CSF
    Cerebrospinal fluid
    DHEAS
    Dehydroepiandrosterone sulfate
    E
    Cortisone
    F
    Cortisol
    HPA
    Hypothalamic pituitary adrenal
    ICP
    intracranial pressure
    IIH
    Idiopathic Intracranial Hypertension
    LC-
    liquid chromatography-tandem mass
    MS/MS
    spectrometry
    OCT
    Optical coherence tomography
    PMD
    Perimetric mean deviation
    RCT
    Randomised Controlled Trial
    RNFL
    Retinal nerve fibre layer
    THE
    tetrahydrocortisone
    THF
    tetrahydrocortisol
    VA
    Visual acuity
  • Copyright 
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    Posted May 31, 2019.
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    11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial
    Keira Markey, James Mitchell, Hannah Botfield, Ryan S Ottridge, Tim Matthews, Anita Krishnan, Rebecca Woolley, Connar Westgate, Andreas Yiangou, Pushkar Shah, Caroline Rick, Natalie Ives, Angela E Taylor, Lorna C Gilligan, Carl Jenkinson, Wiebke Arlt, William Scotton, Rebecca Fairclough, Rishi Singhal, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery, Susan P Mollan, Alexandra J Sinclair
    bioRxiv 648410; doi: https://doi.org/10.1101/648410
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    11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial
    Keira Markey, James Mitchell, Hannah Botfield, Ryan S Ottridge, Tim Matthews, Anita Krishnan, Rebecca Woolley, Connar Westgate, Andreas Yiangou, Pushkar Shah, Caroline Rick, Natalie Ives, Angela E Taylor, Lorna C Gilligan, Carl Jenkinson, Wiebke Arlt, William Scotton, Rebecca Fairclough, Rishi Singhal, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery, Susan P Mollan, Alexandra J Sinclair
    bioRxiv 648410; doi: https://doi.org/10.1101/648410

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