11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

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11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension : a double-blind randomized controlled trial. / Markey, Keira; Mitchell, James; Botfield, Hannah; Ottridge, Ryan; Matthews, Tim ; Krishnan, Anita ; Woolley, Rebecca; Westgate, Connar; Yiangou, Andreas; Alimajstorovic, Zerin; Shah, Pushkar ; Rick, Caroline ; Ives, Natalie; Taylor, Angela; Gilligan, Lorna; Jenkinson, Carl; Arlt, Wiebke; Scotton, William; Fairclough, Rebecca J ; Singhal, Rishi ; Stewart, Paul M ; Tomlinson, Jeremy W ; Lavery, Gareth; Mollan, Susan; Sinclair, Alex.

In: Brain Communications, Vol. 2, No. 1, fcz050, 10.01.2020.

Research output: Contribution to journalArticlepeer-review

Harvard

Markey, K, Mitchell, J, Botfield, H, Ottridge, R, Matthews, T, Krishnan, A, Woolley, R, Westgate, C, Yiangou, A, Alimajstorovic, Z, Shah, P, Rick, C, Ives, N, Taylor, A, Gilligan, L, Jenkinson, C, Arlt, W, Scotton, W, Fairclough, RJ, Singhal, R, Stewart, PM, Tomlinson, JW, Lavery, G, Mollan, S & Sinclair, A 2020, '11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial', Brain Communications, vol. 2, no. 1, fcz050. https://doi.org/10.1093/braincomms/fcz050

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Author

Markey, Keira ; Mitchell, James ; Botfield, Hannah ; Ottridge, Ryan ; Matthews, Tim ; Krishnan, Anita ; Woolley, Rebecca ; Westgate, Connar ; Yiangou, Andreas ; Alimajstorovic, Zerin ; Shah, Pushkar ; Rick, Caroline ; Ives, Natalie ; Taylor, Angela ; Gilligan, Lorna ; Jenkinson, Carl ; Arlt, Wiebke ; Scotton, William ; Fairclough, Rebecca J ; Singhal, Rishi ; Stewart, Paul M ; Tomlinson, Jeremy W ; Lavery, Gareth ; Mollan, Susan ; Sinclair, Alex. / 11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension : a double-blind randomized controlled trial. In: Brain Communications. 2020 ; Vol. 2, No. 1.

Bibtex

@article{1afec1d66e6443fba2f0a5e06be67e4a,
title = "11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial",
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 investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with 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 anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 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 to 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, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure ( P  = 0.005, R  = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest. ",
keywords = "idiopathic intracranial hypertension, 11β-hydroxysteroid dehydrogenase type 1, papilloedema, phase II, randomized controlled trial",
author = "Keira Markey and James Mitchell and Hannah Botfield and Ryan Ottridge and Tim Matthews and Anita Krishnan and Rebecca Woolley and Connar Westgate and Andreas Yiangou and Zerin Alimajstorovic and Pushkar Shah and Caroline Rick and Natalie Ives and Angela Taylor and Lorna Gilligan and Carl Jenkinson and Wiebke Arlt and William Scotton and Fairclough, {Rebecca J} and Rishi Singhal and Stewart, {Paul M} and Tomlinson, {Jeremy W} and Gareth Lavery and Susan Mollan and Alex Sinclair",
note = "{\textcopyright} The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2020",
month = jan,
day = "10",
doi = "10.1093/braincomms/fcz050",
language = "English",
volume = "2",
journal = "Brain Communications",
issn = "2632-1297",
publisher = "Oxford University Press",
number = "1",

}

RIS

TY - JOUR

T1 - 11β-hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension

T2 - a double-blind randomized controlled trial

AU - Markey, Keira

AU - Mitchell, James

AU - Botfield, Hannah

AU - Ottridge, Ryan

AU - Matthews, Tim

AU - Krishnan, Anita

AU - Woolley, Rebecca

AU - Westgate, Connar

AU - Yiangou, Andreas

AU - Alimajstorovic, Zerin

AU - Shah, Pushkar

AU - Rick, Caroline

AU - Ives, Natalie

AU - Taylor, Angela

AU - Gilligan, Lorna

AU - Jenkinson, Carl

AU - Arlt, Wiebke

AU - Scotton, William

AU - Fairclough, Rebecca J

AU - Singhal, Rishi

AU - Stewart, Paul M

AU - Tomlinson, Jeremy W

AU - Lavery, Gareth

AU - Mollan, Susan

AU - Sinclair, Alex

N1 - © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2020/1/10

Y1 - 2020/1/10

N2 - 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 investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with 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 anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 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 to 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, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure ( P  = 0.005, R  = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

AB - 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 investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with 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 anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 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 to 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, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure ( P  = 0.005, R  = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

KW - idiopathic intracranial hypertension

KW - 11β-hydroxysteroid dehydrogenase type 1

KW - papilloedema

KW - phase II

KW - randomized controlled trial

U2 - 10.1093/braincomms/fcz050

DO - 10.1093/braincomms/fcz050

M3 - Article

C2 - 32954315

VL - 2

JO - Brain Communications

JF - Brain Communications

SN - 2632-1297

IS - 1

M1 - fcz050

ER -