The safety, tolerability and efficacy of an 11\( \beta\)-hydroxysteroid dehydrogenase type 1 inhibitor in idiopathic intracranial hypertension

Markey, Keira Annie (2018). The safety, tolerability and efficacy of an 11\( \beta\)-hydroxysteroid dehydrogenase type 1 inhibitor in idiopathic intracranial hypertension. University of Birmingham. Ph.D.

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Pharmacological treatments in idiopathic intracranial hypertension (IIH) are limited. The safety, tolerability and efficacy of a novel drug, an 11 \( \beta\)-hydroxysteroid dehydrogenase type-1 (11\( \beta\)-HSD1) inhibitor (AZD4017), was investigated in a phase II multicentre randomised, double-blind, placebo-controlled trial (IIH:DT). Thirty-one females between 18-55 years with active IIH (lumbar puncture (LP) pressure >25 cmH\( _2\)0 and papilloedema) were randomised 1: 1 to receive either 400 mg twice daily oral AZD4017 (n=17) or matching placebo for 12 weeks (n=14). The primary outcome was the difference in LP pressure between groups at week 12.

LP pressure decreased from 33.7(6.3) to 29.7(5.2) cmH\( _2\)0 at 12 weeks for AZD4017 and from 32.7(4.8) to 31.3(6.7) cmH\( _2\)0 for placebo (adjusted mean difference: -2.8, 95% Cl: -7.1 to 1.5; \( \rho\)=0.2). There were no significant differences between treatment arms at week 12 for visual outcomes and headaches but there was a qualitative improvement up to the week 16 follow-up. One serious adverse event was deemed unrelated to the treatment. Only 9 adverse events were deemed to be drug-related and no patients withdrew. AZD4017 was also shown to be effective at inhibiting systemic, hepatic and potentially CNS 11 \( \beta\)-HSD1.

This is the first phase II trial in IIH to assess an innovative agent, AZD4017. The treatment was safe and tolerable over three months. Greater improvements were noted in the AZD4017 group for LP pressure and visual field mean deviation in particular. Unfortunately, these remained statistically non-significant. A longer and perhaps larger randomised controlled trial would be of interest to establish efficacy.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Metabolism and Systems Research
Funders: Medical Research Council, Other
Other Funders: West Midlands Neuroscience Teaching and Research Fund
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry


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