Clinical Methods and Design for a Phase II Randomised Control Trial to Assess the Efficacy and Safety of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) in Idiopathic Intracranial Hypertension: IIH:DT

Background: Idiopathic intracranial hypertension (IIH) is a condition with few effective management options. So far, there have been no randomized controlled trials evaluating new treatments in IIH.Objectives: The purpose of this paper is to outline the trial design for the Idiopathic Intracranial Hypertension Drug Trial (IIH:DT), assessing an innovative medical treatment in IIH and the rationale for the chosen trial methodology.Methods: IIH:DT is a phase II double-blind randomized placebo-controlled trial recruiting 30 female participants with active IIH (intracranial pressure >25cm H2 O and papilledema). Participants are randomized in a 1:1 ratio to 12 weeks of either AZD4017, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, or a matching placebo. They receive either 400 mg of AZD4017 or placebo twice daily. Participants are followed up at Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 postrandomization. The primary outcome is to examine the effect of AZD4017 on intracranial pressure, measured by lumbar puncture, over 12 weeks. Secondary outcome measures include IIH symptoms, visual function, papilledema, headache measures, safety, and tolerability. Cerebrospinal fluid, serum, plasma, urine, and adipose tissue are also taken for exploratory outcomes.Results: All participants were recruited between April 2014 and August 2016.Conclusions: IIH:DT is the first phase II double-blind randomized placebo-controlled trial assessing the efficacy and safety of the novel pharmacological intervention, AZD4017, for the treatment of IIH.Trial Registration: Clinicaltrials.gov NCT02017444; https://clinicaltrials.gov/ct2/show/NCT02017444 (Archived by WebCite at http://www.webcitation.org/6tVHesN6s

Headache determines quality of life in idiopathic intracranial hypertension

BACKGROUND: The effect of idiopathic intracranial hypertension (IIH) on quality of life (QOL) is poorly understood. Our objectives were to compare QOL in IIH to the normal UK population; to investigate QOL changes with treatment of IIH, using a weight loss intervention, and to determine which clinical factors influence QOL. METHODS: This was a prospective cohort evaluation of QOL, using the 36-Item Short Form (SF-36) Health Survey questionnaire, before and after a therapeutic dietary intervention which resulted in significant reduction in body mass index (BMI), intracranial pressure (ICP), papilloedema, visual acuity, perimetric mean deviation (Humphrey 24–2) and headache (six-item headache impact test (HIT-6) and headache diary). Baseline QOL was compared to an age and gender matched population. The relationship between each clinical outcome and change in QOL was evaluated. RESULTS: At baseline, QOL was significantly lower in IIH compared to an age and gender matched population in most domains, p < 0.001. Therapeutic weight loss led to a significant improvement in 10 out of 11 QOL domains in conjunction with the previously published data demonstrating significant improvement in papilloedema, visual acuity, perimetry and headache (p < 0.001) and large effect size. Despite significant improvement in clinical measures only headache correlated significantly (p < 0.001) with improving QOL domains. CONCLUSIONS: QOL in IIH patients is significantly reduced. It improved with weight loss alongside significant improvement in clinical measures and headache. However, headache was the only clinical outcome that correlated with enhanced QOL. Effective headache management is required to improve QOL in IIH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s10194-015-0521-9) contains supplementary material, which is available to authorized users

Segmentation Error in Spectral Domain Optical Coherence Tomography measures of the retinal nerve fibre layer thickness in idiopathic intracranial hypertension

BACKGROUND: Optical Coherence Tomography (OCT) imaging is being increasingly used in clinical practice for the monitoring of papilloedema. The aim is to characterise the extent and location of the Retinal Nerve Fibre Layer (RNFL) Thickness automated segmentation error (SegE) by manual refinement, in a cohort of Idiopathic Intracranial Hypertension (IIH) patients with papilloedema and compare this to controls. METHODS: Baseline Spectral Domain OCT (SDOCT) scans from patients with IIH, and controls with no retinal or optic nerve pathology, were examined. The internal limiting membrane and RNFL thickness of the most severely affected eye was examined for SegE and re-segmented. Using ImageJ, the total area of the RNFL thickness was calculated pre and post re-segmentation and the percentage change was determined. The distribution of RNFL thickness error was qualitatively assessed. RESULTS: Significantly greater SegE (p = 0.009) was present in RNFL thickness total area, assessed using ImageJ, in IIH patients (n = 46, 5% ± 0-58%) compared to controls (n = 14, 1% ± 0-6%). This was particularly evident in moderate to severe optic disc swelling (n = 23, 10% ± 0-58%, p < 0.001). RNFL thickness was unable to be quantified using SDOCT in patients with severe papilloedema. CONCLUSIONS: SegE remain a concern for clinicians using SDOCT to monitor papilloedema in IIH, particularly in the assessment of eyes with moderate to severe oedema. Systematic assessment and manual refinement of SegE is therefore important to ensure the accuracy in longitudinal monitoring of patients

Topiramate is more effective than acetazolamide at lowering intracranial pressure

BACKGROUND The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH

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

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

Idiopathic intracranial hypertension : expanding our understanding

Idiopathic intracranial hypertension (IIH) affects predominantly overweight women of childbearing age, causing chronically disabling headaches and visual loss. Weight loss remains the most effective management strategy, but innovative treatments and randomized control trials (RCTs) remain few. This paper will review recent IIH research. Pregnancy-related complications, but not losses, are increased in IIH, while symptom severity is not affected. Weight loss of 24% results in normalization of intracranial pressure (ICP) and improvement in papilledema. Prolonged periods of papilledema results in delayed thinning of the ganglion cell layer. Less-invasive telemetry has improved understanding of the positional effects on ICP with rises seen in the supine and lateral decubitus. Exenatide, a GLP-1 agonist, may reduce ICP and improve symptoms. Venous sinus stenting is increasingly popular but its benefits over CSF diversion remains unclear. Early involvement of obstetric care is recommended with pregnancy in IIH. Early intervention is required to avoid chronic papilledema that confers worse visual outcomes. Positional changes may affect ICP readings. The use of novel ICP telemetric devices has significant potential in future disease monitoring. The dual benefits of weight loss and ICP reduction with exenatide have significant potential in IIH management. Surgical RCTs are still required