Assessing the Efficacy and Safety of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) in the Idiopathic Intracranial Hypertension Drug Trial, IIH:DT: Clinical Methods and Design for a Phase II Randomized Controlled Trial

Abstract

BackgroundIdiopathic 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.ObjectivesThe 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.MethodsIIH: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.ResultsAll participants were recruited between April 2014 and August 2016.ConclusionsIIH: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 RegistrationClinicaltrials.gov NCT02017444; https://clinicaltrials.gov/ct2/show/NCT02017444 (Archived by WebCite at http://www.webcitation.org/6tVHesN6s)

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

“…All patients provided written informed consent in accordance with the declaration of Helsinki. Detailed clinical trial methodology has been published ( Markey et al , 2017 ).…”

“…Women (18–55 years) were eligible if they had a clinical diagnosis of active IIH meeting the updated, modified Dandy criteria (ICP > 25 cmH 2 O and active papilledema) and normal brain imaging (including magnetic resonance venography or CT with venography) at recruitment (for detailed eligibility criteria see Supplementary Table 1 ; Friedman et al , 2013 ; Markey et al , 2017 ).…”

What are the research priorities for idiopathic intracranial hypertension? A priority setting partnership between patients and healthcare professionals

“…The 2015 Cochrane review concluded that there is a lack of evidence to guide pharmacological treatment 2. There are a few published randomised clinical trials3 4 and a small number of ongoing trials 5 6. Research is infrequent due to the rarity of the IIH7 8 and the lack of understanding of the underlying pathology 9…”

Emerging themes in idiopathic intracranial hypertension

“…Improved treatment options are an unmet clinical need in this disease area [10]. Recent mechanistic studies have identified therapeutic targets such as glucagon-like peptide-1 (GLP-1) [11] and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which have formed the basis of IIH randomised clinical trials [12][13][14]. The aim of this review is to inform the reader of emerging issues and present new key highlights in the therapeutic development for IIH.…”