Safety and Effectiveness of 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) to Treat Idiopathic Intracranial Hypertension. (IIH:DT)
Assessing the safety and effectiveness of a 11-βhydroxysteroid dehydrogenase type 1 inhibitor (AZD4017), in a placebo controlled trial, in acute idiopathic intracranial hypertension (IIH) IIH is a condition of young, overweight women with characteristic raised intracranial pressure (pressure around the brain) leading to papilloedema (swelling of the nerve supplying the eye), visual loss and headaches. Medical literature (Cochrane review) demonstrates there is little evidence for the treatments used for IIH. Weight control appears the most effective method of improving symptoms but weight loss is difficult to maintain. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme which regulates local steroid levels and our previous research suggests it may influence the production of brain fluid(cerebrospinal fluid or CSF). 11β-HSD1 levels fall with weight loss and this is associated with with decreased intracranial pressure.
Our primary outcome is to determine whether AZD4017, an inhibitor of 11β-HSD1, will reduce the pressure in the brain and as a consequence improve IIH. Patients are eligible to enter the study if they are between 18-55 years old with acute (<6 months) IIH, signs of active disease (papilloedema and raised CSF pressure (>25 cmH20)), no other major illnesses and have no plans for pregnancy during the study period.
This is an MRC funded single centre, phase II, double-blinded, randomised control drug trial. It will be conducted at the University Hospital Birmingham and the University of Birmingham will act as Sponsor. Eligible participants will be randomly assigned to AZD4017 or a placebo ('dummy' with no active drug) for 3 months with a follow up a month later. Investigations during the study will include bloods, urine samples, pregnancy tests, lumbar punctures, DXA scans and small fat/skin biopsies. Participants will benefit from increased monitoring and a potential improvement in their condition.
We hypothesise that specific inhibition of 11β-HSD1 will decrease intracranial pressure and consequently treat patients with IIH, thus opening a new and entirely novel therapeutic avenue.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Lowering Intracranial Pressure in Idiopathic Intracranial Hypertension: Assessing the Therapeutic Efficacy and Safety of an 11β-hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017). Phase II Study.|
- Intracranial Pressure [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]ICP measured by lumbar puncture in mmH2O as the change from week 0 and week 12 of treatment
- IIH Symptoms [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the temporal change in IIH symptoms (presence or absence of tinnitus, visual loss, diplopia, visual obscurations, and headache).
- Visual function [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the temporal change in IIH visual function in both eyes (measured by LogMAR (log of the minimum angle of resolution) chart to assess visual acuity, automated perimetry (Humphrey 24-2 central threshold) to measure the visual field mean deviation and a Pelli-Robson chart to evaluate contrast sensitivity) between the baseline to week 12 and 4 weeks following treatment (follow-up visit).
- Papilloedema [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the temporal change in papilloedema (evaluated using, 1) spectral optical coherence tomography (Stratus OCT V4.0.1, Carl Zeiss, Meditec, Welwyn Garden City) and, 2) stereoscopic fundus photographs with Frisen classification (by masked neuro-ophthalmologists) to grade the images) between the baseline to week 12 and to week 16 (follow-up visit).
- Headache-associated disability [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the changes in headache associated disability through the headache impact test-6 score (HIT 6) and the headache index score (sum of product of daily severity (1-5) and duration (in hours) divided by frequency over 7 days) between the baseline and 12 weeks with a further analysis between week 12 and 16.
- Anthropological measurements [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the temporal change in anthropological measures (blood pressure, BMI, waist/hip ratio and DXA scan to assess body composition) over 12 weeks of treatment.
- Adverse events [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]To examine the safety and tolerability profile of AZD4017 in female patients with IIH through adverse event reporting and safety bloods.
- AZD4017 assay levels in blood and CSF [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the ability of AZD4017 to cross the blood brain barrier through assay of AZD4017 levels in the serum and cerebrospinal fluid (CSF) between baseline and week 12.
- Glucocorticoid metabolites [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the temporal change in changes in daily cortisol secretion rates together with indices of 11β-HSD1 (tetrahydrocortisol (THF) + allo-THF/ tetrahydrocortisone (THE) ratio), 11β-HSD2 (urinary free cortisol/ urinary free cortisone - UFF/UFE ratio) and hypothalamic pituitary adrenal axis (HPA) (total glucocorticoid metabolites) activities through serum and 24 hour urine collections (from baseline to 1,4, 8, 12 and 16 weeks).
- HPA-associated hormone levels [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]To examine the temporal changes in serum and CSF cortisol, cortisone, oestradiol, progesterone, androstenedione, LH, FSH, dehydroepiandrosterone (DHEA), testosterone, Adrenocorticotropic hormone (ACTH) between the baseline, week 12 and week 16.
- Fat mass distribution [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the temporal changes in fat mass distribution measured by DXA scanning between baseline and week 12.
- Fat / Skin 11β-HSD1 activity [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the temporal changes in adipose tissue (preadipocytes) and skin (dermal fibroblasts) 11β-HSD1 activity between baseline and week 12.
- Systemic 11β-HSD1 activity (1st pass metabolism) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the temporal changes in 11β-HSD1 activity through prednisone to prednisolone generation curves between baseline and week 12.
- Adipocyte gene expression [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To examine the temporal changes in adipocyte gene expression between baseline and week 12.
- CSF inflammatory markers [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]To examine the temporal changes in CSF and matched peripheral blood lymphocytes expression (DNA, RNA, protein) of molecules associated with inflammation
|Study Start Date:||January 2014|
|Estimated Study Completion Date:||January 2016|
|Estimated Primary Completion Date:||January 2016 (Final data collection date for primary outcome measure)|
Placebo Comparator: Placebo
Matched placebo tablet B.D for 12 weeks
Active Comparator: AZD4017 (11b-HSD1 inhibitor)
AZD4017 400mg tablet B.D. for 12 weeks
Other Name: 11b-Hydroxysteroid dehydrogenase type 1 inhibitor
Please refer to this study by its ClinicalTrials.gov identifier: NCT02017444
|Contact: Alexandra Sinclair, MbChB PhD MRCPfirstname.lastname@example.org|
|Contact: Keira A Markey, MbChb MNeurosci MRCPemail@example.com|
|University Hospital Birmingham (Queen Elizabeth Hospital)||Recruiting|
|Birmingham, West Midlands, United Kingdom, B15 2TH|
|Contact: Keira Markey, MbChb MNeurosci 01214143713 firstname.lastname@example.org|
|Sub-Investigator: Keira Markey, MbChb MNeurosci|
|Principal Investigator:||Alexandra Sinclair, MbChb MRCP PhD||University of Birmingham|