Safety and Effectiveness of 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) to Treat Idiopathic Intracranial Hypertension.

• AZD4017 (Drug), also known as 11b-Hydroxysteroid dehydrogenase type 1 inhibitor
• Placebo (Other): Matched placebo (matched to AZD4017 arm)

Primary outcomes

• Intracranial Pressure [12 weeks]: ICP measured by lumbar puncture in cmCSF as the change from week 0 and week 12 of treatment, measured at baseline and week 12

Secondary outcomes

• Tinnitus [12 weeks]: The temporal change in IIH symptoms (presence or absence of tinnitus), measured at baseline and week 12
• Anthropometric Measurements (BMI) [12 weeks]: The temporal change in Body Mass Index (in kg/m\^2) over 12 weeks of treatment, measured at baseline and week 12
• Visual Loss [12 weeks]: The temporal change in IIH symptoms (presence or absence of visual loss, measured at baseline and week 12
• Diplopia [12 weeks]: The temporal change in IIH symptoms (presence or absence of diplopia, measured at baseline and week 12
• Visual Obscuration [12 weeks]: The temporal change in IIH symptoms (presence or absence of visual obscuration, measured at baseline and week 12
• Headache [12 weeks]: The temporal change in IIH symptoms (presence or absence of headache, measured at baseline and week 12
• Visual Acuity [12 weeks]: 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, between the baseline to week 12, measured at baseline and week 12
• Papilloedema [12 weeks]: The temporal change in papilloedema (evaluated at the end of trial follow up using stereoscopic fundus photographs by masked neuro-ophthalmologists to grade the images according to Frisen classification) measured at baseline and week 12. There are 6 grades, 0-5, 5 being the worst. The modified Frisén scale for grading papilledema using fundus photography is as follows: Grade 1 - C-Shaped halo with a temporal gap Grade 2 - The halo becomes circumferential Grade 3 - Loss of major vessels as they leave the disc Grade 4 - Loss of major vessels on the disc Grade 5 - Criteria of Grade IV + partial or total obscuration of all vessels on the disc For further details see e.g. Scott, C.J., et al., Diagnosis and grading of papilledema in patients with raised intracranial pressure using optical coherence tomography vs clinical expert assessment using a clinical staging scale. Arch. Ophthalmol, 2010. 128(6): p. 705-711.
• Headache-associated Disability [12 weeks]: The change in headache associated disability through the headache impact test-6 score (HIT 6), measured at baseline and week 12. This is scored 11-66 with higher scores indicating worse headache.
• Adverse Events [16 weeks]: The safety and tolerability profile of AZD4017 in female patients with IIH through adverse event reporting and safety bloods.
• Serious Adverse Events [16 weeks]: The safety and tolerability profile of AZD4017 in female patients with IIH through adverse event reporting and safety bloods.
• OCT Total Average Retinal Nerve Fibre Layer Thickness (μm) [12 weeks]: The temporal change in OCT Total average retinal nerve fibre layer thickness (μm), measured at baseline and week 12
• Visual Field Mean Deviation [12 weeks]: The temporal change in IIH visual function in both eyes using automated perimetry (Humphrey 24-2 central threshold) to measure the visual field mean deviation between the baseline to week 12
• Log Contrast Sensitivity [12 weeks]: The temporal change in IIH visual function in both eyes using a Pelli-Robson chart to evaluate log contrast sensitivity between the baseline to week 12

Sex: Female, ages: 18 Years to 55 Years

Inclusion Criteria:

* Provision of informed consent prior to any study specific procedures.
* Female patients between 18 and 55 years
* Diagnosis of IIH by the Modified Dandy criteria1 with:

  1. acute (<6 months),
  2. active disease (papilloedema (Frisen grade greater than or equal to 1),
  3. significantly raised ICP > 25cmH2O)
  4. normal brain imaging during previous routine diagnostic work up (evaluated by either magnetic resonance venography or computerised tomography with venography).
* Patients must be willing to use one form of highly effective non-hormonal contraception. This would include:

  1. a vasectomised partner (sole partner) or tubal occlusion or
  2. copper containing IUD - all of which should be used in addition to a diaphragm or cervical/vault caps with barrier contraceptive (condom or spermicidal foam/gel/film/suppository)
  3. true abstinence (when this is in line with the preferred and usual lifestyle of the subject. Women should have been stable on their chosen method of birth control for a minimum of 2 months before entering the trial. Patients must agree to undergo a β-hCG pregnancy test and urine dipstick test at screening and urine dipstick testing at all trial visits (including the final follow up visit 4 weeks after discontinuation of study treatment). Note: the use of contraception and pregnancy testing would not be required if the screening LH/FSH levels demonstrate the patient is post-menopausal.
* Participants are able to continue other medications to treat their IIH e.g. acetazolamide, diuretics but this dose must remain fixed throughout the study.
* Patients who take aspirin therapy will be asked to discontinue aspirin 3 days prior to fat and skin biopsy if clinically safe to do so.
* Placebo treatment for the duration of the study must not be considered detrimental to the patient.
* Must be able to understand the consent form and comply with study requirements.

Exclusion Criteria:

* Optic nerve sheath fenestration.
* Patients who undergo CSF shunt insertion (which is not elective or pre- planned) during the study, as a result of deterioration will be withdrawn from the study.
* Abnormal neurological examination (aside from papilloedema and consequent visual loss or VI nerve palsy).
* Subjects with a secondary cause of raised intracranial pressure will be excluded (venous thrombosis, anaemia, drug causes (lithium, vitamin A, tetracycline or others deems responsible for the condition).
* Abnormal CSF contents (except for that compatible with a traumatic LP).
* Unable to perform a visual field reliably.

General Exclusion Criteria:

* Positive hCG or urine dipstick pregnancy test or planning to conceive in the 4 study months.
* Have eGFR calculated by MDRD equation of <60ml/min/1.73m2.
* Have any endocrine disorder, e.g. thyroid dysfunction. This excludes PCOS where there is a known association to IIH.
* Suspicion of or known Gilbert's disease.
* CK >2 x ULN on 2 consecutive measurements.
* ALT and/or AST >2 x ULN.
* ALP > ULN.
* Bilirubin (total) > 2 x ULN.
* Must not have donated blood within 2 months of screening and avoid further donations for 4 months following the study.
* Patient is, at the time of signing the informed consent, a user of recreational or illicit drugs (including marijuana) or has had a recent history (within the last year) of drug or alcohol abuse or dependence.
* Pregnant or breastfeeding mothers, unless willing to discontinue breastfeeding by the baseline visit.
* Have uncontrolled systemic hypertension (BP >160/90), on 3 successive measurements on the morning of the screening visit.
* Are receiving systemic (including vaginal/rectal) glucocorticoid treatment at the time of the screening visit. Note: Topical and inhaled are acceptable
* Are taking any hormone-based medication, including hormone contraceptives, at the time of screening.
* Are taking probenecid at the time of the screening visit.
* Have any screening laboratory abnormality that, in the investigator's judgement, is considered to be clinically significant or any screening laboratory value which is outside the Sponsor specified ranges at screening; testing may be repeated but must be resolved prior to the baseline visit.
* History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation or will influence the results .
* History or presence of significant gastrointestinal, hepatic , or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IP as judged by the investigator.
* Have been involved in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
* Have participated in any other interventional study within 1 month prior to the screening visit. Participation in the IIH National database or other observational studies will not prevent enrolment to this study.
* Previous randomisation for treatment in the present study

Participant flow

Outcome results

• Intracranial Pressure (Primary), Mean, cmCSF: Placebo -0.3 +/- 5.9; AZD4017 (11b-HSD1 Inhibitor) -4.3 +/- 5.7
• Tinnitus (Secondary), Count of participants, Participants: Placebo 7; AZD4017 (11b-HSD1 Inhibitor) 9
• Anthropometric Measurements (BMI) (Secondary), Mean, kg/m^2: Placebo 37.4 +/- 8.4; AZD4017 (11b-HSD1 Inhibitor) 37.5 +/- 6.9
• Visual Loss (Secondary), Count of participants, Participants: Placebo 7; AZD4017 (11b-HSD1 Inhibitor) 6
• Diplopia (Secondary), Count of participants, Participants: Placebo 1; AZD4017 (11b-HSD1 Inhibitor) 2
• Visual Obscuration (Secondary), Count of participants, Participants: Placebo 2; AZD4017 (11b-HSD1 Inhibitor) 2
• Headache (Secondary), Count of participants, Participants: Placebo 10; AZD4017 (11b-HSD1 Inhibitor) 13
• Visual Acuity (Secondary), Mean, LogMAR (log of the minimum angle of reso: Placebo 0.13 +/- 0.22; AZD4017 (11b-HSD1 Inhibitor) 0.08 +/- 0.23
• Papilloedema (Secondary), Count of participants, Participants: Placebo 0; AZD4017 (11b-HSD1 Inhibitor) 0
• Headache-associated Disability (Secondary), Mean, Score on HIT-6 scale: Placebo 59.8 +/- 7.9; AZD4017 (11b-HSD1 Inhibitor) 60.1 +/- 11.6
• Adverse Events (Secondary), Number, AEs related to intervention: Placebo 0; AZD4017 (11b-HSD1 Inhibitor) 9
• Serious Adverse Events (Secondary), Number, Serious adverse events: Placebo 1; AZD4017 (11b-HSD1 Inhibitor) 0
• OCT Total Average Retinal Nerve Fibre Layer Thickness (μm) (Secondary), Mean, μm: Placebo 158.4 +/- 83; AZD4017 (11b-HSD1 Inhibitor) 152 +/- 68.7
• Visual Field Mean Deviation (Secondary), Mean, Visual field mean deviation: Placebo -3.4 +/- 6.8; AZD4017 (11b-HSD1 Inhibitor) -6.1 +/- 5.4
• Log Contrast Sensitivity (Secondary), Mean, Log contrast senstivity: Placebo 1.63 +/- 0.16; AZD4017 (11b-HSD1 Inhibitor) 1.63 +/- 0.22

Adverse events

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A duration of 12 weeks was chosen for the evaluation of safety and tolerability, being the longest duration of dosing to date with AZD4017. This may not have been enough for meaningful evaluation of clinical outcomes. The sample size is small, which may have reduced power and limited meaningful evaluation of clinical measures: the trial was not designed to establish significant changes in the secondary clinical outcome measures.

• Results publication: Gomez C, Alimajstorovic Z, Othonos N, Winter DV, White S, Lavery GG, Tomlinson JW, Sinclair AJ, Odermatt A. Identification of a human blood biomarker of pharmacological 11beta-hydroxysteroid dehydrogenase 1 inhibition. Br J Pharmacol. 2024 Mar;181(5):698-711. doi: 10.1111/bph.16251. Epub 2023 Oct 19. PMID 37740611
• Results publication: Grech O, Seneviratne SY, Alimajstorovic Z, Yiangou A, Mitchell JL, Smith TB, Mollan SP, Lavery GG, Ludwig C, Sinclair AJ. Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache. Neurology. 2022 Oct 17;99(16):e1702-e1714. doi: 10.1212/WNL.0000000000201007. PMID 36240084
• Results publication: Hardy RS, Botfield H, Markey K, Mitchell JL, Alimajstorovic Z, Westgate CSJ, Sagmeister M, Fairclough RJ, Ottridge RS, Yiangou A, Storbeck KH, Taylor AE, Gilligan LC, Arlt W, Stewart PM, Tomlinson JW, Mollan SP, Lavery GG, Sinclair AJ. 11betaHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension. J Clin Endocrinol Metab. 2021 Jan 1;106(1):174-187. doi: 10.1210/clinem/dgaa766. PMID 33098644
• Results publication: Markey KA, Ottridge R, Mitchell JL, Rick C, Woolley R, Ives N, Nightingale P, Sinclair AJ. Assessing the Efficacy and Safety of an 11beta-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. JMIR Res Protoc. 2017 Sep 18;6(9):e181. doi: 10.2196/resprot.7806. PMID 28923789

• Alexandra Sinclair, MbChb PhD, Principal investigator, University of Birmingham