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

NCT02017444 | Completed Phase 2 Results DMC

• 3 other identifiers: RG_13-0222013-003643-31MR/K015184/1
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Idiopathic Intracranial Hypertension

Keywords

Pseudotumor Cerebri; Benign Intracranial Hypertension; Headaches; Tinnitus; Papilledema; Blindness; Optic Disk; Intracranial Hypertension; Clinical Trial, Phase 2; 11beta-Hydroxysteroid Dehydrogenase Type 1; Obesity

Outcome Measures

Primary Outcomes (1)

• Intracranial Pressure

  ICP measured by lumbar puncture in cmCSF as the change from week 0 and week 12 of treatment, measured at baseline and week 12

  12 weeks

Secondary Outcomes (14)

• Tinnitus

  12 weeks

• Anthropometric Measurements (BMI)

  12 weeks

• Visual Loss

  12 weeks

• Diplopia

  12 weeks

• Visual Obscuration

  12 weeks

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Matched placebo tablet B.D for 12 weeks

Other: Placebo

AZD4017 (11b-HSD1 inhibitor)

ACTIVE COMPARATOR

AZD4017 400mg tablet B.D. for 12 weeks

Drug: AZD4017

Interventions

AZD4017 DRUG

Also known as: 11b-Hydroxysteroid dehydrogenase type 1 inhibitor

AZD4017 (11b-HSD1 inhibitor)

Placebo OTHER

Matched placebo (matched to AZD4017 arm)

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• acute (\<6 months),
• active disease (papilloedema (Frisen grade greater than or equal to 1),
• significantly raised ICP \> 25cmH2O)
• 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:
• a vasectomised partner (sole partner) or tubal occlusion or
• 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)
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Birmingham: lead

Study Sites (1)

University Hospital Birmingham (Queen Elizabeth Hospital)

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Related Publications (4)

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Pseudotumor Cerebri; Headache; Tinnitus; Papilledema; Blindness; Intracranial Hypertension; Obesity

Interventions

2-(1-(5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl)-3-piperidyl)acetic acid

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Vision Disorders; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight

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 Point of Contact

• Title: Professor Alex Sinclair
• Organization: University of Birmingham

a.b.sinclair@bham.ac.uk

+44 121 415 9125

Study Officials

• Alexandra Sinclair, MbChb PhD

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Investigator

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: December 20, 2013
• Study Start: April 25, 2014
• Primary Completion: December 19, 2016
• Study Completion: December 19, 2016
• Last Updated: October 27, 2021
• Results First Posted: October 27, 2021

Record last verified: 2021-09

Locations

GB (1)