Trial record 2 of 14 for:    Pseudotumor Cerebri

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University of Birmingham
Sponsor:
Information provided by (Responsible Party):
Dr Alexandra Sinclair, University of Birmingham
ClinicalTrials.gov Identifier:
NCT02017444
First received: December 16, 2013
Last updated: June 26, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Idiopathic Intracranial Hypertension
Drug: AZD4017
Phase 2

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by University of Birmingham:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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


Estimated Enrollment: 30
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)
Arms Assigned Interventions
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
Drug: AZD4017
Other Name: 11b-Hydroxysteroid dehydrogenase type 1 inhibitor

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02017444

Contacts
Contact: Alexandra Sinclair, MbChB PhD MRCP 01214143713 a.b.sinclair@bham.ac.uk
Contact: Keira A Markey, MbChb MNeurosci MRCP 01214143713 k.a.markey@bham.ac.uk

Locations
United Kingdom
University Hospital Birmingham (Queen Elizabeth Hospital) Recruiting
Birmingham, West Midlands, United Kingdom, B15 2TH
Contact: Keira Markey, MbChb MNeurosci    01214143713    k.a.markey@bham.ac.uk   
Sub-Investigator: Keira Markey, MbChb MNeurosci         
Sponsors and Collaborators
University of Birmingham
Investigators
Principal Investigator: Alexandra Sinclair, MbChb MRCP PhD University of Birmingham
  More Information

No publications provided

Responsible Party: Dr Alexandra Sinclair, Chief Investigator, University of Birmingham
ClinicalTrials.gov Identifier: NCT02017444     History of Changes
Other Study ID Numbers: RG_13-022, 2013-003643-31, MR/K015184/1
Study First Received: December 16, 2013
Last Updated: June 26, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Birmingham:
Pseudotumor Cerebri
Benign Intracranial Hypertension
Headaches
Tinnitus
Papilledema
Blindness
Optic Disk
Intracranial Hypertension
Clinical Trial, Phase 2
11beta-Hydroxysteroid Dehydrogenase Type 1
Obesity

Additional relevant MeSH terms:
Hypertension
Intracranial Hypertension
Pseudotumor Cerebri
Brain Diseases
Cardiovascular Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on October 23, 2014