Clinical Trials Register

Summary
EudraCT Number:	2013-003643-31
Sponsor's Protocol Code Number:	rg_13-022
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-003643-31

A.3

Full title of the trial

Assessing the therapeutic efficacy and safety of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in idiopathic intracranial hypertension (IIH).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of the safety and effectiveness of drug AZD4017 at reducing pressure in the brain, in idiopathic intracranial hypertension.

A.3.2

Name or abbreviated title of the trial where available

Efficacy and safety of 11b-HSD1 inhibitor in IIH

A.4.1

Sponsor's protocol code number

rg_13-022

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Birmingham
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical Research Council
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Birmingham
B.5.2	Functional name of contact point	Sinclair
B.5.3	Address:
B.5.3.1	Street Address	IBR West wing, School of Clinical and Experimental Medicine
B.5.3.2	Town/ city	University of Birmingham
B.5.3.3	Post code	B15 2TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01214143713
B.5.6	E-mail	a.b.sinclair@bham.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AZD4017
D.3.2	Product code	AZD4017
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZD4017 (no INN)
D.3.9.1	CAS number	1024033-43-9
D.3.9.2	Current sponsor code	AZD4017
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Idiopathic Intracranial Hypertension

E.1.1.1

Medical condition in easily understood language

A condition of young, obese women characterised by raised pressure in the brain. This results in visual loss and headaches.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10004277
E.1.2	Term	Benign intracranial hypertension
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate whether 12 weeks of a 11β-hydroxysteroid dehydrogenase inhibitor (AZD4017) is effective and safe for reducing the raised intracranial pressure (pressure of fluid around the brain) observed in patients with idiopathic intracranial hypertension, compared to a placebo ('dummy' drug with no active properties).

E.2.2

Secondary objectives of the trial

To look at the effects of AZD4017 on vision, swelling of the nerve behind the eye (papilloedema), headache and bodily measurements (including weight and fat mass distribution) in patients with idiopathic intracranial hypertension (IIH).

To assess the safety and tolerability of a 12 week course of AZD4017 in patients with IIH.

To establish if the drug AZD4017 can cross the blood brain barrier by looking at levels in the blood and cerebrospinal fluid (CSF; fluid surrounding brain).

To look at the effects of AZD4017 on steroid and sex hormone processing in the urine, blood and CSF in patients with IIH.

To determine the effects of AZD4017 on fat mass distribution (measured by DXA scan).

To examine the changes over time of 11β-HSD1 activity in fat and skin tissue with inhibition from AZD4017.

To examine the changes over time of 11β-HSD1 activity in the blood through prednisone to prednisolone generation curves (11β-HSD1 converts prednisone to prednisolone).

To examine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures.

2. Female patients between 18 and 55 years old

3. Diagnosis of IIH by the updated Modified Dandy criteria with acute (<6 months from Neuro-opthalmology diagnosis), active disease (papilloedema (Frisen grade greater than or equal to 1) and significantly raised intracranial pressure >25cmH2O) and normal brain imaging during previous routine diagnostic work up (evaluated by either magnetic resonance venography or computerised tomography with venography).

4. Patients must be willing to use one form of highly effective, non-hormonal contraception. This would include a vasectomised partner, tubal occlusion or copper containing IUD – all of which should be used in addition to a barrier contraceptive (condom or diaphragm or cervical/vault caps with spermicidal foam/gel/film/suppository) or 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 b-hCG blood test at screening and urine testing at all trial visits (including the final follow up visit 4 weeks after discontinuation of study treatment).

5. Participants are able to continue other medications to treat their IIH e.g. acetazolamide, diuretics but this dose must remain fixed throughout the study. It would be expected that there would be an equal number in each trial.

6. Must be able to understand the consent form and comply with study requirements.

E.4

Principal exclusion criteria

1. Optic nerve sheath fenestration (as distortion of the optic nerve would prevent accurate assessment of their disease state). Patients who have had previous failed CSF shunting will be eligible for enrolment if they fulfil all other enrolment criteria.

2. Abnormal neurological examination (aside from papilloedema and consequent visual loss or VI nerve palsy).

3. Subjects with a secondary cause of raised intracranial pressure will be excluded.

4. Abnormal cerebrospinal fluid contents (except for that compatible with a traumatic LP).

5. Unable to perform a visual field test reliably.

General Exclusion Criteria:

1. Positive hCG or urine dipstick pregnancy test or planning to conceive.

2. Have eGFR calculated by MDRD equation of <60ml/min/1.73m2.

3. Have any endocrine disorder, e.g, thyroid dysfunction (potential participants with PCOS will no be excluded as this is a known associated condition).

4. Suspicion of or known Gilbert's disease.

5. Creatinine kinase >2 x upper limit of normal on 2 consecutive measurements.

6. Liver aminotransferases > 2x Upper limit of normal

7. Alkaline phosphatases > Upper limit of normal

8. Bilirubin (total) > 2 x upper limit of normal

9. Must not have donated blood within 2 months of attending the screening
visit and avoid donating blood within the following 4 months.

10. 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, in the opinion of the investigator.

11. Pregnant or breastfeeding mothers, unless willing to discontinue breastfeeding by the baseline visit.

12. Have uncontrolled systemic hypertension (BP >160 systolic or >90 diastolic), on 3 successive measurements on the morning of the screening visit.

13. Are receiving systemic (including vaginal/rectal) glucocorticoid treatment at the time of the screening visit.

14. Are taking any hormone-based medication, including hormone contraceptives, at the time of screening.

15. Are taking probenicid at the time of the screening visit.

16. 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 once to see if the value returns to within the range but any laboratory abnormality must be resolved prior to the baseline visit.

17. 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 in the study, or influence the results of the subject’s ability to participate in the study. Specifically, a diagnosis of any inflammatory disorder that might reasonably need treatment with glucocorticoids during the course of the study.

18. History or presence of sigificant gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

19. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IP as judged by the investigator.

20. Have been involved in the planning and/or conduct of the study

21. Participation in another interventional study in the prevous 1 month prior to screening

22. Previous randomisation for treatment in the present study.

E.5 End points

E.5.1

Primary end point(s)

Change of intracranial pressure (ICP), as measured by lumbar puncture, from the baseline and after 12 weeks of treatment with 11b-HSD1 inhibitor AZD4017.

E.5.1.1

Timepoint(s) of evaluation of this end point

Measurements of ICP, by lumbar puncture in cmH2O, will take place at baseline (week 0) and at week 12 (around day 90) after 3 months treatment with AZD4017 or placebo.

E.5.2

Secondary end point(s)

The change in reported IIH symptoms (presence or absence of tinnitus, visual loss, diplopia, visual obscurations, and headache).

The 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).

The change in papilloedema (evaluated using, 1) optical coherence tomography and, 2) stereoscopic fundus photographs with Frisen classification (by masked neuro-ophthalmologists) to grade the images).

The changes in headache associated disability through the headache impact test-6 score (HIT 6) and the headache index score (sum of the product of daily severity (1-5), duration in hours divided by frequency over 7 days).

The change in anthropological measures (blood pressure, BMI, waist/hip ratio and DXA scan to assess body composition).

To examine the safety and tolerability profile of AZD4017 in female patients with IIH through adverse event reporting.

Exploratory end points:
The ability of AZD4017 to cross the blood brain barrier through assays of AZD4017 levels in the blood and cerebrospinal fluid (CSF).

The change in changes in daily cortisol (steroid) secretion rates together with markers 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 blood and 24 hour urine collections.

The changes in blood and CSF cortisol, cortisone, oestradiol, progesterone, androstenedione, LH, FSH, dehydroepiandrosterone (DHEA), testosterone, Adrenocorticotropic hormone (ACTH) levels.

The changes in fat mass distribution measured by DXA scanning.

The changes in fat and skin 11β-HSD1 activity through assays and measures of gene expression

The changes in 11β-HSD1 activity through prednisone to prednisolone generation curve.

To examine the temporal changes in fat cell gene expression.

The changes in CSF and matched peripheral blood cells and markers inflammation

E.5.2.1

Timepoint(s) of evaluation of this end point

For changes of the presence / absence of IIH symptoms over time and adverse events, this will determined from week 1 to 12 (0,1,2,3,4,6,8,10 & 12) and changes between week 12 and 16 post-treatment
For the changes in the visual function parameters, papilloedema measurements, headache associated disability scores, and anthropological measurements, a comparison will be made between week 0 and 12 and week 12 to 16 (not DXA).
The prednisolone curve (11b-HSD1 activity) will be compared from week 0 to 12
Urine 24 hour collections (cortisol and metabolites), HPA activities and safety bloods will be assessed at week 0,1,4,8,12 and 16
Pharmacokinetic values in serum will be assessed at week 0, 1 and 12 & CSF at week 0 and 12
Inflammatory cells and markers at week 0 & 12

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Completion of data collection analysis

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1