A Trial to Determine the Efficacy and Safety of Presendin in IIH (IIH EVOLVE)

• ClinicalTrials.gov Identifier: NCT05347147
• Recruitment Status: Recruiting
• First Posted: April 26, 2022
• Last Update Posted: November 22, 2022
• Sponsor: Invex Therapeutics Ltd.
• Collaborator: Premier Research Group plc
• Information provided by (Responsible Party): Invex Therapeutics Ltd.

Study Description

Brief Summary:

Idiopathic intracranial hypertension (IIH) has significant associated morbidity and reduced quality of life. There is a significant risk of visual loss and patients also typically suffer with chronic disabling headaches.

This trial has been designed to evaluate the efficacy and safety of a new formulation of exenatide (Presendin) in the reduction of intracranial pressure (ICP) in patients with IIH.

Condition or disease	Intervention/treatment	Phase
Idiopathic Intracranial Hypertension	Drug: Presendin; Drug: Placebo	Phase 3

Detailed Description:

Patients will be provided with training on the self-administration of the trial medication from the site trial co-ordinator.

A 1-week screening period will be followed by a 24-week randomised double-blind treatment period in which patients will be randomised (1:1) to receive a subcutaneous (SC) dose of either Presendin (containing 2 mg of exenatide [active group]) or matching placebo (placebo group), self-administered once weekly.

At the end of the randomised treatment period (Week 24), all patients will have an end-of-treatment clinic visit. Five weeks after the end-of-treatment visit, an end-of-trial safety follow-up telephone visit will be performed.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This will be a placebo-controlled, double-blind, multi-centre clinical trial in approximately 240 randomised patients with IIH.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Investigators and other site personnel, patients, contract research organisation and Sponsor personnel will be blinded regarding the treatment during the randomised period.
• Primary Purpose: Treatment
• Official Title: A Phase III Randomised, Placebo-controlled, Double-blind, Multi-centre, Clinical Trial to Determine the Efficacy and Safety of Presendin in Idiopathic Intracranial Hypertension
• Actual Study Start Date: November 18, 2022
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Presendin; 2.0 mg	Drug: Presendin; Presendin is supplied as 2 parts, one vial consisting of a drug part (white or greyish white powder in a clear vial) and one pre-filled syringe containing the diluent part (colourless liquid). The drug part is suspended in the diluent part solution and administered SC as a suspension.
Placebo Comparator: Placebo	Drug: Placebo; Placebo is supplied as 2 parts (visually identical to the Presendin vial and pre-filled diluent syringe). The drug part will exclude the active pharmaceutical ingredient (exenatide acetate) and the diluent part will be the same as the active treatment diluent. The drug part is suspended in the diluent part solution and administered SC as a suspension.

Outcome Measures

Primary Outcome Measures :

1. Change in ICP from baseline to Week 24 measured by lumbar puncture (LP), where a higher LP value indicates greater ICP [ Time Frame: Baseline to Week 24 ]

Secondary Outcome Measures :

1. Change in Perimetric Mean Deviation (PMD), measured by Humphrey Visual Field (HVF) analysis (24-2 SITA-Standard), where a larger negative result indicates greater visual loss [ Time Frame: Baseline to Week 24 ]
2. Papilloedema by change in retinal nerve fibre layer (RNFL) thickness, with a greater thickness of RNFL indicating greater swelling and greater extent of papilloedema [ Time Frame: Baseline to Week 24 ]
3. Papilloedema by change in optic nerve head size, measured by optical coherence tomography (OCT), where a larger optic nerve head size reflects greater swelling and a greater extent of papilloedema [ Time Frame: Baseline to Week 24 ]
4. The number of monthly headache days (MHD) [ Time Frame: Baseline to Week 24 ]
5. Number of moderate to severe MHD [ Time Frame: Baseline to Week 24 ]
6. Responder rate MHD (defined as a ≥50% reduction in MHD) [ Time Frame: Baseline to Week 24 ]
7. Responder rate moderate to severe MHD (defined as a ≥50% reduction in moderate to severe MHD) [ Time Frame: Baseline to Week 24 ]
8. Headache severity [ Time Frame: Baseline to Week 24 ]
   Headache severity will be assessed by 11-point Numeric Rating Scale (NRS), 0-10 where 0 = no pain and 10 = most severe pain).
9. Use of acute headache analgesic medications (acute headache analgesics in days per month) [ Time Frame: Baseline to Week 24 ]
10. Visual acuity [ Time Frame: Baseline to Week 24 ]
    Corrected visual acuity will be recorded using a Logarithm of the Minimum Angle of Resolution (LogMAR) scoring chart, with a range of -0.3 to 1.00, where a lower score indicates better visual acuity.
11. Number of patients with treatment failure [ Time Frame: Baseline to Week 24 ]
    Treatment failure is defined as the initiation of either medical therapy or a surgical intervention to lower ICP during the study.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥18 years at the time of consent.
2. Diagnosis of new IIH by consensus criteria, including normal structural brain imaging (excluding features of raised ICP and incidentalomas), including either magnetic resonance venography or computed tomographic venography to exclude thrombosis and no evidence of a secondary causes of raised ICP.
3. Newly diagnosed patients with screening commenced no more than 4 weeks after the diagnostic LP.
4. Lumbar puncture opening pressure ≥25 cm cerebrospinal fluid (CSF) at diagnosis.
5. Presence of bilateral papilloedema (Frisén grade ≥1). Verification of papilloedema by the OCT Reading Centre. Where there is uncertainty fundus photography and/or ultrasound scan (B scan) of the optic nerves should be conducted for evaluation by the Independent Adjudication Committee (IAC).
6. Perimetric Mean Deviation defined as between -2 to -7 decibels (dB) in at least one eye. Eyes meeting this criterion will defined as 'study eyes'.
7. Reproducible visual loss present on automated perimetry including no more than 15% false positive responses (reliability confirmed by the Visual Field Reading Centre) in study eyes.
8. Two or more headache days over the 7-day period prior to screening and also the patient must meet this criterion during the 7-day screening period.
9. Females of childbearing potential must have a negative pregnancy test and must agree to use a highly effective birth control method (failure rate less than 1% per year when used consistently and correctly) during the whole trial duration including the last follow-up visit (12 weeks after ceasing drug). Female patients who are lactating must agree to stop breast-feeding OR Female patients of non-childbearing potential (defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal females defined as 12 months of amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulation hormone 25-140 IE/L and oestradiol <200 pmol/L is confirmatory]).
10. Male patients with a female partner of childbearing potential must commit to practice methods of contraception (e.g., condom, vasectomy) and abstain from sperm donation during the trial including the last follow-up visit (12 weeks after ceasing drug). Their partners, if they are women of childbearing potential, must agree to practice contraception and to use a highly effective method of contraception during the trial, including the last follow-up visit (12 weeks after ceasing drug).
11. Able to provide written informed consent.

Exclusion Criteria:

IIH-related exclusion criteria:

1. Presence of venous sinus thrombosis on brain imaging by either magnetic resonance or computerised tomographic venography.
2. Previous IIH surgery including CSF shunt, optic nerve sheath fenestration or dural venous sinus stent or sub-temporal decompression.
3. Previous bariatric surgery within the last 3 months or intention during the trial.
4. Abnormal neurological examination (aside from papilloedema and consequent visual loss or sixth or seventh nerve palsy or palsies).
5. Treatment to lower ICP within 1 week prior to screening visit (e.g., acetazolamide, topiramate [including if used as a migraine preventative], diuretics, glucocorticoids [I.V., injectable steroids or oral (including dexamethasone and prednisolone)]). Nasal, inhaled, or topical steroids are allowed.

6. Use of any drugs known to cause intracranial hypertension, including exposure to fluoroquinolones, lithium, vitamin A, or tetracyclines within 2 months prior to diagnostic LP.

   Vision-related exclusion criteria:

7. Any disease other than refractive error that causes visual loss in the study eyes. Where there is uncertainty this would be determined by the IAC.
8. Refractive error worse than +/- 6.00 sphere or worse than +/- 3.00 cylinder in study eyes. In addition, participants with myopia of worse than -6.00 D sphere but less than or equal to -8.00 D sphere are eligible if the subject wears a contact lens for all perimetry examinations with the appropriate correction.

9. Inability to perform a reliable visual field examination as deemed by the Visual Field Reading Centre in the study eyes. Where there is uncertainty this would be evaluated by the IAC.

   Headache-related exclusion criteria:

10. Does not complete ≥6 days of electronic/paper trial diary during the 7-day screening period.

    Other exclusion criteria:

11. Untreated previously diagnosed obstructive sleep apnoea with historically recorded apnoea-hypopnea index greater than 15.
12. Glucagon like peptide-1 receptor agonist within last 4 weeks prior to screening.
13. COVID-19 vaccine within 2 weeks prior to screening.
14. Allergy/known hypersensitivity to the active substance and/or excipients of the investigational product.
15. Has known contraindications to glucagon like peptide-1 (GLP-1) receptor agonists (e.g., ketoacidosis, severe gastrointestinal disease, pancreatitis, renal impairment) which may affect the safety of the patient.
16. Using any glucose-lowering medication.
17. Currently taking warfarin.
18. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2x the upper limit of normal (ULN), total bilirubin ≥1.5x ULN, or alkaline phosphatase (ALP) ≥1.5 ULN at screening. Note - patients with elevated total bilirubin are not excluded if they meet criteria for Gilbert's syndrome, including: bilirubin is predominantly indirect (with normal direct bilirubin level); and ALT, AST and ALP ≤1x ULN).
19. Kidney disease (as defined by serum cystatin C-based estimated glomerular filtration rate <55 mL/min/1.73 m², calculated at investigator site).
20. Any of the following abnormalities in clinical laboratory tests at screening, as assessed by the central laboratory and confirmed by a single repeat, if deemed necessary: Haemoglobin <10 g/dL (<100 g/L); Platelet count <75 x 10⁹/L (<75,000/mm³).
21. Using recreational or illicit drugs at the time of signing the informed consent, or recent history (within the last year) of drug or alcohol abuse or dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria, that in the opinion of the investigator puts the patient at risk.
22. Is unable to self-administer the trial medication (or unable to administer trial medication with support) after receiving training during the screening period.
23. History of any clinically significant disease or disorder that, in the opinion of the investigator, may either put the patient at risk because of participation in the trial or influence the results or the patient's ability to participate in the trial.
24. Any contraindication to lumbar puncture procedure in the opinion of the investigator.
25. Has participated in any other interventional trial within 1 month prior to the screening visit.
26. Is pregnant or breastfeeding.

Note: Use of headache preventative medication is allowed at enrolment (except for topiramate). Changes to headache preventative medication during the trial should be made in consultation with the IAC.

Contacts and Locations

Contacts

Contact: Alexandra J Sinclair, MBChB, PhD; 44 7598 618309; IIHEVOLVE@invextherapeutics.com

Locations

Australia, South Australia

Vision SA; Recruiting

Kent Town, South Australia, Australia, 5067

Contact: Celia Chen +61 8 83634492 celiachen@visionsaeye.com.au

Principal Investigator: Celia Chen

Sponsors and Collaborators

Invex Therapeutics Ltd.

Premier Research Group plc

More Information

• Responsible Party: Invex Therapeutics Ltd.
• ClinicalTrials.gov Identifier: NCT05347147
• Other Study ID Numbers: INVEX-CLIN-IIH-301
• First Posted: April 26, 2022
• Last Update Posted: November 22, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Invex Therapeutics Ltd.:

Presendin

Additional relevant MeSH terms:

Intracranial Hypertension; Pseudotumor Cerebri; Hypertension; Vascular Diseases; Cardiovascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases