| 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 | | intracranial hypertension with unknown cause | |
| 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 | 23.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10078904 | | E.1.2 | Term | Idiopathic 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 | To determine the efficacy of Presendin administered subcutaneously once weekly for 24 weeks to patients with IIH, as determined by change in ICP, as measured by LP at baseline and at 24 weeks.
The baseline LP is the diagnostic LP.
| |
| E.2.2 | Secondary objectives of the trial | To determine the effect of Presendin on change in:
Perimetric Mean Deviation as measured by Humphrey Visual Field analysis (24-2 SITA-Standard)
• Papilloedema by change in optical coherence tomography (retinal nerve fibre layer (RNFL) thickness and optic nerve head size)
• Monthly headache days (MHD)
• Moderate to severe monthly headache days
• Headache responder rate (≥50% reduction in monthly headache days)
• Headache responder rate (≥50% reduction in moderate to severe monthly headache days)
• Headache severity
• Monthly use of acute headache analgesic medications
• Visual acuity
• Treatment failure
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 intracranial pressure and incidentalomas), including either magnetic resonance venography or computed tomographic venography to exclude thrombosis and no evidence of a secondary causes of raised intracranial pressure
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 (PMD) defined as between -2 to -7 decibels (dB) in at least one eye. Eyes meeting this criteria will be 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 (FSH) 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
Note: This would restrict the ability of vulnerable patients, such as inmates of psychiatric wards, prison or state institutions, with commitment to an institution or a patient who is detained or committed to an institution by a law court or by legal authorities to be included on the grounds that informed consent could not be assumed. | |
| E.4 | Principal 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
7.Any disease other than refractive error that causes visual loss in the study eyes. Where there is uncertainly this would be determined by the Independent Adjudication Committee [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 uncertainly this would be evaluated by the Independent Adjudication Committee [IAC]
10. Does not complete ≥6 days of electronic/paper trial diary during the 7-day screening period
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. History of drug-induced immune-mediated thrombocytopenia from exenatide products
17. Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2
18. Using any glucose-lowering medication
19. Currently taking warfarin
20. 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)
21. Kidney disease (as defined by serum cystatin C-based estimated glomerular filtration rate [eGFR] <55 mL/min/1.73 m2, calculated at investigator site)
22. 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: Hemoglobin <10 g/dL (<100 g/L); Platelet count <75 x 109/L (<75,000/mm3)
23. 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 DSM-5 criteria, that in the opinion of the investigator puts the patient at risk
24. Is unable to self-administer the trial medication (or unable to administer trial
medication with support) after receiving training during the Screening period
25. 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
26. Any contraindication to lumbar puncture procedure in the opinion of the investigator
27. Has participated in any other interventional trial within 1 month prior to the screening visit.
28. Is pregnant or breastfeeding | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Change in ICP from baseline to Week 24 measured by LP.
The baseline LP is the diagnostic LP.
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | • Perimetric Mean Deviation
• Retinal nerve fibre layer (RNFL) thickness
• Optic nerve head size
• The number of monthly headache days (MHD). Monthly headache days will include all headache days, defined as those with an onset, continuation or recurrence, any severity or phenotype of headache, lasting at least 30 minutes or which require acute headache analgesia
• Number of monthly moderate to severe headache days. A moderate/severe headache day will be defined as a day with moderate or severe pain that lasts at least 4 hours or that requires acute headache analgesic medications
• Responder rate monthly headache days (defined as a ≥50% reduction)
• Responder rate moderate to severe monthly headache days (defined as a ≥50% reduction)
• Headache severity (assessed by 11-point Numeric Rating Scale [NRS], 0-10 where 0 = no pain and 10 = most severe pain)
• Use of acute headache analgesic medications (acute headache analgesics in days per month)
• Visual acuity, as measured by logarithm of the minimum angle or resolution (LogMAR) units
• Treatment failure, defined as initiation of either medical therapy or a surgical intervention to lower ICP | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | Refer to Trial assessments in protocol. Table 1 | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Israel | | New Zealand | | United States | | France | | Germany | | United Kingdom | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
