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

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.

• Presendin (Drug): 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 (Drug): 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.

Primary outcomes

• Change in ICP From Baseline to Week 24 Measured by Lumbar Puncture (LP), Where a Higher LP Value Indicates Greater ICP [Baseline to Week 24]: ICP was measured by LP (opening pressure) using an LP manometer; Baseline and Week 24 ICP values (measured in cm CSF) are presented for each subject. A standard operating procedure was followed by all study sites for all study-related ICP measurements by LP.

Secondary outcomes

• 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 [Baseline to Week 24]
• Papilloedema by Change in Retinal Nerve Fibre Layer (RNFL) Thickness, With a Greater Thickness of RNFL Indicating Greater Swelling and Greater Extent of Papilloedema [Baseline to Week 24]
• Papilloedema by Percent 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 [Baseline to Week 24]
• The Number of Monthly Headache Days (MHD) [Baseline to Week 24]: Monthly headache days (according to daily headache diary) = number of days recorded in a 28-day window where data were collected on >7 days and where ≥1 headache on a day met the following criteria: * Onset, continuation, or recurrence of headache * Any severity or phenotype of headache * Lasts at least 30 minutes Baseline headache frequency was calculated over the 7 days prior to the randomization visit; ≥5 days of headache data were needed to obtain a valid baseline value. The number of headache days recorded for a period were linearly scaled by the total number of days of data collected in the period for each subject to give the MHD during the baseline period (linearly scaled to a maximum of 28 days) and the last 28-day period during which data were collected on >7 days for each subject prior to study completion or discontinuation. Period 1 = Weeks 1-4 Period 2 = Weeks 5-8 Period 3 = Weeks 9-12 Period 4 = Weeks 13-16 Period 5 = Weeks 17-20 Period 6 = Weeks 21-24
• Number of Moderate to Severe MHD [Baseline to Week 24]: Moderate to severe (m-s) MHD (according to daily headache diary) = number of days recorded in a 28-day window where data were collected on >7 days and where ≥1 headache on a day met the following criteria: * Severity was of moderate or severe pain and lasted at least 4 hours or, * Required acute headache analgesics Baseline m-s headache frequency was calculated over the 7 days prior to the randomization visit; ≥5 days of headache data were needed to obtain a valid baseline value. The number of m-s headache days recorded for a period were linearly scaled by the total number of days of data collected in the period for each subject to give the m-s MHD during the baseline period (linearly scaled to a max 28 days) and the last 28-day period during which data were collected on >7 days for each subject prior to study completion or discontinuation. Period 1 = Weeks 1-4 Period 2 = Weeks 5-8 Period 3 = Weeks 9-12 Period 4 = Weeks 13-16 Period 5 = Weeks 17-20 Period 6 = Weeks 21-24
• Number of MHD Responders (Defined as a ≥50% Reduction in MHD) [Baseline to Week 24]: A subject was considered a responder if they had at least a 50% reduction in MHD from baseline to Week 24. Subjects who dropped out prior to Week 24 were considered non-responders.
• Number of Moderate to Severe MHD Responders (Defined as a ≥50% Reduction in Moderate to Severe MHD) [Baseline to Week 24]: A subject was considered a responder if they had at least a 50% reduction in moderate to severe MHD from baseline to Week 24. Subjects who dropped out prior to Week 24 were considered non-responders.
• Headache Severity [Baseline to Week 24]: Headache severity was assessed by a 10-point Numeric Rating Scale (NRS), 0-10 where 0 = no pain and 10 = most severe pain. Severity of headaches was assessed on days where a headache occurred. Headache free days were not counted. Baseline headache severity was calculated over the 7 days prior to the randomization visit; at least 5 of 7 days of headache severity data had to be recorded by the subject to obtain a valid baseline value. * 28-day period 1 = Weeks 1-4 * 28-day period 2 = Weeks 5-8 * 28-day period 3 = Weeks 9-12 * 28-day period 4 = Weeks 13-16 * 28-day period 5 = Weeks 17-20 * 28-day period 6 = Weeks 21-24
• Use of Acute Headache Analgesic Medications (Acute Headache Analgesics in Days Per Month) [Baseline to Week 24]: Number of days recorded in a 28-day window, where at least one dose of an acute headache analgesic was recorded. The baseline acute headache analgesic use was calculated over the 7 days prior to the randomization visit; at least 5 of 7 days had to be recorded by the subject to obtain a valid baseline value. The number of acute headache analgesic use days was linearly scaled for each subject to give the number of acute headache analgesic use days during the baseline period and the last 28-day period during which headache data were collected on more than 7 days for each subject prior to study completion or discontinuation. * 28-day period 1 = Weeks 1-4 * 28-day period 2 = Weeks 5-8 * 28-day period 3 = Weeks 9-12 * 28-day period 4 = Weeks 13-16 * 28-day period 5 = Weeks 17-20 * 28-day period 6 = Weeks 21-24
• Visual Acuity [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.
• Number of Patients With Treatment Failure [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.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Change in ICP From Baseline to Week 24 Measured by Lumbar Puncture (LP), Where a Higher LP Value Indicates Greater ICP (Primary), Number, cm CSF: Presendin 25; Placebo
• 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 (Secondary), Number, dB: Presendin -5.89; Placebo
• Papilloedema by Change in Retinal Nerve Fibre Layer (RNFL) Thickness, With a Greater Thickness of RNFL Indicating Greater Swelling and Greater Extent of Papilloedema (Secondary), Number, µm: Presendin 115; Placebo
• Papilloedema by Percent 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 (Secondary), Number, percentage change: Presendin -6.67; Placebo
• The Number of Monthly Headache Days (MHD) (Secondary), Number, Monthly headache days: Presendin 28; Placebo
• Number of Moderate to Severe MHD (Secondary), Number, Monthly headache days: Presendin 5.6; Placebo
• Number of MHD Responders (Defined as a ≥50% Reduction in MHD) (Secondary), Count of participants, Participants: Presendin 1; Placebo 0
• Number of Moderate to Severe MHD Responders (Defined as a ≥50% Reduction in Moderate to Severe MHD) (Secondary), Count of participants, Participants: Presendin 2; Placebo 0
• Headache Severity (Secondary), Median, score on a scale: Presendin 6 (4 to 7); Placebo
• Use of Acute Headache Analgesic Medications (Acute Headache Analgesics in Days Per Month) (Secondary), Number, Acute headache analgesics days per month: Presendin 0; Placebo
• Visual Acuity (Secondary)
• Number of Patients With Treatment Failure (Secondary), Number, participants: Presendin 0; Placebo 1

Adverse events

Time frame: Adverse event data were collected over a period of up to 30 weeks, from the signing of the informed consent form to the end of the follow-up period.

Other adverse events by term

Limitations and caveats: Due to the early termination of the study, planned analyses were not fully conducted but were restricted to the most relevant safety endpoints as per the abbreviated SAP v1. Outcome measure (efficacy) data are raw data from individual subjects, with minimal analysis; e.g., where an outcome measure specified change from baseline to Week 24, baseline and Week 24 values are presented. Efficacy data were not subject to the same verification as safety data and no efficacy conclusions should be drawn.

• Study Protocol (PDF, 2022-12-08)
• Statistical Analysis Plan (PDF, 2023-11-02)