Clinical trial NCT05347147
Conditions: Idiopathic Intracranial Hypertension
Keywords: Presendin
Sponsor: Invex Therapeutics Ltd.
Start date: 2022-11-18; Completion date: 2023-10-20
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 2.0 mg arm 2: None
Interventions: intervention 1: Presendin intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
Study 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 
 
ClinicalTrials.gov ID: NCT05347147 
 
 
 
Final Protocol (EU only), Version 5.0, dated 08-Dec-2022 
Final Protocol, Version 4.0, dated 09-Jul-2022 
Final Protocol, Version 3.0, dated 08-Jun-2022 
Final Protocol, Version 2.0, dated 17-Mar-2022 (not approved by a human subjects review 
board) 
Final Protocol, Version 1.0, dated 02-Dec-2021 
 


Study Number: INVEX-CLIN-IIH-301 
Compound No.: Presendin 
Protocol 
Version: 5.0 for EU countries 
dated 08Dec2022 
Page 1 of 154
CONFIDENTIAL 
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 
Effective Date: 
08Dec2022 
EudraCT # 
2021-006664-24 
Short Title: A Phase III trial to determine the efficacy and safety of Presendin in 
IIH – IIH EVOLVE 
Abstract: 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 release 
formulation of exenatide (Presendin) in the reduction of intracranial pressure (ICP) in 
patients with IIH. The primary outcome will be determined by change in ICP, as 
measured by lumbar puncture (LP).  
Eligible, consenting patients will be randomised in a ratio of 1:1 to receive Presendin or 
placebo as a weekly dose for 24 weeks. 
Author 
Department 
Company 
Emma de Launay 
Clinical Operations 
Invex Therapeutics Ltd. 
The information contained in this document is the property of Invex Therapeutics and 
may not be produced, published or disclosed to others without written authorisation from 
Invex Therapeutics 
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CONFIDENTIAL 
Invex Therapeutics 
 
 
 
 
 
 
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Study Number: INVEX-CLIN-IIH-301 
Protocol 
SPONSOR SIGNATURE PAGE 
Sponsor Signatory: 
~;~c:(c,;~ 
Doctor Alexandra Sinclair 
MBChB, PhD, FRCP 
Chief Scientific Officer 
Invex Therapeutics Ltd. 
 
 
 
 
CONFIDENTIAL 
::: 
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THERAPEUTICS 
Compound No.: Presendin 
Version: 5.0 for EU countries 
dated 08Dec2022 
( 3 . ,i. 2...?. 
Date 
Page 3 of 154 


 
 
Study Number: INVEX-CLIN-IIH-301 
Compound No.: Presendin 
Protocol 
Version: 5.0 for EU countries dated 
08Dec2022 
 
Page 4 of 154 
 
CONFIDENTIAL 
SPONSOR INFORMATION PAGE 
Role 
Name and 
Title 
Email Address 
Address 
Non-
Executive 
Chairman 
Dr Jason 
Loveridge 
 
Invex Therapeutics 
Ltd 
 
 
 
Medical 
Monitor 
(CRO) 
Premier 
Research 
Medical 
Monitor 
Premier Research 
3800 Paramount 
Parkway 
Suite 400 
Morrisville 
NC 27560 
USA 
Chief 
Operating 
Officer 
Carol 
Parish 
 
Invex Therapeutics 
Ltd 
 
 
 
Senior 
Clinical 
Trials 
Manager 
Emma de 
Launay 
 
Invex Therapeutics 
Ltd 
 
 
 
Sponsor Contact Information:   
Invex Therapeutics Ltd 
 
 
 
 
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CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, have read and understood the protocol and am aware of my 
responsibilities as an Investigator. I agree to conduct the study in accordance with this 
protocol, the Trial Reference Manual and any subsequent amendments, the Declaration of 
Helsinki, ICH GCP guidelines, and the laws and regulations of the country in which the 
study is being conducted. 
 
Investigator Name and Qualifications: _____________________________________ 
 
 
 
Investigator Signature 
 
Date 
[Investigator Affiliation] 
 
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INVESTIGATOR INFORMATION PAGE 
Details will be provided in the Investigator Site File  
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS .................................................................................................... 13 
PROTOCOL SUMMARY .......................................................................................... 15 
1. 
INTRODUCTION .............................................................................................. 28 
1.1. 
Background and Rational ............................................................................. 28 
1.1.1. 
Name and Description of the Investigational Product ................... 36 
1.1.2. 
Non-clinical Studies ...................................................................... 36 
1.1.3. 
Clinical Studies ............................................................................. 37 
1.1.4. 
Trial Conduct ................................................................................. 38 
1.2. 
Risk/Benefit Assessment .............................................................................. 40 
1.2.1. 
Benefits ......................................................................................... 40 
1.2.1.1. 
Identified ...................................................................... 40 
1.2.1.2. 
Potential ...................................................................... 40 
1.2.1.3. 
Expected ..................................................................... 40 
1.2.2. 
Risks ............................................................................................. 40 
1.2.2.1. 
Identified ...................................................................... 41 
1.2.2.2. 
Potential ...................................................................... 43 
1.2.2.3. 
Expected ..................................................................... 43 
2. 
OBJECTIVES .................................................................................................... 43 
2.1. 
Primary Objective ......................................................................................... 43 
2.2. 
Secondary Objectives .................................................................................. 43 
2.3. 
Safety Objective ........................................................................................... 44 
2.4. 
Exploratory Objectives ................................................................................. 44 
3. 
ENDPOINTS ..................................................................................................... 45 
3.1. 
Primary Endpoint .......................................................................................... 45 
3.2. 
Secondary Endpoints ................................................................................... 45 
3.3. 
Safety Endpoints .......................................................................................... 46 
3.4. 
Exploratory Endpoints .................................................................................. 46 
4. 
TRIAL DESIGN ................................................................................................. 47 
4.1. 
Summary of Trial Design .............................................................................. 47 
4.1.1. 
Trial Design ................................................................................... 47 
4.1.2. 
Randomisation and Blinding ......................................................... 50 
4.1.3. 
Duration of Patient Participation ................................................... 50 
4.2. 
Stopping Rules ............................................................................................. 51 
4.2.1. 
Trial Stopping Rules ...................................................................... 51 
4.2.2. 
Individual Stopping Rules ............................................................. 51 
4.3. 
End of Trial ................................................................................................... 51 
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5. 
TRIAL POPULATION ........................................................................................ 51 
5.1. 
Number of Patients....................................................................................... 51 
5.2. 
Eligibility Criteria ........................................................................................... 51 
5.2.1. 
Inclusion Criteria ........................................................................... 51 
5.2.2. 
Exclusion Criteria .......................................................................... 53 
6. 
TRIAL ASSESSMENTS AND PROCEDURES ................................................. 56 
6.1. 
Procedures at Each Visit .............................................................................. 56 
6.1.1. 
Visit 1 Screening ........................................................................... 56 
6.1.2. 
Visit 2 Baseline ............................................................................. 57 
6.1.3. 
Visit 3 Telephone call .................................................................... 59 
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits .............................................. 59 
6.1.5. 
Visit 10 .......................................................................................... 60 
6.1.6. 
Visit 11 Follow-Up ......................................................................... 62 
6.1.7. 
Unscheduled visit for repeat visual assessments ......................... 62 
6.2. 
Trial Procedures ........................................................................................... 63 
6.2.1. 
Screening Procedures .................................................................. 63 
6.2.1.1. 
Demographics ............................................................. 63 
6.2.1.2. 
Medical, Headache and Ophthalmic History ............... 64 
6.2.1.3. 
Reporting of Prior and Concomitant Medication .......... 64 
6.2.2. 
Safety Procedures ........................................................................ 65 
6.2.2.1. 
Physical Examination .................................................. 65 
6.2.2.2. 
Twelve- Lead Electrocardiogram ................................. 65 
6.2.2.3. 
Vital Signs ................................................................... 65 
6.2.2.4. 
Laboratory Assessments ............................................. 65 
6.2.2.4.1. 
Haematology ........................................... 65 
6.2.2.4.2. 
Clinical Chemistry ................................... 66 
6.2.2.4.3. 
Urinalysis................................................. 67 
6.2.2.4.4. 
CSF ......................................................... 67 
6.2.2.4.5. 
Pregnancy ............................................... 67 
6.2.2.4.6. 
Pharmacokinetic sampling ...................... 68 
6.2.2.4.7. 
Anti-drug Antibodies sampling ................ 68 
6.2.2.5. 
Adverse Events ........................................................... 68 
6.3. 
Efficacy Procedures ..................................................................................... 68 
6.3.1. 
Intracranial Pressure ..................................................................... 68 
6.3.2. 
Visual Assessments ...................................................................... 69 
6.3.2.1. 
Frisén grade ................................................................ 69 
6.3.2.2. 
Optical Coherence Tomography ................................. 69 
6.3.2.3. 
Humphrey Visual Field ................................................ 70 
6.3.2.4. 
Visual Acuity ................................................................ 70 
6.3.3. 
Headache Assessments ............................................................... 70 
6.3.3.1. 
Headache Preventative Medication Review ................ 70 
6.3.4. 
Patient Reported Outcomes .......................................................... 71 
6.3.4.1. 
Visual related ............................................................... 71 
6.3.4.2. 
Health-related .............................................................. 71 
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6.3.4.3. 
Headache related Quality of Life ................................. 71 
6.3.4.4. 
Patient Global Impression of Change .......................... 71 
6.3.5. 
Body Weight and Body Mass Index .............................................. 71 
7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS ......................................... 72 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS ............................................ 76 
9. 
INVESTIGATIONAL PRODUCT ....................................................................... 76 
9.1. 
Dosage and Administration .......................................................................... 76 
9.1.1. 
Randomised Period ...................................................................... 76 
9.2. 
Dose Rationale ............................................................................................. 77 
9.3. 
Maintaining the Blind .................................................................................... 77 
9.4. 
Treatment Assignment ................................................................................. 78 
9.5. 
Packaging and Labelling .............................................................................. 78 
9.6. 
Preparation ................................................................................................... 78 
9.7. 
Handling and Storage................................................................................... 78 
9.8. 
Product Accountability and Assessment of Compliance .............................. 78 
9.9. 
Treatment of Investigational Product Overdose ........................................... 79 
9.10. 
Occupational Safety ..................................................................................... 79 
10. TREATMENT FAILURE AND RESCUE THERAPY PROCEDURES ............... 79 
10.1. 
Treatment Failure ......................................................................................... 79 
10.1.1. 
Possible treatment failure ............................................................. 79 
10.1.2. 
Definite treatment failure ............................................................... 79 
10.2. 
Rescue Therapy/Rescue Intervention for Progressive Visual Loss ............. 80 
10.2.1. 
Rescue Therapy for Headache ..................................................... 80 
11. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................... 80 
11.1. 
Recording Prior and Concomitant Medication .............................................. 80 
11.2. 
Prohibited Medications ................................................................................. 81 
11.2.1. 
Prior to screening and randomisation ........................................... 81 
11.2.2. 
During the trial ............................................................................... 82 
12. PATIENT COMPLETION AND WITHDRAWAL ................................................ 82 
12.1. 
Patient Completion ....................................................................................... 82 
12.2. 
Patient Withdrawal ....................................................................................... 83 
12.2.1. 
Patient Withdrawal from Trial Treatment ...................................... 83 
12.3. 
Treatment after the End of the Trial ............................................................. 84 
12.4. 
Screen and Baseline Failures ...................................................................... 84 
13. ADVERSE EVENTS ......................................................................................... 84 
13.1. 
Definitions .................................................................................................... 84 
13.1.1. 
Adverse Events ............................................................................. 84 
13.1.2. 
Adverse Drug Reactions ............................................................... 84 
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13.1.3. 
Serious Adverse Events or Serious Adverse Drug 
Reactions ...................................................................................... 84 
13.1.4. 
Suspected Unexpected Serious Adverse Reactions .................... 85 
13.1.5. 
Expected Adverse Events ............................................................. 85 
13.1.6. 
Adverse Events of Special Interest ............................................... 85 
13.2. 
Causal Relationship ..................................................................................... 86 
13.3. 
Severity Criteria ............................................................................................ 86 
13.4. 
Reporting Adverse Events............................................................................ 87 
13.4.1. 
Reporting Serious Adverse Events ............................................... 87 
13.5. 
Reporting and Handling of Pregnancies ....................................................... 88 
14. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................ 89 
14.1. 
Hypotheses .................................................................................................. 89 
14.2. 
Trial Design Considerations ......................................................................... 89 
14.2.1. 
Sample Size Assumptions ............................................................ 89 
14.2.1.1. Intracranial Pressure Power ........................................ 89 
14.2.1.1. Perimetric Mean Deviation Power ............................... 90 
14.2.2. 
Stratification .................................................................................. 91 
14.2.3. 
Sample Size Sensitivity ................................................................. 91 
14.2.3.1. Clinically Meaningful Effect Sizes ................................ 91 
14.2.4. 
Trial Stopping Criteria ................................................................... 92 
14.3. 
Data Analysis Considerations ...................................................................... 93 
14.3.1. 
Estimands ..................................................................................... 93 
14.3.1.1. Outcome: Intracranial pressure (ICP) .......................... 93 
14.3.1.1.1. Intercurrent event: ICP-lowering 
medications ............................................. 93 
14.3.1.1.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 94 
14.3.1.1.3. Inter-current event: Dramatic 
weight-loss .............................................. 94 
14.3.1.2. Outcome: Perimetric Mean Deviation (PMD) .............. 94 
14.3.1.2.1. Intercurrent event: ICP-lowering 
medications ............................................. 94 
14.3.1.2.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 95 
14.3.1.2.3. Intercurrent event: Dramatic 
weight-loss .............................................. 95 
14.3.1.3. Outcome: Papilloedema measured by OCT 
(optic nerve head size, retinal nerve fibre layer) ......... 96 
14.3.1.3.1. Intercurrent event: ICP-lowering 
medications ............................................. 96 
14.3.1.3.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 96 
14.3.1.3.3. Intercurrent event: Dramatic 
weight-loss .............................................. 96 
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14.3.1.4. Outcome: Monthly headache days (MHD) .................. 97 
14.3.1.4.1. Intercurrent event: Headache-
preventative medications ........................ 97 
14.3.1.4.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 97 
14.3.1.4.3. Intercurrent event: Dramatic 
weight-loss .............................................. 97 
14.3.1.4.4. Intercurrent event: ICP-lowering 
medications ............................................. 98 
14.3.1.5. Primary Estimand (Hypothetical assuming no 
concurrent procedures, irrespective of 
adherence to treatment) .............................................. 98 
14.3.1.6. Secondary Estimand (Hypothetical) ............................ 99 
14.3.2. 
Analysis Populations ..................................................................... 99 
14.3.3. 
Treatment Comparisons ............................................................. 100 
14.3.4. 
Safety Analyses .......................................................................... 100 
14.3.4.1. Adverse Events ......................................................... 100 
14.3.4.2. Clinical Laboratory Evaluations ................................. 101 
14.3.4.3. Vital Signs and Body Mass Index Evaluations .......... 101 
14.3.4.4. Electrocardiogram ..................................................... 101 
14.3.4.1. Other Safety Evaluations ........................................... 102 
14.3.5. 
Patient Reported Outcomes Analyses ........................................ 102 
14.3.6. 
Missing Data ............................................................................... 102 
14.3.7. 
Reporting Deviations from the Statistical Plan ............................ 103 
15. TRIAL ADMINISTRATION .............................................................................. 104 
15.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 104 
15.2. 
Trial Monitoring .......................................................................................... 104 
15.2.1. 
Access to Source Data ............................................................... 105 
15.2.2. 
Data Handling and Record Keeping ........................................... 105 
15.3. 
Provision of Trial Results and Information to Investigators ........................ 106 
15.4. 
Publication .................................................................................................. 106 
15.5. 
Data Management ...................................................................................... 106 
15.6. 
Independent Adjudication Committee ........................................................ 107 
15.7. 
Data Safety Monitoring Committee ............................................................ 108 
15.8. 
Insurance, Indemnity and Finance ............................................................. 108 
16. REFERENCES ............................................................................................... 109 
17. APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-301 ....................... 119 
17.1. 
Appendix 1: LP SOP .................................................................................. 119 
17.2. 
Appendix 2: IIH Diagnostic criteria [Mollan, 2018] ...................................... 122 
17.3. 
Appendix 3: 36-item short from survey ....................................................... 123 
17.4. 
Appendix 4: EuroQol -5 dimension-5 level survey ..................................... 129 
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17.5. 
Appendix 5: Headache Impact Test-6 ........................................................ 133 
17.6. 
Appendix 6: Visual Function Questionnaire-25 & 10-item 
Supplement ................................................................................................ 135 
17.7. 
Appendix 7: Patient Global Impression of Change ..................................... 153 
17.8. 
Appendix 8: Contraception ......................................................................... 154 
 
 
 
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ABBREVIATIONS 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCRF 
Electronic Case Report Form 
BMI 
Body Mass Index 
CGRP 
Calcitonin Gene-Related Peptide 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DGM 
Data-Generating Models 
DSMC 
Data Safety Monitoring Committee 
ECG 
EU 
Electrocardiogram 
European Union 
GCL 
Ganglion Cell Layer 
GLP-1 
Glucagon Like Peptide-1 
HVF 
Humphrey Visual Field 
ICF 
Informed Consent Form 
ICP 
Intracranial Pressure 
IAC 
Independent Adjudication Committee 
ICH-GCP 
International Council of Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IIH 
Idiopathic Intracranial Hypertension 
ITT 
Intention-to-Treat 
LP 
Lumbar Puncture 
MAR 
Missing At Random 
MD 
Mean Deviation 
MHD 
Monthly Headache Days 
NRS 
Numeric Rating Scale 
OCT 
Optical Coherence Tomography 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QTcF 
QT Interval corrected according to Fridericia’s formula 
RNFL 
Retinal Nerve Fibre Layer 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SF-36 
36-item short form survey 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
VFQ-25-10 item  
Upper Limit of Normal 
Visual Function Questionnaire-25 and 10-item supplement 
 
 
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PROTOCOL SUMMARY 
Rationale 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends.  
IIH has significant associated morbidity and reduced quality of life. Elevated ICP causes 
papilloedema universally at disease onset and can lead to permanent visual loss. Visual 
loss occurs in greater than 90% of those with IIH [Wall 1991] and can be severe and 
permanent in between 5-25%. Besides risk of visual loss, the most disabling aspect for 
patients is severe chronic headaches driven by elevated ICP. Existing pharmacotherapies 
are limited. The most frequently used drug therapy, acetazolamide, is used off label and 
has been shown to have efficacy but due to side effects and treatment failures new drugs 
are needed. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but the failure rates are high and frequent complications and side 
effects occur. 
A modified release formulation of exenatide (Presendin) has been developed and this trial 
has been designed to evaluate the efficacy and safety of Presendin in IIH. The modified 
release formulation has been chosen to enable a once weekly dosing.  
Objectives 
Primary Objective 
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 lumbar 
puncture (LP) at baseline and at 24 weeks. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
Secondary Objectives 
To determine the effect of Presendin on change in: 
• 
Perimetric Mean Deviation (PMD) as measured by the Humphrey Visual Field 
analyser (24-2 SITA (Swedish Interactive Testing Algorithm)-Standard) 
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• 
Papilloedema as measured by optical coherence tomography imaging (retinal nerve 
fibre layer (RNFL) thickness and optic nerve head volume measurements)  
• 
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 
Safety Objectives 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Macular ganglion cell layer/complex thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes (PROs) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation 
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Endpoints 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
Secondary Endpoints 
• 
Perimetric Mean Deviation 
• 
Retinal nerve fibre layer 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 and 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.* 
*criteria defined in rescue therapy section 10.1.1 
Safety Endpoints 
• 
Vital Signs 
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• 
Adverse events: Treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs) 
• 
Resting 12-lead ECG 
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
Exploratory Endpoints 
• 
Macular ganglion cell layer/complex thickness 
• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes: 
• 
Visual Function Questionnaire-25 and 10-item supplement (VFQ-25-10 item 
supp) 
• 
Headache Impact Test -6 (HIT-6) 
• 
36-item short from survey (SF-36) 
• 
EuroQol -5 dimension -5 level (EQ-5D-5L) survey  
• 
Patient Global Impression of Change (PGIC) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation  
Trial Design 
 
This is a randomised, placebo-controlled, double-blind, multi-centre trial requiring 
240 adult randomised patients with IIH to determine the efficacy and safety of Presendin. 
Exenatide pharmacokinetics will be conducted and population PK modelling may be 
performed. 
Consenting patients with a diagnosis of IIH will enter a 1-week screening period, in 
which there will be no investigational treatment, to gather baseline measurements and to 
check eligibility. Although a headache diary is typically over 28 days, it was felt 
unethical to have patients off treatment for this more prolonged period due to the real risk 
of visual loss. Headache diaries designed to measure headache frequency have 
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successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [Wall, 2014, Markey, 2017 and Mollan, 2021]. Hence the baseline 
headache frequency will be calculated over 1 week as has been done in other trials. 
At the screening visit, patients will be provided with training on the self-administration of 
the trial medication and provided with a leaflet to take home. Patients will be asked to 
self-administer one (1) dose of placebo during the screening visit to ensure they are 
comfortable with self-injection. Patients who are not comfortable with self-administration 
will be deemed a screen failure and will not be randomised into the trial. Eligible patients 
will then be randomised to receive either Presendin or matching placebo for 24 weeks in 
a 1:1 ratio. After completion of the randomisation period 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 also be performed.  
The duration of the double-blind treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy over a 3-month time 
horizon. Additionally, an alternative off label drug used in IIH (acetazolamide) evaluated 
efficacy over a 6-month period. Hence efficacy is relevant over this time frame. A longer 
period of randomisation would not be ethical if patients were expected to remain on 
placebo for 12 months as this could place their overall health at risk. The duration of the 
trial for each patient will be up to 30 weeks, which includes a 1-week screening period, a 
24-week randomised double-blind treatment period, and a treatment follow-up period of 
5 weeks. 
Trial Population 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.2, Appendix 2), 
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 
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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 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 – see Section 16.8, Appendix 8 for 
further details) 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 
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legal authorities to be included on the grounds that informed consent could not 
be assumed. 
Patients must not be enrolled if they meet any of the following 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 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] 
Headache related exclusion criteria: 
10. Does not complete ≥6 days of electronic/paper trial diary during the 7-day 
screening period 
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Other exclusion criteria: 
11. Untreated previously diagnosed obstructive sleep apnoea with historically 
recorded apnoea­hypopnea 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 
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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 
 
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 – see section 10.1.2
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Trial Assessments 
Table 1: Time and Events 
 
 
SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Informed consent  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X  
(review) 
 
 
 
 
 
 
 
 
 
 
Demography (sex, age, 
ethnicity) 
X 
 
 
 
 
 
 
 
 
Medical & Ophthalmic 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Headache history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Headache preventative 
medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Train and dispense 
headache diary 
X 
 
 
 
 
 
 
 
 
 
 
 
Review headache diary1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Body weight and BMI 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examination 
(T = targeted) 
X  
(Full) 
X (T) 
 
 
 
X (T) 
 
X (T) 
X(T) 
X (T) 
 
(X) 
Pregnancy Test3 
X 
(Serum) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
OCT Imaging  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
Papilloedema Frisén 
grade4   
X 
X 
 
 
 
 
 
 
 
 
 
 
Perimetry  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visual Acuity Testing 
(LogMAR score) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
 
Patient Reported 
Outcomes 
(HIT-6, SF-36, EQ-5D-5L, 
VFQ-25 & 10-item supp) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Health Utilisation Form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC assessment 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments5  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Pharmacokinetic (PK) 
sampling6 
 
X7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-Drug Antibodies 
(ADA) sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Lumbar Puncture8 
 
 
 
 
 
 
 
 
 
X9 
 
 
Trial medication training10 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
Trial medication 
Dispensing  
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Trial medication 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
1 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Patients who do not meet the eligibility criteria based on diary review at 
randomisation/baseline (e.g., too few headache days or unacceptable concomitant medication use) will be considered screen failures; however, if the patient wishes and 
the Investigator is in agreement, he/she can be re-screened as a new patient. If the screening period exceeds 7 days, then eligibility will be based on the last 7 days of the 
screening period, i.e., the 7 days prior to randomisation visit. Trial site research team should review diaries remotely on a weekly basis to ensure compliance and follow 
up any patients with missing data 
2 
Vital signs to include: blood pressure and heart rate 
3 
Women of child-bearing potential. Serum pregnancy test to be conducted at screening, thereafter, highly sensitive urine pregnancy tests will be conducted. Visit 11 urine 
pregnancy test may be conducted at home 
4 
Frisén grade will be evaluated locally and the presence of papilloedema verified by the OCT Reading Centre at screening to confirm eligibility. Indeterminate cases 
should be referred to the IAC (and supplemented with fundus photography and ultrasound scan of the optic nerve) to confirm papilloedema prior to randomisation visit 
5 
Haematology, coagulation, biochemistry and urinalysis 
6 
All actual sampling times and dosing times will be recorded 
7 
Baseline Post-dose PK blood sample 
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8 
The diagnostic LP will be the baseline LP and must be performed in lateral decubitus position. Patients with ICP <25 cm  CSF at diagnosis will be excluded  
9 
Lumbar puncture to be performed after visual assessment. LP to be performed as per Appendix 1. CSF sample from visit 10 LP will be retained for future potential 
analysis 
10 
Patients will be provided with training on the self-administration of the trial medication. The patient will be asked to self-administer placebo at visit 1 to demonstrate 
ability to self-inject. Patients who are not comfortable to self-inject will be excluded 
11 
If patients discontinue in the randomised double-blind treatment period they will be encouraged to return for all trial visits up to visit 11. If a patient does not want to 
return for all visits then they will be asked to return at a minimum for visit 11 procedures for safety follow up 
12 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial medication and must have self-administered their final dose within 7 days of 
visit 10. Patients will be reminded by the trial site to self-administer trial medication weekly, to continue this until the completion of visit 10 and to bring their trial 
medication with them at visit 10 for return. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial medication has been missed in the previous 4 weeks. Visit 10 should be delayed no 
more than 14 days 
13 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients in whom there is concern about visual decline or who perform inadequately or where 
there is technical failure (more than 15% false positive responses or inadequate performance indicated by the Visual Field Reading Centre for HVF; or OCT imaging not 
of satisfactory quality as determined by the OCT Reading Centre) 
14 
In the event of any abnormal safety assessments identified at end of treatment, e.g., abnormal ECG, abnormal routine laboratory results or ongoing adverse events, this 
visit may be performed at the clinic to repeat or follow up safety assessments 
15 
Reporting of AEs/SAEs will continue up to the final follow up visit 11 
 
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background and Rational 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends [Mollan, 2019a]. There is a high rate of repeat hospital admission in 
IIH (increased by 446% in last decade), reflected in escalating healthcare costs (in 
England £462 million/year predicted by 2030 [Mollan, 2019a] and more than $444 
million in the USA [Friesner, 2011]). 
The cause of IIH is not fully understood. Recent research suggests that IIH is a disease of 
systemic metabolic dysregulation characterised by central adiposity [Hornby, 2017], 
double the risk of cardiovascular disease in excess to that mediated by obesity [Adderley, 
2019] and dysfunctional adipocyte metabolism primed for weight gain [Westgate, 2021]. 
Patients are also insulin resistant and have a unique hormone signature of androgen 
excess both systemically and in the cerebrospinal fluid.[O’Reilly, 2019] 
Morbidity in IIH is due to the elevated intracranial pressure which can cause severe 
papilloedema (swelling of the optic nerve) which can ultimately lead to blindness. The 
risk of permanent visual loss is a major concern in IIH. Visual loss occurs in greater than 
90% of those with IIH [Wall 1991] and can be severe and permanent in between 5-25%. 
Headache is an additional major disabler and affects the majority of IIH patients (over 
90%) [Yri, 2014; Markey, 2016; Mulla 2015] in the long term. Headaches significantly 
reducing quality of life [Mulla, 2015; Digre, 2015] are driven by raised intracranial 
pressure and often have a migraine- like phenotype (> 90%) [Mollan 2021a].  
Existing pharmacotherapies are limited. The most frequently used drug therapy, 
acetazolamide, is used off label and has been shown to have efficacy but due to side 
effects and treatment failures new drugs are needed. [Piper, 2015; Mollan, 2018; 
Hoffmann, 2018]. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but there is a high failure rate and frequent complications. The 
lack of licenced or targeted treatments in IIH perpetuates poor outcomes for patients. A 
priority setting exercise was run by patients with IIH (James Lind methodology) [Mollan, 
2019c] establishing effective therapy was the top priority from the patient group. 
This trial will investigate an alternative therapeutic option for lowering ICP and thereby 
reducing papilloedema and consequently reducing the risk of visual loss. By reducing 
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ICP it would also aim to improve headache, improving overall patient quality of life in 
IIH [Mollan 2021a]. 
Gut neuropeptides are increasingly being recognised for their role in the central nervous 
system (CNS). A principal gut neuropeptide is glucagon like peptide-1 (GLP-1), which is 
known to stimulate insulin release, proliferation of pancreatic beta cells and control of 
glucose regulation in diabetes [Campbell, 2013]. Exenatide is a GLP-1 receptor agonist. 
It has also been shown to have some actions in the CNS; GLP­1 is involved in regulating 
satiety and weight through signalling at the hypothalamus [Astrup, 2009]. There is also 
evidence that GLP-1 may have a role in fluid secretion. In the renal proximal tubule 
GLP-1 acts to reduce sodium resorption to promote diuresis [Gutzwiller, 2004; 
Websky, 2014]. The choroid plexus is the fluid secreting structure within the brain 
producing the majority of CSF. The structure of the choroid plexus epithelial cells is 
analogous to an inverted renal proximal tubule with a similar mechanism of secretion and 
hence GLP-1 receptor agonists may also reduce CSF secretion in the brain, leading to a 
decrease in ICP in patients with IIH. 
Exenatide as well as other GLP-1 receptor agonists can lead to weight loss. In diabetic 
patients, weight loss of 2.8 - 4.4 kg has been reported over 6 months [Di Dalmazi 2020; 
Pujante 2012]. Whilst in non-diabetic overweight and obese patients exenatide caused 
sufficient weight loss between 2.0 – 5.1 kg [Moreno 2012]. In overweight and obese 
patients with polycystic ovarian syndrome exenatide led to 2kg more weight loss 
compared to placebo in over 12 weeks [Liu 2017]. Weight loss with exenatide therapy is 
increased in the setting of calorie restriction [Rosenstock 2010]. Weight loss is a 
desirable effect of exenatide as weight loss is therapeutic in IIH. Changes in body weight 
will be monitored during the trial and the impact on outcomes measures evaluated. 
Exenatide is the active ingredient in Byetta, an immediate-release (IR) formulation and 
Bydureon, an extended-release (ER) formulation. These have been licenced for use in 
adults with type-2 diabetes since 2005 and 2014, respectively. Therefore, there is a 
wealth of available safety data from both clinical trials and real-world experience. 
Exenatide has been identified as a potential candidate for the treatment of neurological 
conditions involving raised ICP and a polylactic-co-glycolic acid (PLGA) ER exenatide 
formulation under the name Presendin, has been developed by Invex Therapeutics for the 
treatment of IIH.  
Byetta has a known issue of rapid elimination of the product when given to humans, and 
because of this it needs to be administered twice daily to achieve its pharmacological 
effects. The data on file from the IIH Pressure trial has shown that in patients with IIH, 
exenatide administered twice daily was well tolerated and produced a positive effect on 
reducing CSF pressure. However, it is considered that the immediate release formulation 
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of exenatide is not ideal for treating patients with IIH on a long-term basis. Presendin has 
been developed as an extended release formulation to allow for a reduction in dosing 
frequency to once weekly and more consistent therapeutic plasma levels. 
This trial is designed to investigate the efficacy and safety of a modified release 
formulation of exenatide (Presendin) in patients with IIH.  
Intracranial pressure 
IIH is a debilitating condition characterised by raised ICP, which is clinically measured 
by LP [Mollan, 2018]. The units for measurement of LP are cm CSF and cm H2O and 
these should be thought of as interchangeable and reflect the measurement of the height 
of the CSF column at LP. The measurement must be taken in the lateral decubitus 
position. Lumbar puncture is conducted to make a diagnosis of IIH. Lumbar puncture 
may be conducted in a clinical setting during the disease course to both monitor and treat 
the condition. Frequent therapeutic LPs are no longer recommended by the International 
IIH guidelines [Mollan, 2018]. This is because LP can be traumatic for patients and can 
occasionally cause significant complications (meningitis, spinal haematoma, pain) 
[Wright, 2012]. Hence, unnecessary LP’s should be avoided. In some patients LP can 
alter other outcome measures, including measurements of papilloedema and headache 
[Yiangou, 2019]. Hence ideally, LP should be performed after these measures and 
symptoms have been assessed. Lumbar puncture can cause post-dural puncture 
headaches. The risk is 9-36% using a traumatic needle and 3-19% using an atraumatic 
needle [Wright, 2012]. Post-dural puncture headaches typically last less than a week but 
in some patients this can be longer [Yiangou, 2019]. Lumbar puncture pressure 
assessment of ICP reflects disease activity and is a useful and recognised outcome 
measure that has been utilised in other IIH trials [Markey 2020; Mollan 2021b]. 
Due to the invasive nature of LP, non-invasive measures of ICP are valuable. The 
majority of techniques historically evaluated as non-invasive surrogate measures of ICP 
lack sufficient quantification to be used clinically or in clinical trials.  Optical coherence 
tomography (OCT) measures of the optic nerve have been shown to provide a useful 
surrogate measure to quantify changes in ICP [Vijay, 2020]. For example, at 12 months, 
Vijay et al showed that a change in optic nerve head height of 50 µ predicted a 5 cm CSF 
change in ICP [Vijay, 2020]. 
Visual Function 
Perimetry is used to measure visual function in IIH clinical practice. This is assessed 
using a Humphrey Field Analyzer (program 24-2 SITA standard using a size III white 
stimulus) test. Patients are often unaware of their visual field loss until this becomes more 
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severe and compromises daily activities. In patients with severe papilloedema optic 
atrophy can develop (measured objectively as loss of the macular ganglion cell layer on 
OCT imaging) and the loss of visual field becomes permanent. Patients at risk of rapidly 
progressive visual loss (also termed fulminant IIH) should receive emergency surgical 
intervention (most commonly a CSF shunt operation) [Mollan, 2018]. Patients requiring 
emergency surgery will not be recruited into this trial. Medical therapy is used to treat 
those IIH patients not requiring emergency surgical intervention and will be included in 
this trial. But it is expected that approximately 5-10% will go on to need more aggressive 
intervention. 
Measuring visual function with perimetry has a number of challenges in IIH which need 
to be carefully considered. The visual field test is dependent on technician and patient 
performance and can be prone to variability and inaccuracy [Cello, 2016; Wall, 2016]. 
Patients can perform poorly on automated perimetry [Cello, 2016], and there is a learning 
effect [Kutzko, 2000; Wall, 2016]. There are further confounding factors when 
considering interpretation of automated visual field testing in IIH. The high prevalence of 
functional vision loss, presenting as non-organic visual fields results in this disease, may 
bias trial outcomes [Kutzko, 2000; Ney, 2009]. Additionally, impaired executive function 
and attention deficits have been noted in IIH [Sørensen, 1986], and have been shown to 
impair performance of visual field testing in IIH [Grech, 2021]. 
The protocol has been designed with these challenges in mind and visual field testing 
performance will be assessed at trial entry and throughout with opportunity for repeated 
assessment if there is performance failure (a performance failure is defined as a 
substantial worsening of the perimetric mean deviation due to human factors rather than 
visual damage) [Cello, 2016].. The visual fields will be assessed by the Visual Field 
Reading Centre. 
Papilloedema by change in optic nerve head size measured by OCT imaging. 
Papilloedema is a reliable sign of raised ICP [Dunn, 2002]. Change in papilloedema has 
been used by all the randomised control trials in IIH to date to determine clinical 
improvement [Ball, 2011; Wall, 2014; Mollan 2021b]. Change in papilloedema has been 
graded by experts using the Frisén classification, although it is more reliably measured by 
OCT imaging [Ball, 2011; Wall, 2014]. Professional bodies and the literature endorse the 
use of OCT imaging for monitoring papilloedema in IIH [Mollan, 2018]. 
 OCT imaging measures various aspects of the optic nerve. The retinal nerve fibre layer 
(RNFL) and optic nerve head volume  are measurements that both reflect swelling of the 
optic nerve and hence the extent of papilloedema. Measures of macular volume can 
quantify the ganglion cell layer (GCL) thickness which reflects axonal loss. Optic nerve 
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head measures on OCT correlate with visual field sensitivity loss [Salgarello, 2001]. 
Analysis has shown that OCT measures of the RNFL significantly reflect changes in 
visual field perimetric mean deviation (MD) (for every 10µm increase in RNFL there was 
associated with a 0.6dB decrease in MD) [Rebolleda, 2009]. Optical coherence 
tomography measures of the macula volume have been shown to predict axonal loss of 
the optic nerve [Albrecht, 2017]. Most importantly, ganglion cell volume has been shown 
to significantly correlate with the Humphrey visual field MD [Vijay, 2020]. This 
indicates that the GCL can be measured to reflect visual function. In other neurological 
diseases OCT has also been found to measure neuronal loss and correlated with visual 
loss [Petzold, 2010]. In summary, OCT assessment of the optic nerve and GCL represent 
objective measures of papilloedema and optic nerve axons which reflects visual function. 
The scan quality can be compromised if the automated software segmentation of the OCT 
is not accurate. This occurs particularly in those optic nerves with more pronounced 
papilloedema [Aojula, 2018]. Hence the quality and segmentation of all OCT scans will 
be assured by the OCT Reading Centre and scans will be repeated if of insufficient 
quality. 
Headache 
Headache is the predominant presenting feature in IIH [Mollan, 2019a]. Patient morbidity 
is high because of disabling headaches and they have been found to be the key driver for 
poor quality of life [Mulla, 2015; Digre, 2015]. Research into headache treatments were 
endorsed as clinically relevant by a priority setting partnership which included the 
opinions of the patients’ carers and physicians [Mollan, 2019c].  
It has been well documented that headache characteristics in IIH are typically migraine-
like (up to 90%) [Mollan, 2019b; Mollan 2021a]. The headache location can be halo-
cranial, frontal, temporal or parietal with features including nausea, throbbing pain, 
photophobia and phonophobia [Yri, 2015]. A Danish trial of 44 IIH patients noted that 
82% of patients had migraine-like attacks [Yri, 2014]. A prospective trial in 52 IIH 
patients in the UK characterised 80% of headaches as migraine-like [Yiangou, 2019]. As 
reported by the Idiopathic Intracranial Hypertension Treatment Trial, US, the headache 
phenotype was recorded as migraine or probable migraine in 68% of 144 patients with 
active IIH [Friedman, 2017]. A retrospective trial in Iran in 68 IIH patients characterised 
migraine-like headaches in 63% [Sina, 2017]. Other headache characteristics are typically 
tension-type or unclassified [Mollan, 2019b]. 
Hence whilst IIH headaches are not diagnostically the same as migraine according to the 
International Classification of Headache Disorders, 3rd edition Beta, they are very similar 
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in character [Olesen, 2018]. The International Headache Society core outcomes for 
migraine are therefore applicable to IIH headaches [Tassorelli, 2018]. 
Headache in active IIH is driven by ICP. This is evidenced by the fact that removal of 
CSF fluid results in improved headache severity. In a prospective cohort study, headache 
severity improved in 71% following a standardised LP [Yiangou, 2019]. Ninety-five 
percent of IIH patients had improvement in headache symptoms at 1 month following 
shunt placement [Daou, 2020]. Weight loss leading to reduction in ICP also significantly 
reduced headache [Sinclair, 2010].  
Medications that reduce ICP have been shown to modulate headache. In an open label 
trial using topiramate and acetazolamide, both of which are known to modulate ICP 
[Scotton, 2019], relief of headache was reported after a mean treatment period of 3.75 
months in the topiramate group and 3.3 months in the acetazolamide group [Çelebisoy, 
2007]. 
Importantly, headache measures (severity and monthly headache days) in IIH 
significantly correlate with changes in ICP [Mollan 2021a]. The IIH weight trial [Mollan, 
2021b], a randomised controlled parallel group multicentre trial in the United Kingdom, 
investigates weight management methods in IIH. Participants with active IIH (evidenced 
by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. The primary 
outcome was ICP as measured by LP opening pressure at 12 months, with secondary 
outcomes of ICP at 24 months and headache outcomes at 12 and 24 months. Headache 
severity was correlated with ICP at baseline; change in headache severity and monthly 
headache days correlated with change in ICP at 12 months. Importantly those with the 
greatest reduction in ICP over 12 months had the greatest reduction in headache 
frequency and severity. This implies that treatment of ICP should improve headache in 
IIH. 
The following headache outcomes are clinically relevant and are recommended by the 
American Headache Society [American Headache Society] and International Headache 
Society to identify patients who are benefiting from treatments. Headache outcomes are 
derived from a 28-day diagnostic headache diary. This is used in clinical trials to 
prospectively collect daily information on headache occurrence, severity, associated 
symptoms, and use of acute analgesic medications.  
Although a headache diary is typically over 28 days, for IIH headache it was felt 
necessary to shorten this period during which no other planned assessments of vision 
were scheduled.  Headache diaries designed to measure headache frequency have 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
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representative [Mollan 2021b]. Hence the baseline headache frequency will be calculated 
over 1 week as has been done in other trials. 
Monthly headache days  
Monthly headache days (MHD) will include all headache days, defined as those with an 
onset, continuation or recurrence, any severity or phenotype of headache and lasting at 
least 30 minutes or which require acute headache analgesia. This is the most relevant and 
objective measure of headache. 
Moderate to severe monthly 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. This 
outcome captures the more disabling headaches. 
Moderate to severe MHD was recently reported as the primary endpoint in a prospective 
open label study providing evaluation of the effectiveness of erenumab, a calcitonin 
gene-related peptide (CGRP) monoclonal antibody, to treat headaches in IIH patients 
[Yiangou, 2021]. It is also used to measure headache in other secondary headache 
conditions such as persistent post traumatic headache [Aojula 2018; Ashina, 2020]. 
Headache responder rate (≥50% reduction in MHD) 
Headache responder rate (≥50% reduction in MHD) is the proportion of patients 
achieving at least 50% reduction in the mean number of MHD, of any intensity, from 
baseline to the defined trial end point. This criterion is clinically relevant as it is used as 
an empirical review for continuing or discontinuing headache therapy [Diener, 2020]. 
Responder rates can be used in meta-analyses of placebo controlled randomised 
controlled trials. 
Headache responder rate (≥50% reduction in moderate to severe MHD) 
Headache responder rate (≥50% reduction in moderate to severe MHD) is the proportion 
of patients achieving at least 50% reduction in the moderate to severe MHD from 
baseline to the defined trial end point. It is well recognized that 50% responder rates may 
not fully capture the benefits of treatment [Matharu, 2017]. For example, a patient may 
improve from a disabling 20 severe headache days per month to 11 moderate headache 
days per month. Despite this considerable clinical benefit, such a patient would not be 
considered a responder because headache days were not reduced by ≥50%, and as a result 
might lose access to beneficial treatment. Hence, responder rates of ≥30% are also 
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important [Vernieri, 2019]. In IIH, a disorder of chronic severe headaches, a clinically 
meaningful treatment responder rate has not been definitively established, although the 
International Headache Society Clinical Trials Subcommittee has suggested the use of a 
≥30% reduction from baseline for chronic migraine.  
Headache severity 
Headache severity is an important measure and impacts quality of life. It is vital to 
consider some treatments which benefit headache may not reduce the MHD but if the 
severity is markedly improved this will lead to great overall functional benefit to the 
patient and is clinically relevant [Silberstein, 2008]. Recording the decrease in intensity is 
an indicator of reduced disability, which is clinically meaningful. 
Monthly use of acute headache rescue medications 
Use of acute headache analgesics reflects a judgement of the inefficacy of the test 
treatment; hence it is a helpful secondary outcome. In Sinclair et al. reduction in 
analgesic days was significant and associated with clinical remission of IIH [Sinclair, 
2010]. Additionally, a high portion of IIH, up to 48% [Yiangou, 2021] have medication 
overuse and medication overuse headache, and reduction in analgesic days mitigates 
these. Reduction in monthly use of acute headache analgesic is an additional endpoint 
that contributes to clinically meaningful results. 
Quality of life in IIH 
IIH has a detrimental effect on all aspects of the patient’s quality of life; the majority of 
which is driven by headache [Kleinschmidt, 2000, Mulla, 2015; Daniels, 2007; Digre 
2015]. IIH also impacts visual function with PMD correlating with quality of life 
[Bruce 2016]. Patient reported outcomes in clinical trials are essential not only to permit 
health technology assessments and cost effectiveness analysis, but also as key outcomes 
for a therapy’s effectiveness [Deiner, 2019]. There is currently no IIH disease specific 
quality of life outcome measure. 
Whilst there are differences in the choice of the tools used in the trials, they all 
commonly used the short-form 36 health survey (SF-36) [Mollan, 2021, Wall, 2014, 
Digre, 2015; Bruce, 2016; Ball, 2011]. The physical component score of the SF-36 has 
been shown to correlate significantly with changes in ICP [Grech 2021]. The EuroQol –5 
dimension (EQ-5D-5L) [Euroqol, 1990] is typically employed for health technology 
assessments and cost effectiveness [Ottridge, 2017; Ball, 2011]. Using the EQ-5D-5L in 
isolation may lack sensitivity as compared to the SF-36 for IIH. The National Eye 
Institute Visual Function Questionnaire-25 and 10-item supplement [Mangione, 2001] 
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has also been utilised to assess visual related quality of life in IIH and is associated with 
improvement in visual field [Bruce 2016; Mangione 1998; Raphael 2006]. The 10-Item 
neuro-ophthalmic supplement was found to be significantly discriminating in a previous 
IIH drug trial [Wall 2014].  
Pharmacokinetics 
Exenatide pharmacokinetics will be conducted and population PK modelling may be 
performed. 
1.1.1. 
Name and Description of the Investigational Product 
Patients will receive active treatment, Presendin, or matching placebo.  
Presendin is a modified release formulation of exenatide. Exenatide is a GLP-1 receptor 
agonist currently used in the management of type 2 diabetes. Presendin consists of a drug 
part (white or greyish white powder in a clear vial) and a diluent part (colourless liquid in 
a pre-filled syringe). The drug part is suspended in the diluent part solution and 
administered as a suspension. The patient or responsible person will be responsible for 
rehydrating the product for injection. Presendin is administered as a once weekly SC 
sustained-release injection containing 2.0 mg exenatide. Matching placebo will also be 
supplied as 2 parts, as visually identical vial and pre-filled 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. Placebo is administered once weekly as a SC 
injection. 
1.1.2. 
Non-clinical Studies 
Exenatide, the active ingredient of Presendin, has been previously developed and licensed 
as Byetta for the treatment of type 2 diabetes. A wealth of historical toxicological and 
pharmacological safety data is available in the public domain. Please see the 
Investigator’s brochure for data from rat and mouse studies which have investigated the 
Presendin formulation of exenatide. 
In vitro and in vivo data suggests that the choroid plexus, the CSF secreting structure in 
the brain, contains GLP-1 receptors [Ast 2020]. Preclinical studies in rodents demonstrate 
that GLP-1 agonists can regulate cerebrospinal fluid dynamics and reduce ICP [Botfield, 
2017]. 
Nonclinical pharmacology studies have shown that exenatide and GLP-1 agonists bind to 
and stimulate GLP-1 receptors equipotently. Due to the ability of exenatide to affect fluid 
homeostasis in the kidney, it was investigated for its potential to modulate CSF secretion 
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and reduce ICP in rats. A single SC injection of exenatide rapidly (within 30 minutes) 
reduced ICP and maintained lower ICP for 6 days of dosing, suggesting that GLP-1 
receptor agonists could provide an alternative treatment for conditions with raised ICP 
[Botfield, 2017]. 
Exenatide was subjected to full toxicological assessments during its nonclinical 
development programme, details of which are publicly available in the Byetta® Product 
Monograph, 2019 and the FDA Pharmacology Review, June 2004 (Section 15). In 
summary, no lethality or serious toxicity was observed in mice, rats and monkeys 
following single doses up to 1500 µg/kg, 3000 µg/kg and 5000 µg/kg respectively. In 
repeat-dose toxicity studies decreased body weight gain and food consumption, a known 
pharmacological effect of exenatide, were observed in all studies. Exenatide caused no 
mortality or target organ toxicities in mice, rats and monkeys at doses up to 760μg/kg/day 
(182 days), 250 μg/kg/day (91 days), or 150 μg/kg/day (273 days) respectively. 
Reproductive toxicity data from animal studies showed that Byetta had a toxicological 
effect on foetal development at three times the human exposure levels in treatment of 
diabetes. A summary of the findings of the exenatide toxicological assessment 
programme is presented in the Investigator Brochure for Presendin.  
1.1.3. 
Clinical Studies 
Exenatide has undergone extensive healthy volunteer studies and clinical trials for over 
15 years. It is licensed as a formulation for SC injection to be used in conjunction with 
diet and exercise to improve glycaemic control in adults with type 2 diabetes. Details of 
the trials conducted on exenatide, SC injection formulation, are presented in the Byetta 
Product Monograph (Section 15). Data from these studies are notable as the dose of 
exenatide to be used in the indication of IIH is intended to produce exposure levels not 
exceeding those experienced by patients receiving Byetta. It is anticipated that the 
proposed therapeutic dose of exenatide, in the modified release formulation Presendin, 
for treatment of IIH will be within the approved dose range of Byetta, achieving a level 
of total systemic exposure comparable with the immediate release Byetta formulation. 
Therefore, safety data available from the Byetta clinical development program are 
considered relevant and supportive of exenatide development in IIH.  
The efficacy of exenatide (Byetta) was evaluated in a Phase 2 randomised, placebo 
controlled, double-blind trial of exenatide in patients with active IIH (IIH:Pressure Trial). 
Sixteen patients with a diagnosis of active IIH (LP opening pressure >25 cm CSF and 
papilloedema) were identified and recruited to the trial. Participants had a telemetric ICP 
monitor implanted and were randomised to either exenatide (first dose was 2. 0 mcg 
followed by 10 mcg BD sub-cutaneous) or a matched placebo; allocation was 1:1. The 
treatment duration was 12 weeks. The trial was powered to seek significance to at least 
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alpha < 0.1 and power at least 80% using equal group sizes. Data was analysed by 
hierarchical regression analysis. 16 participants were recruited, 15 were randomised and 
completed the study. At baseline the mean age was 28 ± 9 years, BMI 38.1 ± 6.2 kg/m2, 
ICP 23.5 ± 3.9 (equivalent to 32.0 ± 5.3 cm CSF). The primary outcome, change in 
intracranial pressure between arms, was significant: at 2.5 hours -4.2 ± 2.1 mmHg 
(equivalent to 5.7 ± 2.9 cm CSF), p=0.04, at 24 hours -4.7 ± 2.1 mmHg (equivalent to 6.4 
± 2.9 cm CSF), p=0.03, and at 12 weeks -4.1 ± 2.2 mmHg (equivalent to 5.6 ± 3.0 cm 
CSF), p=0.05. A significant reduction in monthly headache days was also observed 
amongst those on exenatide (-7.7 ± 9.2, p-0.069). LogMar visual acuity also significantly 
improved in the exenatide treated arm (-0.1 ± 0.05, p=0.036). No significant weight loss 
was observed in either arm and hence weight change is unlikely to have contributed to 
the reduction kin ICP observed. Exenatide was safe and well tolerated: no treatment 
related SAE’s were reported, 8 adverse events were reported in those taking exenatide. 
The most frequent adverse event, amongst those taking exenatide, was nausea (7 reports), 
the majority of these were mild and all reports were self-limiting. There were no patient 
withdrawals due to adverse events.  
 
1.1.4. 
Trial Conduct 
This trial will be conducted in accordance with the requirements of this document (the 
Clinical Trial Protocol), the Trial Reference Manual and also in accordance with the 
following as per country specific requirements:  
• 
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013) 
• 
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016) 
• 
The United Kingdom Statutory Instrument 2004 No. 1031 and UKSI 2006 No.1928 
• 
European Union Directives 2001/20/EC and 2005/28/EC 
• 
United States Code of Federal Regulations Title 21 
• 
The Australian Therapeutic Goods Act, 1989, amended December 2020 and 
Therapeutic Goods Regulations, 1990, amended January 2021 
• 
Other country specific laws and regulations 
• 
Any amendments to these regulations  
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The safety of the study participants is of primary importance, and risks of involvement in 
the study, in particular with added challenges due to global pandemia of COVID-19, will 
be weighed against anticipated benefit for the study participants and society. 
Study sites may continue to recruit new participants, if deemed appropriate on benefit-
risk assessment as described, and provided that ALL of the following activities to 
preserve study integrity can be met: 
• 
Upon discussion with the site monitor, the study site has confirmed the ability to 
enrol and manage studies and participants effectively and in compliance with the 
protocol. 
• 
Upon discussion with the sponsor, medical monitor, or designee, the study site has 
confirmed that appropriate safety monitoring can take place, in compliance with the 
protocol. 
• 
Data will continue to be entered into the electronic Case Report Form (eCRF) and 
queries resolved in a timely manner. 
• 
The site monitor is able to access the study site to perform onsite monitoring or is 
able to perform remote monitoring of data. 
The sponsor recognizes that COVID-19 presents an increased risk for all participants. 
Due to the potential impact of COVID-19 on multiple organ systems, the sponsor 
recommends the following dose modification and management plan for participants with 
confirmed or suspected COVID-19 while receiving treatment with Presendin.  
All confirmed or suspected COVID-19–related adverse events (AEs) must be recorded in 
the eCRF and the Serious Adverse Event (SAE) Report Form if the event meets the 
seriousness criteria. SAEs are reportable to the sponsor immediately without undue delay 
after becoming aware of the event. All study-drug interruptions or modifications must be 
recorded on the AE and drug administration eCRFs. 
If a participant is diagnosed with COVID-19 or is suspected to have COVID-19, 
continuation of study drug, and any dose modifications should be assessed on a case-by-
case basis by the investigator, depending on the participant’s health status, and discussed 
with the medical monitor if needed. The COVID-19 infection should be managed as per 
local treatment guidance. 
. 
 
 
 
 
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1.2. 
Risk/Benefit Assessment 
1.2.1. 
Benefits 
1.2.1.1. 
Identified 
Improving IIH morbidity with new therapeutics is clearly identified as an unmet need. 
However, as this trial will study the use of an experimental, new drug against a placebo 
(no drug with a proven effect will be given as part of this study), no benefit can be 
assessed as identified.  
1.2.1.2. 
Potential  
Immediate-release exenatide (Byetta) was tested in the indication of IIH as a phase 2 
study. Reductions in ICP from baseline were observed in the exenatide group 2.5 hours, 
24 hours and 12 weeks after initiation of dosing (the level of significance was establish a 
prior as p<0.1).; the reduction achieved statistical significance at 24 hours (p=0.042; 
t-test). This suggests a potential benefit of exenatide, the active ingredient of Presendin, 
in treatment of IIH. The IIH Evolve trial is the first Phase 3 trial aiming to bring to 
market, and thus into clinical practice, a new drug to treat IIH. 
New treatments for IIH are a top priority as identified by patient groups. [Mollan 2019c]. 
Patients receiving the active treatment during the randomised period may benefit by 
experiencing an improvement in their IIH symptoms, although this cannot be guaranteed. 
1.2.1.3. 
Expected 
For the participants, there is no guarantee of an expected benefit from taking Presendin. 
However, patients in research trials typically benefit from increased disease monitoring 
and access to health care professionals.  
1.2.2. 
Risks  
Safety data for Presendin (exenatide) is based on the IB (Peptron Inc.). Warnings include 
pancreatitis and hypoglycaemia when used in combination with a sulfonylurea, renal 
impairment, severe gastrointestinal disease, and hypersensitivity.  
Invex Therapeutics has considered these warnings and has defined eligibility criteria to 
ensure patient safety is paramount. As such patients with known contraindications to 
GLP-1 agonists, such as pancreatitis, ketoacidosis, severe gastrointestinal disease and 
renal impairment, will not be included. Additionally, diabetic patients receiving glucose 
lowering medication will be excluded. 
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An Independent Adjudication Committee (IAC), as described in Section 14.5, will assist 
the Investigators (when required) with the eligibility criteria of the patients to be enrolled, 
and also to determine treatment failures to ensure patient safety and the efficacy of the 
trial 
1.2.2.1. 
Identified 
The active ingredient of Presendin, exenatide, has been used in clinical practice for over 
15 years. The most common adverse reactions experienced with exenatide in patients 
with other diseases under study (namely diabetes mellitus type 2) are nausea, 
hypoglycaemia (only when used with other glucose lowering drugs, but these patients are 
excluded from the trial), vomiting, diarrhoea, feeling jittery, dizziness, headache and 
dyspepsia. There is limited clinical data about Presendin itself, therefore the presented 
risk are based on the data available for a different extended-release formulation of the 
same active ingredient (exenatide). Based on that, the possible risks related to Presendin 
treatment are not all known. T following side effects have been reported (in patients with 
diabetes mellitus type 2) and identified as risks associated with the use of extended-
release exenatide. 
Very common: more than 10 out of 100 persons treated  
• Hypoglycaemia (with sulphylurea) 
• Nausea 
• Diarrhoea 
 
Common: 1 to 10 out of 100 persons treated  
• Injection site erythema 
• Injection site pruritus 
• Asthenia 
• Vomiting  
• Headache  
• Dizziness 
• Dyspepsia 
• Abdominal pain 
• Abdominal distension   
• Gastrooesophageal reflux disease 
• Constipation 
• Flatulence 
• Decreased appetite 
• Hypoglycaemia (with insulin) 
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• Pruritus and/or urticaria 
• Fatigue 
 
Uncommon: 1 to 10 out of 1000 persons treated   
• Dehydration 
• Dysgeusia 
• Somnolence 
• Intestinal obstruction 
• Eructation 
• Hyperhidrosis 
• Alopecia 
• Injection site rash  
• Altered renal function (including acute renal failure, worsened chronic renal failure, 
renal impairment, increased serum creatinine) 
 
Rare: 1 to 10 out of 10000 persons treated   
• Anaphylactic reaction 
• Feeling jittery  
 
The safety of the study drug, Presendin, has been investigated in two previous clinical 
studies involving healthy volunteers and diabetic patients, altogether 103 participants. 
Presendin has not been tested in IIH. The table below represents the expected side effects 
reported with Presendin given during a Phase 2 Presendin study to participants who 
received a similar dose of Presendin (1.6 mg Presendin every week). These studies are 
detailed in the Presendin IB. 
Side effects 
Percentage participants with an 
adverse reaction 
Injection site induration 
57.1%   
Injection site pruritus 
23.8% 
Injection site mass 
4.8% 
Injection site erythema 
4.8% 
Nausea 
9.5% 
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Dyspepsia  
9.5% 
Diarrhoea 
4.8% 
Decreased appetite 
4.8% 
Rash 
4.8% 
Itchy Rash (Urticaria) 
4.8% 
 
1.2.2.2. 
Potential  
There may be side effects that are not expected or not previously known, and these have 
the potential to be severe and/or serious. There is a potential risk of allergic reaction 
(anaphylaxis) that can be severe and/or serious. 
1.2.2.3. Expected 
Presendin is a new formulation of exenatide and is used in a new indication, all reported 
serious adverse reactions will be considered unexpected for the purpose of safety 
reporting. 
A Data Safety Monitoring Committee will be reviewing the safety data and will take 
decisions in order to protect the safety of participants.  
 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
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. Week 24 LP to be performed as per Appendix 1. 
2.2. 
Secondary Objectives 
To determine the effect of Presendin on change in:  
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• 
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 
 
2.3. 
Safety Objective 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
2.4. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Macular ganglion cell layer/complex thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes 
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
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3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
 
3.2. 
Secondary Endpoints 
• 
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.* 
*criteria defined in rescue therapy section 10.1.1 
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3.3. 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), , serious adverse 
events (SAEs) 
• 
Resting 12-lead electrocardiogram  
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
 
3.4. 
Exploratory Endpoints 
• 
Macular ganglion cell layer/complex thickness 
• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes (PRO): 
• 
Visual Function Questionnaire-25 and 10-item supplement 
• 
Headache Impact Test-6 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
• 
Patient Global Impression of Change  
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
 
 
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4.
TRIAL DESIGN
4.1. 
Summary of Trial Design 
4.1.1. 
Trial Design 
This will be a randomised, placebo-controlled, double-blind, multi-centre clinical trial in 
approximately 240 randomised patients with IIH.  
Exenatide pharmacokinetics will be conducted and population PK modelling may be 
performed. 
Randomised, double-blind, placebo-controlled trials are considered the “gold standard” 
for determining the efficacy and safety of an investigational drug where there is no 
approved therapy. The trial is designed to compare the efficacy and safety between an 
investigational drug group and a placebo control group. The randomised, double-blind, 
placebo-controlled trial design is clinically and methodologically justified because it 
reduces bias. Use of this trial design will provide reliable evidence that supports the 
efficacy of the investigational drug, Presendin, for the treatment of IIH. 
Participants assigned to the placebo arm are not expected to be exposed to serious or 
irreversible harm as a result of not receiving unlicensed, potentially (intracranial) 
pressure lowering medication. There is no licensed therapy to treat IIH. In a previous 
investigator led randomised controlled trial (RCT), the IIH Treatment Trial (IIHTT), a 
similar population of IIH patients were recruited. (Wall et al., 2014) Both the previous 
IIHTT and this trial (IIH EVOLVE) will recruit medically treated IIH patients with 
analogous eligibility criteria and disease severity (papilloedema and visual fields which 
are mild to moderately impaired (Humphrey visual field mean deviation between -2dB 
and -7dB). Akin to this trial, the IIHTT had a 6 month randomisation period (and hence 
79 patients were on placebo for 6 months). Of these 79 patients, 6 deteriorated (classified 
as treatment failures requiring rescue therapy). We would predict that a similar 
proportion of patients in this trial (6.7%) will require rescue therapy whilst on placebo.  
No irreversible harm came to those on placebo in the IIHTT and we would anticipate the 
same in this trial. The pathway to identify treatment failures and initiate rescue therapy in 
the IIHTT was well described and will be akin to the pathway in this trial to ensure that 
those patients requiring rescue therapy are rapidly identified and treated. In those patients 
with treatment failure requiring rescue therapy, the medical team at the site can initiate 
the most appropriate rescue therapy as per usual clinical practice. This could include 
adding in an off-licence intracranial pressure lowering medication (as is sometimes done 
in some current clinical practices) or a surgical procedure if appropriate.  
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We do not predict a meaningful placebo response rate for the primary outcome measure 
as this is an objective measure with negligible placebo response observed in previous 
randomised placebo controlled trials. This is akin for other objectively measured 
outcomes (including perimetric mean deviation and optical coherence tomography 
measures) where changes in the placebo arm have been noted in previous IIH studies and 
interpreted as regression to the mean and disease remission. (NORDIC study working 
group JAMA 2014). A placebo response is, however,  well described for headache 
outcomes (Mitsikostas DD et al, 2020). In trial participant taking an oral headache 
preventative therapeutic, this is estimated at 21%  and higher for an injected therapy 
(Autret A et al, 2012). A systematic review of placebo response rates established that the 
more invasive the placebo the higher the placebo response rate  (33.5% for injection vs 
27.5% for oral drugs) (Evans K et al, 2021). In the IIH Evolve trial, headaches outcomes 
are secondary outcome, s measures and as such the IIH Evolve trial is not explicitly 
powered for these measures, but awareness of the placebo response was considered 
during the study design. 
The trial will begin with a 1-week screening period. Although a headache diary is 
typically over 28 days, for IIH headache it was felt necessary to shorten this period 
during which no other planned assessments of vision were scheduled.   Headache diaries 
designed to measure headache frequency have been successfully utilised over shorter 
time periods in previous IIH trials and noted to be representative [NORDIC, 2018; 
Mollan, 2021b]. Hence the baseline headache frequency will be calculated over 1 week. 
Patients will be provided with training on the self-administration of the trial medication 
from the site trial coordinator and provided with a leaflet to take home at the screening 
visit. Patients will be asked to self-administer placebo during the screening visit to ensure 
they are comfortable with self-injection. Patients who are not comfortable with self-
administration will be deemed screen failures, and not be randomised into the trial. The 
purpose of the screening period will be to establish baseline measurements and assess 
trial eligibility.  
The 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 SC dose of either Presendin 
(containing 2mg 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 that treatment visit, an end of trial 
safety follow-up telephone visit will be performed. In the event of any abnormal safety 
assessments or ongoing adverse event(s) identified at end of treatment; for example, an 
abnormal ECG or abnormal routine laboratory results, this visit may be performed at the 
clinic and a safety follow-up performed as appropriate.  
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The duration of the randomised treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy by 3 months. 
Additionally, an alternative off label drug used in IIH (acetazolamide) was evaluated over 
a 6-month period. Hence efficacy is relevant over this time frame. A longer period of 
randomisation would not be ethical if patients were expected to remain on placebo for 12 
months as this could place their overall health at risk. 
Assessments will be performed as outlined in Table 1. 
A schematic diagram of the trial can be seen in Figure 1. 
 
 
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Figure 1: Schematic Diagram 
 
 
4.1.2. 
Randomisation and Blinding 
At the end of the Screening period, eligible patients will be randomised to receive either 
Presendin or matching placebo in a 1:1 ratio using a computer system to generate 
randomisation codes. 
Investigators and other site personnel, patients, contract research organisation and 
Sponsor personnel will be blinded regarding the treatment during the randomised period. 
Only designated unblinded staff, not involved in the operational conduct of the trial, will 
be aware of the randomisation codes. 
The placebo will have the same appearance and reveal no differences, during 
administration, to either the Investigator or the patient. 
4.1.3. 
Duration of Patient Participation 
The duration of the trial for each patient will be up to 30 weeks, which includes a 1-week 
screening period, a 24-week randomised treatment period and a treatment follow-up 
period of 5 weeks.  
1 week 
screening period 
Treatment 
___ 
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Placebo 
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24 ·weeks rand-
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double-blind treatment 
period 
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Eadof 
Treatm•t mit 
-----+-
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Safety follow 
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4.2. 
Stopping Rules 
4.2.1. 
Trial Stopping Rules 
There are no trial-specific stopping rules. The Sponsor maintains the right to stop the trial 
at any point. If this is done, then the Sponsor will provide the Investigators with the 
rationale for such early termination. 
4.2.2. 
Individual Stopping Rules 
Patients will be withdrawn from the trial medication if they are unable to tolerate the trial 
medication and will continue to attend trial visits as per protocol. See Section 11 for 
further details. A Data Safety Monitoring Committee (DSMC) will be involved in 
decisions for patient safety (Section 14.6). 
4.3. 
End of Trial 
The end of trial is defined as last patient last visit. 
5. 
TRIAL POPULATION 
5.1. 
Number of Patients 
It is anticipated that approximately 350 patients will be required to enter the screening 
phase for 240 patients to be randomised into the treatment phase. 
5.2. 
Eligibility Criteria 
5.2.1. 
Inclusion Criteria 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.2, Appendix 2), 
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  
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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 – see Section 16.8, Appendix 8 for
further details) 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.
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5.2.2. 
Exclusion Criteria 
Patients will not be enrolled if they meet any of the following 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 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] 
Headache related exclusion criteria: 
10. Does not complete ≥6 days of electronic/paper trial diary during the 7-day 
screening period 
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Other exclusion criteria: 
11. Untreated previously diagnosed obstructive sleep apnoea with historically 
recorded apnoea­hypopnea 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 
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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 
 
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 – see section 10.1.2
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6. 
TRIAL ASSESSMENTS AND PROCEDURES 
6.1. 
Procedures at Each Visit 
Trial procedures and timings are presented in the Time and Events Table, Table 1. 
No procedures should be performed prior to obtaining informed consent. All visits (except 
telephone call visits) should be performed at the clinic. Should a clinic visit not be possible, 
due to a patient self-isolating, the visit will be conducted at the earliest opportunity and 
will not constitute a protocol deviation. 
6.1.1. 
Visit 1 Screening 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Visit 
procedures can be performed in a single visit or over a number of visits during the 
screening period. Ideally all screening procedures should be performed on the same day.  
• 
Obtain patient’s written informed consent 
• 
Eligibility criteria 
• 
Including confirmation that diagnostic LP occurred within the last 4 weeks with 
an opening pressure ≥ 25 cm CSF in lateral decubitus position  
• 
Demographics (sex, age and ethnicity) 
• 
Medical and ophthalmic history 
• 
Concomitant mediation history 
• 
Headache history (including family history of migraine (a first degree relative with 
and migraine) and headache in the 7 days prior to diagnostic LP) 
• 
Headache preventative medication review 
• 
Headache diary dispensed and diary training – to be performed on first day of 
screening. 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Height, body weight and BMI 
• 
Full physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
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• 
Visual Assessments to both eyes 
• 
Frisén grading will be initially assessed by the site and then the presence of 
papilloedema verified by the OCT Reading Centre. Where there is uncertainty, 
fundus photos and or ultrasound scan (B scan) of the optic nerve may be 
conducted for evaluation by the IAC to confirm eligibility. 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site.  
• 
Humphrey Visual Field (24-2 SITA-Standard using a size III white stimulus)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay, and where there is uncertainty about 
eligibility this should be referred to the IAC. 
• 
Visual Acuity (LogMAR score) 
• 
Laboratory assessments 
• 
Trial medication training. Patients will be asked to self-administer 1 dose of placebo 
at the screening visit to ensure they are comfortable with self-injection. Patients who 
are not comfortable will be excluded 
6.1.2. 
Visit 2 Baseline 
• 
Review eligibility criteria 
• 
Concomitant medications review 
• 
Headache preventative medication review 
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• 
Review headache diary (Patient must meet required number of headache days as per 
inclusion criteria. If the headache diary exceeds 7 days, then eligibility will be based 
on the last 7 days of the screening period, i.e., the 7 days prior to randomisation visit) 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI 
• 
Adverse events review 
• 
Targeted physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
• 
Visual Assessments to both eyes 
• 
Frisén grading will be assessed by the site 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary 
• 
Health Utilisation Form 
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• 
Laboratory assessments 
• 
Anti-Drug Antibodies (ADA) blood sampling  
• 
Patient randomised  
• 
Trial medication training 
• 
Trial medication dispensed and first dose self-administered at clinic. This is a drug 
with a known tolerability and safety profile and hence there is so specific 
requirement on the duration of observation after injection. Subjects can be 
discharged from the site at the investigator’s discretion. Patients will then be 
instructed to administer subsequent doses once weekly. 
• 
Pharmacokinetic sampling (post-dose) 
6.1.3. 
Visit 3 Telephone call 
All patients will receive a telephone call at visit 3 to conduct headache preventative 
medication review, check for any AEs or changes in medication, procedures outside of 
protocol, health utilisation, to remind them to complete their diary and to answer any 
questions they may have on administration or storage of the trial medication.  
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI (not visit 4) 
• 
Adverse event review 
• 
Targeted physical examination (visit 6, 8 and 9 only) 
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
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 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload processes to the OCT Reading Centre, without delay. 
The OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary (not visit 4)  
• 
Health Utilisation Form 
• 
Laboratory assessments  
• 
Pharmacokinetic blood sampling  
• 
Anti-Drug Antibodies blood sampling  
• 
Trial medication dispensing (not Visit 4) and accountability - patients should be 
reminded by the trial site to self-administer the trial medication weekly and to return 
used and unused trial medication at clinic visits 
6.1.5. 
Visit 10 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial 
medication and must have self-administered their final dose within 7 days of visit 10. 
Patients will be reminded by the trial site to self-administer trial medication weekly, to 
continue this until the completion of visit 10 and to bring their trial medication with them 
at visit 10 for return.  
Where more than one dose has been missed during the 4 weeks preceding visit 10, visit 
10 should be delayed. Self-administration of trial medication should continue at 7-day 
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intervals and then visit 10 rescheduled to ensure no more than one dose of the trial 
medication has been missed in the previous 4 weeks. Visit 10 should be delayed no more 
than 14 days. 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI  
• 
Adverse event review 
• 
Targeted physical examination  
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Lumbar puncture (within 7 days of last dose of trial medication) 
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• 
Lumbar puncture to be performed ideally after visual assessments 
• 
Performed in the lateral decubitus position according to LP SOP Appendix 1 
• 
In some cases the lumbar puncture might be conducted using imaging guidance 
according to the preference of the individual and site. This could be using x-
rays, computer tomography or ultrasound guidance. 
• 
If the procedure is not successfully performed it should be re-booked and 
repeated as soon as possible and the patient should remain on trial medication 
with the last dose within 7 days of the LP. 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary  
• 
Health Utilisation Form 
• 
Patient global impression of change question 
• 
Laboratory assessments 
• 
Pharmacokinetic blood sampling 
• 
Anti-drug antibodies blood sampling  
• 
Trial medication accountability 
Where it is not feasible to conduct all of visit 10 procedures on the same day, these could 
be split provided visual assessments are performed before the LP and the patient remains 
on trial medication with the last dose within 7 days of the LP. 
6.1.6. 
Visit 11 Follow-Up  
This visit will be performed as a telephone call to conduct headache preventative 
medication review and check for any AEs or changes in medication. In the event of any 
abnormal safety assessments identified at the end of treatment, e.g., abnormal ECG, 
abnormal routine laboratory results or ongoing adverse events, this visit may be 
performed at the clinic to repeat or follow up safety assessments. 
A urine pregnancy test (for women of childbearing potential) will be performed, this can 
be conducted at home if the visit is performed by telephone call. 
 
6.1.7. 
Unscheduled visit for repeat visual assessments 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients where 
there is concern about their visual decline or who perform inadequately or where there is 
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technical failure (more than 15% false positive responses or inadequate performance 
indicated by the Visual Field Reading Centre for HVF; or OCT imaging not of 
satisfactory quality as determined by the OCT Reading Centre). Imaging only in the 
study eye(s). 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should go 
through the upload process to the OCT Reading Centre. The OCT scan will 
then be reviewed by the OCT Reading Centre for a full quality assessment. 
The report from the OCT Reading Centre will be sent to the site. Where the 
OCT is of insufficient quality it should be repeated as soon as possible at an 
unscheduled visit. Where the OCT processing is of insufficient quality it 
should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. Quality 
reports from the Visual Field Reading Centre will be received by the site. 
Where the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
 
6.2. 
Trial Procedures 
6.2.1. 
Screening Procedures 
6.2.1.1. 
Demographics 
The Investigator, or designee, should record the patient’s sex, ethnicity, age, height, body 
weight and BMI at screening. 
Ethnicity data will be collected in order to monitor any response differences in IIH 
disease progression/symptoms in different ethnicities. 
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6.2.1.2. 
Medical, Headache and Ophthalmic History 
The Investigator, or designee, should record any ongoing co-morbidities and significant 
medical, headache and ophthalmic history along with the year in which such 
co-morbidities began (where known).  
6.2.1.3. 
Reporting of Prior and Concomitant Medication 
Concomitant treatment is any medication or therapeutic intervention being continued by 
the patient at trial entry and any new medication received during the trial. Prior treatment 
includes previous medications, treatments and interventions received in the past but no 
longer ongoing. 
For this trial, only relevant prior concomitant medications within the last 4 months will 
be recorded. These include: 
• 
Treatment to lower ICP (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)  
• 
Headache preventative medication (including oral or botulism toxin A or monoclonal 
antibodies against CGRP or CGRP antagonists, or greater occipital nerve block)  
• 
GLP-1 receptor agonist 
• 
Warfarin 
• 
Glucose lowering medication 
• 
Recreational or illicit drugs 
At every visit the Investigator or a qualified designee will ask the patient about relevant 
concomitant medication. 
No new medication should be started during the trial, unless medically necessary. The 
patient should be advised to consult the Investigator or designee before taking any 
prescribed or over-the-counter medications. In the case of headache preventative 
medications or ICP lowering medications please see details in the rescue therapy section. 
Acute headache analgesics are permitted and should be reported in the diary. 
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6.2.2. 
Safety Procedures 
6.2.2.1. 
Physical Examination 
A full physical examination will be performed at the screening visit. At a minimum the 
following will be assessed: ear, nose and throat, cardiovascular system, pulmonary 
system, skin, abdomen and neurological system. At all other time points a targeted 
(symptom directed) examination will be performed at the Investigator’s discretion. 
6.2.2.2. 
Twelve- Lead Electrocardiogram  
Twelve lead ECGs should be performed at the times outlined in the Time and Events 
table (Table 1) in a standardized manner, i.e., after the patient has rested in the semi-
supine position for at least 10 minutes. Measurements will be made using an ECG 
machine that automatically calculates the heart rate and measures PR, RR, QRS, and QT 
intervals.  
All ECG traces will be reviewed and signed by the Investigator or designee and any 
abnormalities will be marked as clinically significant or not clinically significant. 
6.2.2.3. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure and heart rate, will be 
measured at the time points specified in Table 1. 
Patients should rest in a supine position for 10 minutes before the vital signs are assessed. 
Three recordings will be taken and averaged.  
6.2.2.4. 
Laboratory Assessments 
Blood and urine samples will be processed at the site. Routine biochemistry and 
haematology samples will be evaluated at the trial appointed central laboratory. PK, ADA 
and CSF samples will be stored at the central laboratory and evaluated at a qualified 
international laboratory. Details of handling and shipping are described in the Laboratory 
Manual.  
6.2.2.4.1. Haematology 
Blood for the assessment of haematology parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
• 
Total blood count; consisting of: 
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• 
Red blood cells  
• 
Haematocrit 
• 
Mean cell volume 
• 
Mean cell haemoglobin 
• 
Mean cell haemoglobin concentration 
• 
Glycated haemoglobin (HbA1C) 
• 
Blood glucose (non-fasting) 
• 
Platelets 
• 
White blood cells 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Coagulation (prothrombin time, international normalised ratio, activated partial 
thromboplastin time, thrombin time, fibrinogen) 
• 
Basophils 
6.2.2.4.2. Clinical Chemistry 
Blood for the assessment of clinical chemistry parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be assessed 
during the trial: 
• 
Sodium  
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Total bilirubin 
• 
Total protein 
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•
Albumin
•
Alanine transaminase
•
Aspartate aminotransferase
•
Alkaline phosphatase
6.2.2.4.3. Urinalysis 
Urine samples will be collected at the times outlined in the Time and Events table (Table 1). 
The following parameters will be assessed at each time point: 
•
Glucose
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Protein
•
Urobilinogen
6.2.2.4.4. CSF
CSF sample from visit 10 LP will be retained for future potential analysis of disease and 
drug related biomarkers. 
6.2.2.4.5. Pregnancy 
At screening blood will be collected to enable a serum pregnancy test to be performed. At 
visits thereafter, urine will be collected from female patients of childbearing potential at 
the times outlined in the Time and Events table (Table 1) to enable highly sensitive urine-
based pregnancy tests to be performed. Female patients who are identified as being 
pregnant during the trial will be withdrawn from further treatment but will continue to 
attend safety follow-up visits.  
The Investigator or designee should report any pregnancies in female patients to the 
Sponsor or designee, using the Pregnancy Report Form, within 24 hours. The contact 
details for reporting are: 
 
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Female patients or partners of patients who become pregnant should be followed until 
delivery, stillbirth or termination. The outcome of the pregnancy and, if applicable, the 
health of the baby, should be reported to the Sponsor using the Pregnancy Report Form. 
6.2.2.4.6. Pharmacokinetic sampling 
Pharmacokinetic sampling is to characterize the pharmacokinetics of exenatide after once 
weekly subcutaneous administration of Presendin at the times outlined in the Time and 
Events table (Table 1). 
The primary purpose of the pharmacokinetic sampling is to characterize the steady state 
concentrations of exenatide. All actual sampling times and dosing times will be recorded. 
Sampling and processing will be performed as described in the Laboratory Manual. 
6.2.2.4.7. Anti-drug Antibodies sampling 
Anti-drug antibodies sampling will be performed in all subjects at the times outlined in 
the Time and Events table (Table 1). 
Sampling and processing will be performed as described in the Laboratory Manual. 
6.2.2.5. 
Adverse Events 
Patients will be asked non-leading questions to assess how they are feeling at each clinic 
visit. Adverse events will be assessed and reported as outlined in Section 12. 
6.3. 
Efficacy Procedures 
6.3.1. 
Intracranial Pressure 
Assessment of ICP will be measured by LP in the lateral decubitus position. The 
diagnostic LP is performed by the clinical team prior to recruitment and the measurement 
must be made from the lateral decubitus position. The research LP will be performed 
according to LP standard operating procedure (SOP), Appendix 1. Lumbar puncture will 
ideally be performed after visual assessments as outlined in the Time and Events table 
(Table 1).  
In some cases the lumbar puncture might be conducted using imaging guidance according 
to the preference of the individual and site. This could be using x-rays, computer 
tomography or ultrasound guidance. 
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Any additional LP procedures, outside of the protocol would constitute a protocol 
deviation and ideally should be discussed with the Investigator before the procedure is 
performed.  
Non-protocol LPs should be recorded in the Case Report Form. 
6.3.2. 
Visual Assessments 
Visual assessments should be performed on both eyes. All visual assessments should be 
uploaded without delay on the day of the visit to the OCT and Visual Field Reading 
Centres. In all cases the site is responsible for initial checks of the clinical data in the 
wider context of the patient’s disease, as well as a data quality check. 
6.3.2.1. 
Frisén grade  
At Screening (visit 1) Frisén grading (0 – 5) should initially be performed at the site 
through a dilated pupil. The presence of papilloedema  will be verified  by the OCT 
Reading Centre at screening (visit 1) and a report sent to the site.  During screening, 
where there is uncertainty regarding the presence of papilloedema and / or Frisén grade a 
fundus photo and or ultrasound scan (B scan) of the optic nerve may be conducted (or 
may be requested by the OCT Reading Centre) and if uncertainty persists evaluated by 
the IAC. 
At Baseline (visit 2) sites will reconfirm the Frisén grade 
6.3.2.2. 
Optical Coherence Tomography 
Imaging may be acquired using Heidelberg Engineering or Cirrus platforms according to 
the OCT SOP. Key measures are RNFL, optic nerve head size, and macular ganglion cell 
layer/complex thickness.. 
• 
Sites should initially check the clinical interpretation of the OCT scan and scan 
quality. The OCT should then go through the upload processes to the OCT Reading 
Centre. The OCT will then be reviewed by the OCT Reading Centre for a full quality 
assessment. The report from the OCT Reading Centre will then be sent to the site. 
Where the OCT is of insufficient quality, it should be repeated as soon as possible. 
Where the OCT has not been processed correctly at the site the processing should be 
re-performed as soon as possible thereafter. Repeated or reprocessed images would 
then be again transmitted to the OCT Reading Centre for a full assessment. 
• 
If the site is concerned with the OCT findings, suggesting that the patient is a 
potential treatment failure and may require rescue therapy, the OCT Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
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6.3.2.3. 
Humphrey Visual Field 
The visual field will be measured by Humphrey Visual Field analysis (24-2 SITA-
Standard) including standardised refraction as indicated, according to the Visual Field 
Centre SOP (Manual of Procedures).  
• 
At screening HVF will be reviewed by the Visual Field Reading Centre to confirm 
eligibility. 
• 
Inability to perform a reliable visual field examination as deemed by the Visual Field 
Reading Centre in study eyes (including >15% false positives), is an exclusion 
criterion. HVF can be repeated to obtain as assessment with reliable performance. 
• 
If the site is concerned with the HVF findings, suggesting that the patient is a 
treatment failure and may require rescue therapy, the Visual Field Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
6.3.2.4. 
Visual Acuity  
Assessment of visual acuity will be recorded using a LogMAR chart (unaided, best 
corrected, and with pin hole). 
6.3.3. 
Headache Assessments 
Patients will be provided with an electronic/paper diary at screening to complete during 
the trial. Information collected will be used to assess the following headache parameters: 
• 
Monthly headache days 
• 
Monthly moderate to severe headache days 
• 
Responder rate 
• 
Monthly acute analgesic use 
• 
Headache severity (11-point NRS) 
 
6.3.3.1. 
Headache Preventative Medication Review 
A review of any headache preventative medications taken by the patient will be 
undertaken at each clinic visit. If the Investigator alters the headache preventative 
medication, this will be considered rescue medication (Section 10.1.1) and the IAC 
consulted. Use of headache preventative medication will be recorded at trial visits as 
outlined in the Time and Events table (Table 1). 
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Patients will record their acute headache analgesic use in their trial diary. 
6.3.4. 
Patient Reported Outcomes 
6.3.4.1. 
Visual related 
Assessment of visual related quality of life will be derived from self-reported responses 
to the VFQ-25-10 item supp (see Section 16.6 Appendix 6). 
6.3.4.2. 
Health-related 
Assessment of health-related quality of life will be derived from self-reported responses 
using the following questionnaires: 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
A Healthcare Utilisation Form will be completed by the trial site staff at clinic visits. 
All questionnaires can be found in Section 16, Appendix 3 for SF-36 and Appendix 4 for 
the EuroQoL- 5D-5L survey. 
6.3.4.3. 
Headache related Quality of Life 
Assessment of headache-related quality of life will be derived from self-reported 
responses to the Headache Impact Test-6 questionnaire and performed at time points as 
outlined in the Time and Events table (Table 1). A copy of this questionnaire can be 
found in Section 16.5, Appendix 5. 
6.3.4.4. 
Patient Global Impression of Change  
The Patient Global Impression of Change will be conducted at visit 10, as outlined in the 
Time and Events table (Table 1).  
It is a single item questionnaire using a seven-point verbal response scale to assess 
overall change in the patient’s status since taking trial medication. A copy of this 
questionnaire can be found in Section 16.7, Appendix 7 
6.3.5. 
Body Weight and Body Mass Index 
The patient’s body weight and BMI will be measured at the time points as outlined in the 
Time and Events table (Table 1).  
The patient’s height will be measured at Screening (shoes off).  
 
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7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS 
The COVID-19 global pandemic presents numerous challenges to the conduct of ongoing 
clinical trials. In line with the FDA and European Medicines Agency's Guidance on the 
Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic 
(EMA, 2021), the following protocol considerations are provided to ensure patients 
safety is maintained and adequate benefit/risk analyses are applied relative to the 
completion of study procedures and maintaining the investigational product supply chain.   
Recognizing the flexibility required to manage the impact of the pandemic (or other 
global crisis) on this clinical study, additional details will be added to respective study 
manuals, project plan documents, and communicated to the investigative sites as needed.  
For any additional questions, the investigator should confer with the sponsor. 
Number of Trial Patients 
The evolving situation of the pandemic (or other global crisis) may result in a substantial 
number of patients’ early withdrawal from the study, which could affect the data integrity 
of the study.  Because of this risk, the sponsor may decide to recruit additional patients in 
the study, beyond the expected number, to mitigate such risk. 
Study Visits 
There are a number of on-site visits that would be required to ensure study validity.  If 
there are local travel restrictions, isolation requirements, or the investigator determines it 
to be unsafe for patients to attend their scheduled study visits, the site staff may conduct 
certain visits via telemedicine (phone or video calls) to minimize patient risk as follows. 
Screening Period 
The following visit must be performed in person: 
• Screening/Visit 1 
Note:  To minimize direct, in-person contact between site personnel and patients, 
certain screening procedures may be performed remotely via telemedicine.  All 
other procedures should be done in-person while the subject is on-site.  
Specifically, the following procedures may be done remotely: 
o Informed consent (where applicable, per approved IRB/IEC process) 
o Demography 
o Medical and ophthalmic history 
o Concomitant medication history 
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o Headache history 
o Headache preventative medication review 
o Train and dispense headache diary 
o Trial medication training 
Randomised period 
• Baseline (Visit 2) 
There are essential aspects to the baseline visit which must be performed in 
person. 
If the baseline visit is delayed the headache diary should utilise the preceding 7 
days data. Where the visit is delayed by more than 10 days due to a global crisis 
the patient will be considered to have failed screening.  Patients who screen failed 
due to the pandemic (or other global crisis) may be rescreened at a later time, if 
feasible. 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 4, 5, 6, 7, and 8 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
o Urine pregnancy test 
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o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 10 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
o Lumbar puncture* 
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* Lumbar puncture to be ideally performed after visual assessments. In the 4 weeks prior 
to visit 10, patients must not have missed more than one dose of trial medication and 
must have self-administered their final dose within 7 days of visit 10. Patients will be 
reminded by the trial site to self-administer trial medication weekly, to continue this until 
the completion of visit 10 and to bring their trial medication with them at visit 10 for 
return.  
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days, if 
possible, but this can be extended according to local government policy if a patient is 
unable to attend (for example if a patient is self-isolating) as long as medication use is 
maintained as above. 
 
• Follow up/ Visit 11 
This should be performed as a telephone visit unless clinical contact is necessary, as 
per protocol. Where face to face contact is required, this should be conducted at the 
earliest available opportunity.  
 
Study Drug Dispensation and Distribution 
If a patient is not able to attend a clinic visit, to ensure the continuity of providing 
patients’ study drug within the constraints imposed by the pandemic (or other global 
crisis), the site staff may decide to supply study drug to patient as follows: 
o Adequate supplies of study drug can be shipped to the patient by the study staff 
using a third-party service with approval from the patient.  The third-party vendor 
will be agreed upon with the sponsor. 
o The patient may request, with prior arrangement/agreement with the site, an 
authorized individual (a relative or delegate) to retrieve the study drug from the 
study site if the patient is unable to personally to do so. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed; however, the site monitor will continue to 
employ off-site monitoring practices such as routine communication methods (e.g., phone 
calls, emails, video visits) with the sites to get information on study progress, patient 
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status, and information on issue resolution as detailed in the Data Monitoring Guidelines, 
Remote source data verification. 
If the trial site monitor cannot be on-site to carry out the final drug accountability for 
reconciliation purposes, and the operation cannot be postponed, it may be carried out by a 
pharmacist from the site pharmacy or by the study coordinator/data manager with suitable 
training. The study drug can be returned to the sponsor by the site pharmacy directly, or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 
Direct Contracts with Third Parties/Specialized Service Companies 
If necessary, direct contracts can be established with third-party local physicians to 
conduct activities related to the clinical management of patient for whom the investigator 
is responsible and maintains oversight.  In such situations, the investigator is required to 
provide the local physician with a delegation letter listing all delegated activities.  The 
sponsor, through the study investigator or institution, will reimburse the local physician 
for the test/procedures conducted outside of the standard of care. 
Clinic visits should take place to the extent possible and usual protocol requirements 
adopted for all subjects as soon as the crisis-related limitations permit. 
All safety data that are possible to obtain locally should be collected at a remote visit. 
These measurements may include the use of local practitioners and resources. 
Exceptional measures taken in response to a crisis (e.g., COVID-19) and their impact on 
study results, such as tests done in a local laboratory, will be explained, assessed and 
reported in the clinical study report following ICH E3 guidance. 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS 
Patients will receive lifestyle advice as per routine care from their treating physician. 
9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Dosage and Administration 
9.1.1. 
Randomised Period 
During the 24-week randomised treatment period (Figure 1) patients will be randomised 
in a 1:1 ratio to receive active treatment or placebo. 
Either 
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Presendin (2.0mg exenatide) as a SC injection, self-administered once weekly. 
Presendin is supplied as 2 parts, one vial consisting of a drug part (white or grayish 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 as a 
suspension.  
or 
Placebo as a SC injection, self-administered once weekly. 
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 as a suspension. 
9.2. 
Dose Rationale 
The proposed 2mg weekly dose was based on the pharmacokinetic performance of the 
Peptron formulation (PT320). Pharmacokinetic profiles obtained after repeated once 
weekly dosing of 2mg of PT320 s.c. (as specified in the Presendin IB phase 2 clinical 
study in patients with type 2 diabetes) were comparable to those predicted by the 
population PK model developed for weekly s.c. administration of the recommended dose 
of the 2mg Bydureon extended-release formulation [Cirincione 2017],with time to reach 
the steady state slightly shorter for PT320 than for Bydureon (7-8 weeks vs 8-10 weeks) 
and with steady state plasma concentrations remaining within a comparable range for 
both products. Based on the same molecule and dose, comparable plasma concentrations 
for PT320 and Bydureon and the established safety profile of Bydureon a similarly 
acceptable safety and tolerability profile for PT320 is expected. 
9.3. 
Maintaining the Blind 
This is a double-blind trial.  
A computer/website system will be used to maintain the blind for this trial. The site will 
be provided with website login details for the system. If the Investigator needs to unblind 
a patient’s treatment, due to a medical emergency, the website should be accessed to 
unblind for that patient. . 
The responsibility to break the treatment code in emergency situations resides solely with 
the investigator. 
 
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9.4. 
Treatment Assignment 
Patients will be randomised in a ratio of 1:1 to receive active treatment (Presendin) or 
placebo. A computer/website system will be used to randomly assign each patient to a 
treatment arm.  
9.5. 
Packaging and Labelling 
Individual supplies of trial medication will be provided to the sites in a double-blind 
format. The labels will contain all information required to meet the applicable local 
regulatory requirements. 
Further information on packaging, labelling and dispensing are included in the Pharmacy 
Manual. 
9.6. 
Preparation 
Each dose of trial medication is provided as two parts, a single use vial and a pre-filled 
syringe of diluent. Patients will receive training and be provided with an instruction sheet 
with details, on how to store, prepare, self-administer and discard/keep used trial 
medication.  
9.7. 
Handling and Storage 
Presendin, the active trial medication, contains the active ingredient, exenatide, which is 
hygroscopic and light sensitive and must be protected from light during storage. Prior to 
use, all trial medication should be stored refrigerated at 2-8ºC.  
9.8. 
Product Accountability and Assessment of Compliance 
In accordance with International Council of Harmonisation – Good Clinical Practice 
(ICH-GCP), each trial centre will account for all supplies of trial medication. Details of 
receipt, storage, assembly, and return will be recorded. The unit of accountability will be 
one single active or placebo vial. Needles will be disposed of in a sharps box. 
All unused supplies will either be destroyed or returned to the trial Sponsor at the end of 
the trial in accordance with instruction by the Sponsor. 
All trial medication will be self-administered by the patients. If a dose is not administered 
as planned, patients will record the missed dose in their electronic/paper diaries and it 
will be documented in the electronic case report form (eCRF). 
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9.9. 
Treatment of Investigational Product Overdose 
Definition of Overdose: More than 1 (one) dose in 24 hours. 
In the event a patient overdoses on trial medication the Investigator should be notified as 
soon as possible. If symptoms appear, the Investigator will treat the patient according to 
their clinical judgement depending on the type of clinical signs and symptoms exhibited 
by the patient. The Sponsor should be notified in writing within 24 hours of the 
Investigator becoming aware. 
Effects of overdose that may be seen include severe nausea, severe vomiting and rapidly 
declining blood glucose concentrations. 
9.10. 
Occupational Safety 
There are no known occupational safety risks to staff. The Material Safety Data Sheet 
will be made available where required by local regulations. 
10. 
TREATMENT FAILURE AND RESCUE THERAPY 
PROCEDURES 
10.1. 
Treatment Failure 
Rescue therapy can be initiated when there is a treatment failure. Since perimetric 
variability increases with increasing visual field damage, a two-tiered approach is used 
[Wall, 2013].  
10.1.1. 
Possible treatment failure  
Possible treatment failure is defined as those with baseline PMD between -2 and -3.5dB 
who experience a decline of > or equal to 2dB. In those with a baseline PMD between -
3.5 and -7 dB, those who experience a decline of  > or equal to 3 dB.  
When a possible treatment failure is identified, perimetry, and if needed, other visual 
tests, should be repeated at an unscheduled visit. 
 
10.1.2. 
Definite treatment failure  
A definite treatment failure occurs when a patient with baseline PMD between -2 and -
3.5dB experiences a decline of  > or equal to 2dB which remains after repeat perimetry. 
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Or in those with a baseline PMD between -3.5 and -7 dB who experience a decline of > 
or equal to 3 dB which remains after repeat perimetry.  
These cases should be reviewed without delay by the IAC (who will review all visual and 
clinical data) to confirm or refute a definite treatment failure. 
10.2. 
Rescue Therapy/Rescue Intervention for Progressive Visual 
Loss 
When a treatment failure occurs, rescue therapy can be initiated, in addition to study 
treatment, based on the medical judgement of the Investigator. Decisions should always 
be discussed with the IAC without delay and if possible before any action is taken, unless 
in the opinion of the Investigator there is no time to do so as it is judged to be a medical 
emergency. In all cases the final decision lies with the Investigator. 
Patients showing progressive visual loss will be considered for rescue therapy with 
acetazolamide or an alternative diuretic. In cases where the visual loss is severe and 
“rapid”, and believed by the Investigator to necessitate surgical intervention, the 
intervention will be conducted in accordance with local emergency practice. 
10.2.1. 
Rescue Therapy for Headache 
If the Investigator wishes to alter the headache preventative medication (any drug can be 
considered), this decision should always be discussed with the IAC before any action is 
taken, unless in the opinion of the Investigator there is no time to do so as it is judged to 
be a medical emergency. Use of headache preventative medication will be recorded at 
trial visits. 
Use of acute headache analgesics is not considered as rescue medication and is permitted 
but must be documented in the headache diary (monthly analgesic use). 
 
11. 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
11.1. 
Recording Prior and Concomitant Medication 
All relevant medication taken within 4 months of screening should be recorded in the 
eCRF along with all relevant medication taken from the start of the screening period until 
the final follow-up visit (Section 6.2.1.3). 
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At a minimum the following information will be collected: 
• 
Generic name 
• 
Dose 
• 
Frequency 
• 
Date started 
• 
If ongoing (or if not, then the date stopped will be recorded) 
• 
Reason for taking the medication  
11.2. 
Prohibited Medications 
11.2.1. 
Prior to screening and randomisation  
• 
Treatment to lower ICP within 1 week prior to screening (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).  
• 
Exposure to fluoroquinolones, lithium, vitamin A, or tetracyclines within 2 months 
of diagnostic LP 
• 
Glucagon like peptide-1 receptor agonist within last 4 weeks prior to screening 
• 
Warfarin 
• 
Glucose-lowering medicationCOVID-19 vaccine within 2 weeks prior to screening  
• 
Recreational or illicit drugs during screening period 
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 – see section 10.1.2.
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11.2.2. 
During the trial 
• 
Treatment to lower ICP (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). These will all be considered rescue medication (Section 10.1.2) and the 
IAC consulted. Use will be considered a protocol deviation. 
• 
If the Investigator alters the headache preventative medication (including oral or 
botulism toxin A or monoclonal antibodies against CGRP or CGRP antagonists, or 
greater occipital nerve block) this will be considered headache rescue medication 
(Section 10.1.2) and the IAC consulted.  
• 
Glucagon like peptide-1 receptor agonists 
• 
Recreational or illicit drugs  
• 
Warfarin 
• 
Glucose-lowering medication 
• 
Regarding COVID-19 vaccination, the risks of receiving or not receiving the 
vaccination have been considered in relation to the IMP and no additional risks are 
envisaged. Hence patients may choose to have or not have COVID-19 vaccination or 
booster during this trial. 
The investigator should follow the cautions and guidance on the management of other 
concomitant medication or DDIs as detailed in section 9.2.5.2 (Drug-Drug Interactions) 
of the IB. 
 
12. 
PATIENT COMPLETION AND WITHDRAWAL 
12.1. 
Patient Completion 
Patients will be classed as having completed the trial once they have completed all 
required trial visits. See Section 11.2.1 for early discontinuations. 
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12.2. 
Patient Withdrawal 
12.2.1. 
Patient Withdrawal from Trial Treatment 
A patient will be withdrawn from treatment for any of the following reasons: 
• 
Withdrawal of consent to continue in the trial. The reason for this will be 
documented if provided 
• 
The Investigator or Sponsor, for any reason, decides the patient should be withdrawn 
from the treatment 
• 
Lack of compliance with the trial medication is classified as <75% or >125% of 
scheduled doses over the course of the trial, excluding supply issues 
• 
Adverse events, which cannot be tolerated by the patient 
• 
Pregnancy during the treatment period 
• 
Retroactive failure to fulfil inclusion/ exclusion criteria (in this clinical drug trial 
designated phase III), if individual Benefit/Risk does not overrule 
• 
New medical conditions not allowing for continuation of the protocol conform 
treatment 
• 
Enrolment in any other clinical trial involving an investigational product, or 
enrolment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
• 
 If the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication 
• 
 If the patient, for any reason, requires treatment with a concomitant medication that 
during this trial should be avoided for reasons of safety and/or efficacy reasons  
• 
Any code breaking/unblinding requested by the investigator  
• 
Protocol-mandated permanent discontinuation of the investigational study treatment 
Patients will be encouraged to continue in the trial to the end of the randomised treatment 
period even if they stop trial medication so that data can be collected for the Intention-
To-Treat (ITT) population.  
If a patient is withdrawn from treatment during the randomised treatment period, they 
will be encouraged to return for all trial visits up to visit 10. If a patient does not want to 
return then at a minimum they should be encouraged to attend for visit 11 procedures as a 
safety follow-up visit.  
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12.3. 
Treatment after the End of the Trial 
Patients will not be provided with trial medication following the end of the trial. 
12.4. 
Screen and Baseline Failures 
Information will be collected on all patients who sign the Informed Consent Form (ICF). 
 
13. 
ADVERSE EVENTS  
13.1. 
Definitions 
13.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
13.1.2. 
Adverse Drug Reactions 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established: all noxious and unintended 
responses to a medicinal product related to any dose should be considered adverse drug 
reactions. The phrase responses to a medicinal product means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, i.e. 
the relationship cannot be ruled out. 
13.1.3. 
Serious Adverse Events or Serious Adverse Drug Reactions 
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
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• 
Is a congenital anomaly/birth defect 
Medical and scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not reach the 
above definition but may jeopardise the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive or malignant 
cancers, intensive treatment in an accident and emergency department or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse. 
Deterioration of IIH necessitating CSF shunting or optic nerve sheath fenestration or 
dural venous sinus stenting will be recorded as an SAE and reported. 
Deterioration of IIH necessitating hospital admission will be recorded as an SAE and 
reported. 
Pre-defined exclusions: 
• 
Hospitalisation for unrelated elective procedures 
• 
Post LP headache 
13.1.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to be 
related to the trial medication and are both unexpected (i.e., the nature or severity is not 
expected from the information provided in the Investigator Brochure) and serious. 
13.1.5. 
Expected Adverse Events 
Perceived deterioration of IIH necessitating attendance or admission to hospital will not 
be reported as an SAE, but these events will be reported and recorded at follow-up. Non-
protocol LPs will be reported at follow-up. 
13.1.6. 
Adverse Events of Special Interest  
There are no Adverse Events of Special Interest (AESIs). 
 
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13.2. 
Causal Relationship 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs. To promote consistency, the following guidelines should be taken into consideration 
along with good clinical and scientific judgment when determining the relationship of drug 
treatments to an AE: 
• 
Probable relationship: event occurs in a plausible time relationship to the medication 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals; the response to the withdrawal of the drug should be clinically plausible 
• 
Possible relationship/ relationship cannot be ruled out: event occurs with a reasonable 
time sequence to the medication administration, but could also be explained by 
concurrent disease or other drugs or chemicals; information on the drug withdrawal 
may be lacking or unclear 
• 
Unlikely relationship: event occurs with little temporal relationship to the medication 
administration and other factors such as drugs, chemicals or underlying disease 
provide plausible explanations 
• 
Not related: event has no temporal relationship to the medication administration or 
there is a definite alternative aetiology 
 
13.3. 
Severity Criteria 
An assessment of severity grade will be made using the following categorical descriptors: 
• 
Grade 1 means a relatively minor side effect 
• 
Grade 2 means a moderate side-effect  
• 
Grade 3 means a severe or medically significant but not immediately life-threatening 
side-effect  
• 
Grade 4 means life-threatening consequences 
• 
Grade 5 death related to AE 
The exact definition of each number in the scale depends on the particular side effect 
according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
[CTCAE].  
The Investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the patient (e.g., laboratory abnormalities). 
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Adverse events occurring as a result of LP should be specifically recorded. Occurrence of 
post lumbar headache will be specifically reported. 
13.4. 
Reporting Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated informed consent form is obtained until completion of 
the patient's final safety follow-up visit. The Sponsor will evaluate any safety information 
that is spontaneously reported by an Investigator beyond the time frame specified in the 
protocol. Adverse events reported after dosing will be classed as treatment emergent AEs. 
All AEs, regardless of seriousness, severity, or presumed relationship to trial therapy, must 
be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common 
aetiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the source 
documents and the eCRF their opinion concerning the relationship of the AE to trial 
therapy. All measures required for AE management must be recorded in the source 
document and reported according to Sponsor instructions.The patient must be provided, on 
the first day of trial medication (Day 1), with a "patient card" indicating the following: 
• Patient number 
• Name of the investigational product 
• Investigator's name and 24-hour contact information 
• Statement that the patient is participating in a clinical trial 
13.4.1. 
Reporting Serious Adverse Events 
All SAEs occurring during clinical studies must be reported to the appropriate Sponsor 
designee (contract research organisation) immediately without undue delay of the 
investigator becoming aware of the event. 
SAEs will be reported from the time a signed and dated informed consent form is obtained 
until completion of the patient's final safety follow-up visit.  
However, the investigator must immediately notify the sponsor if, after completion of the 
clinical trial, he/she becomes aware of a serious adverse event in a subject suspected of 
being causally related to the investigational product. 
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Information regarding SAEs will be transmitted to the Sponsor’s safety contact using the 
SAE Form, which must be completed and signed by the Investigator, and transmitted to 
the Sponsor’s safety contact immediately without undue delay.  
The contact details are: 
 
The Sponsor assumes responsibility for appropriate reporting of SAEs or SUSARs to the 
regulatory authorities. The Investigator (or Sponsor where required) must report these 
events to the appropriate Independent Ethics Committee (IEC) that approved the protocol 
unless otherwise required and documented by the IEC. 
An annual safety report will be submitted to the Institutional Review Board once a year via 
the Investigator. 
13.5. 
Reporting and Handling of Pregnancies 
Pregnant patients will be withdrawn from the trial. 
Female patients will be instructed to notify the Investigator immediately if they become 
pregnant during the trial and up to 12 weeks after discontinuation/completion of trial 
medication. Pregnant patients will be withdrawn from further trial treatment. The patients 
will also be instructed to report pregnancies discovered after the last visit, if they believe 
that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the trial medication 
has interfered with the efficiency of any contraceptive measures. The Investigator should 
report all pregnancies to the Sponsor contact or designee within 24 hours of being 
informed of them. The pregnancy report form should be used instead of the SAE form. 
The pregnant patients will be followed until the end of the pregnancy. Any complication 
during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, 
stillbirth, birth defect/congenital anomaly, death, or other serious infant condition must be 
reported and followed up as an SAE. 
Patients will give consent on enrolment that the Investigator will report any pregnancy to 
the Sponsor and that further information will be collected until delivery. 
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14. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will be finalised prior to database lock providing 
detailed methods for the analyses outlined below. 
14.1. 
Hypotheses 
This trial compares outcomes in IIH patients under Presendin and matched placebo. The 
primary hypothesis that will be tested is: 
• 
The ICP measurement in the Presendin group is equal to the ICP measurement in the 
placebo group at Week 24; against the alternative that the outcomes differ 
14.2. 
Trial Design Considerations 
14.2.1. 
Sample Size Assumptions 
The target sample size for the trial is 240 randomised patients, i.e., 120 patients per arm. 
We justify this figure in the following sections. The two outcomes for which we sought to 
power the study are ICP and PMD.  
14.2.1.1. Intracranial Pressure Power 
The most difficult parameters to specify for a sample size calculation pertain to the 
variability of outcomes. We present a brief summary of the literature. Baseline standard 
deviations (SD) of ICP in previous trials were: 5.4 (n=10) and 6.3 (n=17) in the Drug 
Trial [Markey, 2017]; 5.0 (n=16) (data on file); and 5.7 (n=32) and 5.3 (n=30) in the 
Weight Trial [Ottridge, 2017]. Post-baseline standard deviations were slightly lower (and 
less than 6.0) in three of these five arms; and increased slightly in one (but remained less 
than 6.0). The post-baseline standard deviation however increased to over 8.0 in the 
surgery arm of the Weight Trial because the surgical intervention dramatically impacted 
ICP in some patients.  In the NORDIC trial [Wall, 2014] however, the standard deviation 
of baseline ICP was much higher, at 9.4 in the treatment arm (n=86). Seeking to avoid 
underpowering the study, we elected to proceed with the SD estimate for the NORDIC 
trial as this is the most similar trial population to the planned IIH EVOLVE trial (both 
recruiting acute IIH). We assume that control arm baseline and 24-week ICP SD equals 
9.4, Presendin baseline ICP SD equals 9.4, and Presendin 24-week ICP SD equals 10.4. 
These values assume the variability of ICP measures in untreated patients is as high as 
has been seen in the NORDIC trial and assumes that the variability in treated patients is 
slightly higher still. We anticipate that the standard deviation will be slightly higher in the 
experimental arm as treatment effects will potentially manifest changes in ICP. However, 
we do not expect such variability to be as inflated in this trial relative to control as it was 
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in the Weight Trial because of the likely difference in treatment effect between surgical 
and drug interventions.  
Under this parameterisation, when testing for a difference between arms at 24-weeks of 5 
CSF (justified below) using a total sample size of 240, assuming that up to 50% of 
observations are missing (i.e. 60 final LPs are completed in each arm), using a 5% 
significance level by Analysis of Covariance (ANCOVA) adjusted for baseline ICP, the 
two stratification variables, and treatment arm, we expect to have approximately 85% 
power. If 40% of observations are missing (i.e. 72 final LPs are completed in each arm), 
we expect power to be 91%. These figures have been inferred by computer simulation. Of 
the 165 patients in IIHTT [Wall, 2014] it was reported that “only 85 participants (47 
[55%] in the [treated] group and 38 [48%] in the placebo group) agreed to a lumbar 
puncture at month 6.” 
We expect a high rate of missing data because lumbar puncture is an invasive procedure 
that patients can find painful and traumatising [Scotton, 2018]. If patients have an 
unpleasant experience at the diagnostic LP they are also more likely to decline the LP at 
trial outcome. If patients do decline the final LP, logically it will be because of the 
baseline experience rather than their prevailing ICP. If data for the LP at 24 weeks is 
missing, the reason will be recorded. 
Outcomes from previous trials show that baseline and post-baseline distributions of ICP 
show central tendency with approximate symmetry, so we conclude that normality is a 
reasonable assumption and therefore ANCOVA is a defensible analysis method. 
14.2.1.1. Perimetric Mean Deviation Power 
We summarise here the estimated power for detecting differences between arms in the 
PMD outcome measure. In the NORDIC trial [Wall, 2014], the authors observed that the 
improvement from baseline to 6-months in PMD was 0.71dB greater in the experimental 
arm than the control arm. Cross-sectional SD of PMD was 1.1-1.2 at baseline. Table 2 in 
their publication shows that the standard error of mean PMD is higher at 6m than at 
baseline, likely reflecting a combined effect of missing data at 6-months and greater 
variability of post-baseline measures. We plan to take repeated measures of PMD at 
baseline, 2 weeks, 1-month (m), 2m, 3 m, 4m, 5m and 6m. Assuming that the overall SD 
of PMD scores is 1.8, thus introducing some reasonable inflation on Wall et al.’s baseline 
variability parameter for the reasons identified, using the formula given on p.31 of 
Diggle, Liang & Zeger (1994) we would expect to require 142 patients in total to detect a 
difference of 0.71dB (justified below) with 90% power at a 5% significance level, if the 
serial correlation between repeated measures is 0.4 (and we expect a value in this region) 
[Diggle, 1994]. If the serial correlation parameter is as low as 0.3, the required sample 
size increases to 166.  
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Note that the method used above assumes full follow-up and data collection. Although 
every effort will be made to collect all outcomes, naturally some missing data is 
expected. If we inflate the maximum sample size identified above by up to 30% to 
account for some data loss, we require up to 166 / 0.7 = 237 patients. The assumed 30% 
missing data rate was adjudged to be realistic by the Sponsor based on previous trials in 
IIH. Thus, we expect to be able to cover the impact of missing data using the extra 
patients necessitated by the sample size calculation for ICP. 
The above assumes only one eye is measured per patient. In actuality, some patients may 
provide outcomes for both eyes because any eye that satisfies the eligibility criteria (see 
Section 5.2) will be enlisted in the study. Put another way, all patients will provide 
outcomes in at least one eye, and some will provide outcomes in two. Second eyes will 
naturally be highly correlated with first eyes. From a sample size perspective, this means 
the additional information in second eyes will be of modest value. Nevertheless, 
outcomes on second eyes will contain some additional information and should be 
included in the analysis in the interest of efficiency. When estimating sample size, for the 
sake of simplicity and because of uncertainty in the rate of eligibility in second eyes, we 
have assumed that each patient yields outcomes from only one eye. Eligible second eyes 
will be included in the analysis with appropriate model terms to handle the within-patient 
correlation (further details are included in the SAP). As such we expect outcomes from 
second eyes to provide a modest uplift in power to the scenarios presented here. 
This section assumes a longitudinal analysis method such as hierarchical regression. 
14.2.2. 
Stratification 
At the outset, it is expected that markers of disease severity will be prognostic of 
potential efficacy. For this reason, it is proposed to stratify randomisation by, baseline 
ICP (<35cm or ≥35 cm), baseline body mass index (< 30 kg/m2 or ≥30 kg/m2) and 
baseline PMD (worse than or equal to -3.5dB or better than -3.5dB).   
14.2.3. 
Sample Size Sensitivity 
14.2.3.1. Clinically Meaningful Effect Sizes 
Minimally relevant effect sizes have not been fully determined in IIH given it is a rare 
disease with relatively few previous trials.  
The ICP diagnostic threshold in IIH is 25 cm CSF [Mollan, 2018]. However, it is not 
necessary to reduce ICP <25 cm CSF to achieve remission from signs and symptoms of 
IIH in all patients [Sinclair, 2010]. The clinical importance of a particular change in ICP 
will vary depending on the starting ICP and the impact this pressure has on vision and 
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headache. Changes in ICP of 5 cm CSF are generally considered meaningful when 
treating IIH patients. For example, in a clinical study evaluating the benefits of weight 
loss in IIH patients, a 16.5% (6.2 cm CSF) reduction in ICP resulted in a statistically 
significant improvement in headache and vision measures as well as quality of life 
[Sinclair, 2010]. In the IIH Treatment trail (n=165), a study evaluating the drug treatment 
acetazolamide against placebo, a reduction of -5.9 cm CSF was seen in association with 
significant improvement in PMD, OCT measures of papilloedema and quality of life 
measures [Wall, 2014]. 
The minimally clinically important change in the perimetric mean deviation adopted into 
clinical practice was stablished by the Neuro-Ophthalmology Research Disease 
Investigator Consortium (NORDIC) group and the IIH Treatment Trial (IIHTT). The 
investigators found a 0.71dB difference in the PMD between the two trial arms 
(comparing acetazolamide with placebo) that was clinically meaningful. The change of 
0.71dB was interpreted as clinically meaningful as this was accompanied by significant 
changes in LP opening pressure, papilloedema (measured by OCT), general quality of life 
and visual related quality of life [Wall, 2014, Bruce, 2016].  
The clinically meaningful effect size for MHD reflects that for a phenotypically similar 
headache, chronic migraine. Recent randomised trials in patients with chronic migraine 
[Tepper, 2017; Silberstein, 2017], episodic migraine [Goadsby, 2017], or both 
[Camporeale, 2018] have shown in post-baseline months 1–3, odds of migraine relative 
to baseline of 0.5–0.8 with placebo and 0.5–0.3 with experimental drugs. Decreases in 
MHD relative to baseline grew in time, and placebo responses were stronger in chronic 
migraine than episodic migraine. In the three placebo-controlled, blinded trials, these 
equated to odds-ratios of migraine compared with placebo of 0.8–0.6, or absolute 
differences of 1.5–2.5 MHD [Sinclair, 2010; Tepper 2017; Silberstein, 2017; 
Goadsby, 2017].  
14.2.4. 
Trial Stopping Criteria 
There are no trial-specific stopping rules.  
The following events, if applicable, may cause premature termination of the clinical study 
or study arms:  
• 
unjustifiable risk and/or toxicity in risk-benefit analysis (decision taken by sponsor 
or representative), e.g. when adverse events occur, unknown to date in respect of 
their nature, severity, duration or frequency in relation to the current established 
safety profile (substantial changes in risk-benefit considerations), and therefore 
medical and/or ethical reasons affect the continued performance of the study;  
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• 
new scientific evidence becomes available during the study that could affect the 
patient's safety (benefit-risk analysis no longer positive), e.g. new insights from other 
clinical trials;  
• 
request of the sponsor with or without recommendation from the data safety 
monitoring committee, or of a regulatory agency, e.g. as a consequence of 
inspection;  
• 
favourable opinion withdrawn by the ethics commission;  
• 
in case of difficulties in the recruitment of the planned number of subjects in the 
indicated time (insufficient recruitment rate); -withdrawal of the license to 
manufacture and/or of the permission to import, it must either be adjusted or the 
clinical study/trial must be discontinued. 
 
14.3. 
Data Analysis Considerations 
14.3.1. 
Estimands 
We have specified intercurrent events that are material to the measurement of our 
primary and secondary outcomes, and unbiased estimation of treatment effects 
attributable to Presendin. 
ICP-lowering medication include:  acetazolamide, topiramate, diuretics, glucocorticoids 
(oral dexamethasone and oral prednisolone). Headache-preventative medications include: 
amitriptyline, topiramate, nortriptyline, beta blockers, candesartan, sodium valproate, 
pizotifen, botox, CGRP-therapy. 
14.3.1.1. Outcome: Intracranial pressure (ICP) 
14.3.1.1.1. Intercurrent event: ICP-lowering medications 
All patients are expected to have elevated ICP because it is a defining characteristic of 
the disease. ICP is a physiological variable that is unlikely to show spontaneous 
improvement without treatment. For these reasons, we expect ICP-lowering medication 
use to be greater in the placebo arm. If a patient takes medication that is intended to 
reduce their ICP, it is logical to expect that their ICP will be reduced. Outcomes from 
patients that take ICP-lowering medications will confound the estimation of the causal 
treatment effect of Presendin. We have no data to estimate the length of effects of ICP-
lowering medications. For these reasons, we propose to remove 24-week ICP outcomes 
from all patients that have used ICP-lowering medications and replace these observations 
with arm-specific imputations. This will allow estimation of the treatment effect that is 
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purely and causally attributable to Presendin. Patients will consent at enrolment to forgo 
the use of ICP-lowering medications and be informed that taking ICP-lowering 
medications during the trial would constitute rescue therapy and a treatment failure and 
be a protocol deviation. 
14.3.1.1.2. Intercurrent event: Off-protocol lumbar punctures 
Lumbar punctures are commonly conducted to reduce intracranial pressure [Weisberg, 
1977; Johnston, 1981; De Simone, 2005]. In some centres, they are given routinely 
although this has now been advised against in the International IIH Guidelines (Soler, 
1998; Mollan, 2018). As such, they remain a material therapeutic option. LP is expected 
to reduce ICP mean opening pressure 32 (28-37) cm CSF to 19 (17-21) cm CSF post LP 
[Yiangou, 2019]. Beneficial effects dissipate with time and whilst there has been no 
longitudinal assessment to quantify change in ICP after an LP, it is expected that effects 
in the majority of change would have dissipated completely within two months [Yiangou, 
2019]. Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove 24-week ICP outcomes from all patients that have had an off-protocol LP within 
two months of the protocol-scheduled 24-week LP and replace these observations with 
arm-specific imputations. Where patients require off-protocol LP this would be a protocol 
deviation. 
14.3.1.1.3. Inter-current event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in ICP [Sinclair, 2010]., Sudden dramatic weight loss, 
e.g. arising from a surgical procedure will likely yield material changes to IIH symptoms. 
This will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove 24-week ICP outcomes from all patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure and 
replace with arm-specific imputations. Patients will be ineligible for the trial if they have 
had a surgical weight-loss procedure within 3 months of randomisation or fail to confirm 
that they do not intend to undertake such a procedure during the trial. They will also be 
informed at enrolment that undergoing a surgical weight-loss procedure would be a 
protocol deviation. 
14.3.1.2. Outcome: Perimetric Mean Deviation (PMD) 
14.3.1.2.1. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
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patient takes ICP-lowering medication (rescue medication due to treatment failure ), it is 
logical to expect that their ICP will decrease and that papilloedema will reduce as a 
result, allowing visual fields to improve. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the PMD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
14.3.1.2.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema, allowing visual fields to improve. Patients that have LPs are expected to 
experience less pressure on the optic nerve, less papilloedema, and have better chances of 
their visual fields improving. Beneficial effects dissipate with time and whilst there has 
been no longitudinal assessment to quantify papilloedema after an LP the consensus of 
clinicians would predict that effects of the LP on papilloedema and therefore visual fields 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
PMD outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove PMD outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
14.3.1.2.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including improvements in visual fields [Sinclair, 2010]. Sudden dramatic 
weight loss, e.g. arising from a surgical procedure will likely yield material changes to 
IIH symptoms. This will confound the estimation of the causal treatment effect of 
Presendin. For these reasons, we propose to remove PMD outcomes of patients that 
experience weight loss exceeding 10% of baseline weight after a surgical weight-loss 
procedure from the date of procedure. These outcomes will be replaced with patient-
within-arm imputations generated by a method suitable for longitudinal data imputation. 
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14.3.1.3. Outcome: Papilloedema measured by OCT (optic nerve head size, 
retinal nerve fibre layer) 
14.3.1.3.1. Intercurrent event: ICP-lowering medications 
All patients will suffer from papilloedema at enrolment as it is the hallmark feature of the 
disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient takes ICP-lowering 
medication, it is logical to expect that their ICP will decrease and that the papilloedema 
will reduce in turn. As stated, we expect ICP-lowering medication use to be greater in the 
placebo arm. Outcomes from patients that take these medications will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove the OCT outcomes following the administration of ICP-lowering medications and 
replace these observations with imputations generated by a method suitable for 
longitudinal data imputation. Outcomes recorded at the unscheduled visit when the 
treatment failure is confirmed (and just prior to starting ICP lowering medication) will be 
defined as the last analysed visit. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. 
14.3.1.3.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema. Patients that have LPs are expected to experience less pressure on the optic 
nerve and therefore relatively less papilloedema. Beneficial effects dissipate with time 
and whilst there has been no longitudinal assessment to quantify papilloedema after an 
LP the consensus of clinicians would predict that effects of the LP on papilloedema 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
OCT outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove OCT outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
14.3.1.3.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in papilloedema [Sinclair, 2010]. Sudden dramatic weight 
loss, e.g. arising from a surgical procedure will likely yield material changes to IIH 
symptoms. This will confound the estimation of the causal treatment effect of Presendin. 
For these reasons, we propose to remove OCT outcomes of patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure from 
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the date of procedure. These outcomes will be replaced with patient-within-arm 
imputations generated by a method suitable for longitudinal data imputation. 
14.3.1.4. Outcome: Monthly headache days (MHD)  
14.3.1.4.1. Intercurrent event: Headache-preventative medications 
The great majority of patients are expected to suffer from headache because it is a 
common symptom of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient 
takes medication that is intended to prevent headache, it is logical to expect that their 
headache burden will be decreased. Despite the widely-observed short-term placebo-
effect observed in headache outcomes, we expect headache-preventative medication use 
to be greater in the placebo arm. Outcomes from patients that take headache-preventative 
medications will confound the estimation of the causal treatment effect of Presendin 
(more so with botulinum toxin A and CGRP therapies). For these reasons, we propose to 
remove the headache outcomes following the administration of headache-preventative 
medications and replace these observations with imputations generated by a method 
suitable for longitudinal data imputation. This will allow estimation of the treatment 
effect that is purely and causally attributable to Presendin. Patients who require a change 
to their headache preventative medications will do this through consultation with the IAC 
and such a change would be regarded as headache rescue therapy. 
14.3.1.4.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing the frequency and intensity of 
headache. Beneficial effects dissipate with time. Prospective data documents alterations 
in headache for at least 7 days and whilst there is no prospective longitudinal data over a 
longer time period consensus amongst clinicians would widely acknowledge that 
headache in some individuals can be influenced for up to a month [Yiangou, 2019]. 
Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. MHD outcomes will be recorded 
daily via diaries. For the reasons stated, we propose to remove MHD outcomes recorded 
in the 4-weeks following each off-protocol LP and replace these observations with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
14.3.1.4.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in headache frequency and severity [Sinclair, 2010]. 
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Sudden dramatic weight loss, e.g. arising from a surgical procedure will likely yield 
material changes to IIH symptoms. This will confound the estimation of the causal 
treatment effect of Presendin. For these reasons, we propose to remove MHD outcomes 
of patients that experience weight loss exceeding 10% of baseline weight after a surgical 
weight-loss procedure from the date of procedure. These outcomes will be replaced with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
14.3.1.4.4. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication, it is logical to expect that their ICP will decrease 
and that headache will reduce as a result. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the MHD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
14.3.1.5. Primary Estimand (Hypothetical assuming no concurrent procedures, 
irrespective of adherence to treatment) 
The primary estimand is defined as the following for the primary endpoint: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect ICP. 
The primary estimand for the initial secondary endpoint will be handled similarly to the 
primary endpoint using the “Hypothetical” approach. The initial secondary endpoint is 
defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect PMD. 
 
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14.3.1.6. Secondary Estimand (Hypothetical) 
The secondary estimand for the primary endpoint is defined as follows: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, if all patients adhered to 
treatment, where patients did not have medications or procedures likely to materially 
affect ICP. 
The secondary estimand for the initial secondary endpoint will be defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, if all patients adhered to treatment, 
where patients did not have medications or procedures likely to materially affect 
PMD. 
All details will be defined in the SAP. 
 
14.3.2. 
Analysis Populations 
The following analysis populations are planned for this trial:  
• 
Safety Population: The Safety population includes all patients randomised to 
treatment who receive at least one dose of trial medication. This will be the 
population used for all safety analyses unless otherwise specified. 
• 
Intent-To-Treat Population (ITT): The ITT population includes all patients 
randomised to treatment. This will be the main population for all efficacy analyses 
unless otherwise specified. 
• 
Per Protocol (PP): The PP population includes all patients randomised to treatment 
without important non-evaluable protocol deviations. Only protocol deviations with 
the potential to affect the trial results significantly, or to invalidate the interpretation 
of the data obtained, will lead to exclusion of patients from the PP population. 
Protocol deviations to be considered will include (but will not be limited to): 
• 
Failure to meet inclusion/exclusion criteria 
• 
Wrong treatment or incorrect volume of drug administration 
• 
Prohibited concomitant medications 
• 
Compliance of less than 75% or>125% with trial drug administration 
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• 
Use of rescue procedures, including, off-protocol LPs, LP shunts or bariatric 
surgery 
Assignment of patients to populations will be confirmed at a blinded data review meeting 
to be held before the trial database is locked. 
If a patient is randomised incorrectly or is administered the incorrect trial medication, 
analyses of the ITT will be based on the assigned treatment, whereas all other analyses 
will be based on the actual treatment received. 
14.3.3. 
Treatment Comparisons 
Treatment comparisons will be undertaken between active and control groups. The 
primary outcome will be analysed as described in Section 13.2.1.  
14.3.4. 
Safety Analyses 
Safety will be evaluated from reported AEs, changes in clinical laboratory values, 
changes in vital signs, and ECG results. 
All safety analyses will be performed on the Safety population. 
14.3.4.1. Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (the most recent 
version before starting the trial will be used).  
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of trial medication. 
The number and percentage of patients reporting TEAEs, grouped by MedDRA system 
organ class and preferred term will be tabulated by treatment group. Summaries will be 
presented for all TEAEs, TEAEs by severity and TEAEs by relationship to trial 
medication. 
In the AE data listings, all AEs will be displayed. Adverse events that are not treatment-
emergent will be flagged. The observation period in which an AE started will also be 
provided. 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm. Treatment failures will be displayed by trial arm. 
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14.3.4.2. Clinical Laboratory Evaluations  
Laboratory test results for each biochemistry and haematology parameter will be 
summarized descriptively by treatment group and time point as both observed values and 
change from baseline values. 
The number of patients with clinical laboratory (biochemistry, haematology, and 
urinalysis) values categorized as below, within, or above the normal ranges (or as either 
normal or abnormal for urinalysis variables that do not have quantitative ranges), will be 
tabulated in relation to baseline (shift tables), for each clinical laboratory analyte by 
treatment group and time point. 
Laboratory values will be displayed in the data listings and those that are outside the 
reference ranges will be flagged, along with corresponding normal ranges. Any patients 
with any markedly abnormal laboratory results will also be provided in a listing. 
Pregnancy test results including reason, if not performed, will be listed. 
14.3.4.3. Vital Signs and Body Mass Index Evaluations 
Descriptive summaries of observed values and changes from baseline will be calculated 
for systolic blood pressure, diastolic blood pressure and heart rate by treatment group and 
time point.  
Body mass index will be derived at Screening, Baseline and Weeks 4, 8, 16, 24, 32 and 
48 using height captured at Screening and weight at the respective assessment. Body 
mass index and weight will be summarized descriptively by treatment group and time 
point as both observed values and change from baseline values for Safety and ITT 
populations. 
14.3.4.4. Electrocardiogram 
Descriptive statistics of observed values and change from baseline will be presented for 
ECG measures of PR interval, QRS interval, QT interval, QT interval corrected 
according to Fridericia’s formula (QTcF). These summaries will be presented by 
treatment and time point for the Safety population.  
The number and percentage of patients with values beyond clinically important limits 
will be summarised including those with an increase in QTcF >30 msec increase from 
baseline and >60 msec increase from baseline or those with an absolute QTcF value of 
>450 msec (male patients) or >470 msec (female patients). 
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14.3.4.1. Other Safety Evaluations 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm.  
14.3.5. 
Patient Reported Outcomes Analyses 
All patient reported outcome endpoints (VFQ-25, HIT-6, SF-36, EQ-5D-5L) will be 
analysed as observed and presented with change from baseline in a descriptive summary 
of treatment and visit  
The number and percentages of PGIC responses will be tabulated by treatment and visit. 
14.3.6. 
Missing Data 
Although every effort will be made to collect responses from all patients at all scheduled 
time points, there undoubtedly will be some missing data.  The SAP describes in detail 
steps for dealing with missing data using relevant imputation strategies for specific 
endpoints that adjust for treatment arm, centre, baseline value, and stratification 
variables. 
We briefly describe our imputation strategy for the analysis of primary and secondary 
efficacy endpoints here. Our imputation strategy generally applies for data being set to 
missing by having an intercurrent event or data that is not captured at all. 
For the primary efficacy variable (lumbar puncture) there is only one post-baseline 
assessment planned at Week 24. In this case we will multiply impute missing values from 
the posterior predictive distribution of a generative regression model that will use 
explanatory variables: 
• 
the randomisation stratification variables; 
• 
treatment allocation; 
• the baseline values of the outcome  
Values for these variables must be established for all patients at baseline so we do not 
expect missing values here. 
For outcomes with repeated measures (secondary efficacy variables), to the above list we 
will also add historic observations of the outcome in question, including imputed values. 
In chained equation models that seek to incrementally estimate repeated measures 
outwards from baseline, missing values are imputed for the first assessment time, then 
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values for the first assessment are included when imputing missing values for the second 
assessment time, etc. 
The above multiple imputation models for both primary and secondary efficacy endpoints 
will be applied in a way that missing data will be imputed in different ways dependent on 
the reason for missingness. In case the data can be assumed to be missing at random (e.g. 
early discontinuation from study due to withdrawal of consent), the missing data will be 
imputed using the treatment arm to which the patient was randomised to. In case the data 
needs to be assumed to be missing not at random (e.g. early discontinuation due to 
adverse event), the missing data will be imputed to reflect outcomes in the placebo arm 
(e.g. for endpoints that are observed once, like ICP), or to reflect changes through time 
that are typical in the placebo arm (e.g. for repeated measures endpoints, like headache 
days). A detailed list of reasons for missingness and the corresponding way of imputation 
will be specified in the SAP. For the analysis of the secondary estimands, the same model 
will be used, but additional treatment events will be considered which require further 
imputations. 
In both cases, the imputation process will finally be repeated several times to reflect the 
uncertainty in missing values. The analysis method described in this protocol will be 
performed on each complete imputed dataset. Final estimates of the treatment effect and 
its uncertainty will be derived by combining the analyses on the complete imputed 
datasets using standard methods, described in several sources including. (White et al, 
2011). 
For the analysis of the primary efficacy endpoint and for some of the important secondary 
endpoints, further sensitivity analyses for missing values will be planned to investigate 
the effect of missing values on the results, using simpler statistical models. For the 
primary efficacy endpoint this will include a completer analysis, as well as an analysis 
using baseline observation carried forward (BOCF), for the important secondary 
endpoints this will cover a mixed model for repeated measures (MMRM) model without 
replacing missing values, assuming that all missing values are missing at random as well 
as an analysis using last observation carried forward (LOCF). Details will be described in 
the SAP. 
 
14.3.7. 
Reporting Deviations from the Statistical Plan 
Any deviations from the planned analyses will be described and justified in the final 
clinical trial report. 
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15. 
TRIAL ADMINISTRATION 
15.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Before initiation of a trial site, the Sponsor will obtain approval from the appropriate 
regulatory agency to conduct the trial in accordance with ICH-GCP and applicable 
country-specific regulatory requirements. 
The trial will be conducted in accordance with all applicable regulatory requirements. 
The trial will be conducted in accordance with the EU Clinical Trial Regulation 
536/2014, ICH-GCP, all applicable patient privacy requirements and the ethical 
principles that are outlined in the Declaration of Helsinki 2013, including, but not limited 
to: 
• 
An IEC/Institutional Review Board review and approval of trial protocol and any 
subsequent amendments and all ICFs or other information given to the patient 
• 
Patient informed consent 
• 
Investigator reporting requirements 
The Sponsor will provide full details of the above procedures, either verbally, in writing, 
or both. 
Written informed consent must be obtained from each patient before participation in the 
trial. Written informed consent will be collected following a review of the patient’s 
information leaflet by the potential patient and a discussion between the patient and the 
Investigator or suitably qualified designee. 
The Investigator will cooperate with all regulatory inspections and will notify the 
Sponsor as soon as they are aware of an inspection which may involve this trial. With the 
exception of statutory regulatory authority inspections, the Sponsor will be consulted in 
the event of inspection of the clinical site(s) by an outside authority before the Inspectors 
are permitted access to any of the trial records or the trial areas. 
15.2. 
Trial Monitoring 
In accordance with applicable regulations, ICH-GCP, the monitoring plan and the 
Sponsor’s and/or delegate procedures, monitors will contact the site before the start of the 
trial to review with the site staff the protocol, trial requirements, and their responsibilities 
to satisfy regulatory, ethical, and the Sponsor’s requirements. When reviewing data 
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collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. 
The Sponsor and or delegated monitors will perform risk-based monitoring during the 
conduct of the trial to ensure that: 
• 
The data are authentic, accurate and complete 
• 
The patient’s safety and rights are being protected 
• 
The trial is conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH-GCP and all applicable regulatory requirements 
15.2.1. 
Access to Source Data 
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor, Sponsor-appointed auditors and regulatory inspectors direct access to 
all relevant documents. 
Information recorded in the eCRF should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory reports, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. 
 
15.2.2. 
Data Handling and Record Keeping 
Following closure of the trial, the Investigator or head of the medical institution (where 
applicable) must maintain all site trial records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
Investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The Investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
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The Sponsor will inform the Investigator of the time period for retaining the site records 
in order to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, the Sponsor SOPs and/or institutional requirements. 
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the Investigator is no longer associated with the 
site. 
15.3. 
Provision of Trial Results and Information to Investigators  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical trial report. The Investigator will be provided 
reasonable access to statistical tables, figures and relevant reports and will have the 
opportunity to review the complete trial results at a mutually agreeable location. 
The Sponsor will also provide the Investigator with the full summary of the trial results. 
The Investigator is encouraged to share the summary results with the trial patients, as 
appropriate. 
15.4. 
Publication 
The sponsor will comply with the requirements for publication of study results in a 
publicly available trials registry such as clinical trials.gov. Results may be published in 
peer-reviewed journals and presented at scientific meetings. Authorship will be 
determined by mutual agreement and in line with International Committee of Medical 
Journal Editors authorship requirements. In accordance with standard editorial and ethical 
practice, the sponsor supports publication of multicenter studies only in their entirety and 
not as individual site data. Sponsor  will  allow the Investigator  to review the manuscript 
before publication by Sponsor. If the Investigator wishes to publish anything related to 
the trial, then they must provide the Sponsor with the draft publication and allow them no 
less than 30 days to review the document. The Investigator cannot publish without 
written authorisation from the Sponsor. 
15.5. 
Data Management 
For this trial, patient data will be collected using an eCRF and combined with data 
provided from other sources in a validated data system. Patient’s identifiable data (e.g., 
name, initials, address etc.) will not be collected in the eCRF or transferred to Invex 
Therapeutics. Clinical data management will be performed with the objective of 
removing errors and inconsistencies in the data which would otherwise impact on the 
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statistical analysis or the credibility of the Clinical Study Report. Original CRFs will be 
retained by Invex Therapeutics; the Investigator will also retain a copy. 
Management of clinical data will be performed in accordance with the applicable Sponsor 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using the Medical Dictionary for Regulatory Affairs and World Health 
Organisation Drug dictionary.  
When using electronic trial data handling and/or remote electronic trial data systems, the 
Sponsor or designee will:  
a. 
Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation) 
b. Maintain SOPs for using these systems 
c. 
Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail) 
d. Maintain a security system that prevents unauthorised access to the data 
e. 
Maintain a list of the individuals who are authorised to make data changes 
f. 
Maintain adequate backup of the data 
g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing) 
Training on the use of the electronic data collection system will be provided to all 
relevant trial site staff. 
15.6. 
Independent Adjudication Committee 
The IAC will consist of  international medical experts in neurology or ophthalmology 
who are independent of the Sponsor team. 
The role of the IAC will be: 
• 
To support the Investigators with opinions on the eligibility of potential patients 
• 
To provide opinions regarding treatment failure and need for rescue medications 
required during the trial 
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Further details on the composition, activities and responsibilities of the IAC can be found 
in the IAC charter. 
15.7. 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) consisting of experts in neurology, neuro-
ophthalmology and ophthalmology will oversee the conduct of the study and ensure the 
safety of patients. The role and responsibilities of the DSMC, as well as the data review 
process are outlined in detail in a separate charter. DSMC reviews of safety data will be 
planned every 6 months (anticipating the first meeting will occur at approximately 6 
months or when 25% of the patients recruited). In addition, unscheduled ad-hoc DSMC 
meetings will be triggered in case of emerging safety concerns. Based on clinical data 
reviewed, the DSMC may recommend an amendment to the study protocol or premature 
termination of the study. Such DSMC recommendations will be submitted to all IRB/IEC 
and health authorities.  
Details on the composition, activities and responsibilities of the DSMC can be found in 
the DSMC charter. 
15.8. 
Insurance, Indemnity and Finance 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
The Sponsor will indemnify all Investigators participating in this trial against future 
claims by trial patients; the terms of this will be detailed within a separate letter of 
indemnification. The indemnity will only apply where all trial procedures have been 
carried out according to this protocol. 
The financial aspects of the trial are addressed in a separate agreement. 
 
 
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McDermott MP, Kieburtz KD et al. Effect of acetazolamide on visual function in patients 
with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial 
hypertension treatment trial. JAMA, 2014 Apr 23-30;311(16):1641-51. 
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Olesen, J. Headache Classification Committee of the International Headache Society 
(IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 
2018 Jan;38(1):1-211. 
O’Reilly MW, Westgate CS, Hornby C et al. A unique androgen excess signature in 
idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. JCI insight. 
2019 Mar 21;4(6). 
Ottridge R, Mollan SP, Botfield H et al. Randomised controlled trial of bariatric surgery 
versus a community weight loss programme for the sustained treatment of idiopathic 
intracranial hypertension: The Idiopathic Intracranial Hypertension Weight Trial 
(IIH:WT) protocol. BMJ Open. 2017 Sep 27;7(9):e017426. 
Petzold A, de Boer JF, Schippling S et al. Optical coherence tomography in multiple 
sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010 Sep;9(9):921-32. 
Piper RJ, Kalyvas AV, Young AMH, Hughes MA, Jamjoom AAB, Fouyas IP. 
Interventions for idiopathic intracranial hypertension. Cochrane Database of Systematic 
Reviews. 2015 Aug 7;2015(8):CD003434. 
Pujante Alarcón P, Hellín Gil MD, Román LM, Ferrer Gómez M, García Zafra MV, 
Tébar Massó J. Metabolic control and weight loss in patients with obesity and type 2 
diabetes mellitus, treated with exenatide. Med Clin (Barc). 2012 Dec 1;139(13):572-8. 
Raphael BA, Galetta KM, Jacobs DA et al. Validation and test characteristics of a 10-
item neuro-ophthalmic supplement to the NEI-VFQ-25 Am J Ophthtalmol 2006 
Dec;142(6):1026-35 
Rebolleda G, Munoz-Negrete FJ. Follow-up of mild papilledema in idiopathic 
intracranial hypertension with optical coherence tomography. Invest Ophthalmol Vis Sci. 
2009 Nov;50(11):5197-200. 
Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, Trautmann 
M. Effects of exenatide and lifestyle modification on body weight and glucose tolerance 
in obese subjects with and without pre-diabetes. Diabetes Care. 2010 Jun;33(6):1173-5. 
Salgarello T, Falsini B, Tedesco S, Galan ME, Colotto A, Scullica L. Correlation of optic 
nerve head tomography with visual field sensitivity in papilledema. Invest Ophthalmol 
Vis Sci. 2001 Jun;42(7):1487-94. 
Scotton WJ, Mollan SP, Walters T et al. Characterising the patient experience of 
diagnostic lumbar puncture in idiopathic intracranial hypertension: a cross-sectional 
online survey. BMJ Open 2018 May 30;8(5):e020445. 
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Scotton WJ, Botfield HF, Westgate CSj et al. Topiramate is more effective than 
acetazolamide at lowering intracranial pressure. Cephalalgia. 2019 Feb;39(2):209-218. 
Silberstein S, Tfelt-Hansen P, Dodick DW et al. Guidelines for Controlled Trials of 
Prophylactic Treatment of Chronic Migraine in Adults. Cephalalgia. 2008 
May;28(5):484-495. 
Silberstein SD, Dodick DW, Bigal ME et al. Fremanezumab for the preventive treatment 
of chronic migraine. N. Engl. J. Med. 2017 Nov; 377(22):2113–2122. 
Sinclair AJ, Burdon MA, Nightingale PG et al. Low energy diet and intracranial pressure 
in women with idiopathic intracranial hypertension: Prospective cohort study. BMJ. 2010 
Jul 7;341:c2701. 
Sina F, Razmeh S, Habibzadeh N, Zavari A, Nabovvati M. Migraine headache in patients 
with idiopathic intracranial hypertension; Neurology international 2017 Oct 2;9(3):7280. 
Soler D, Cox T, Bullock P, Calver DM, Robinson RO. Diagnosis and management of 
benign intracranial hypertension. Arch Dis Child. 1998 Jan;78(1):89-94. 
Sørensen PS, Thomsen AM, Gjerris F. Persistent disturbances of cognitive functions in 
patients with pseudotumor cerebri. Acta Neurologica Scandinavica, 1986 Mar;73(3)264–
268. 
Tassorelli C, Diener H-C, Dodick DW et al. Guidelines of the International Headache 
Society for controlled trials of preventive treatment of chronic migraine in adults. 
Cephalalgia. 2018 Apr;38(5):815–832.  
Tepper S, Ashina M, Reuter U et al. Safety and efficacy of erenumab for preventive 
treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 
trial. Lancet Neurol. 2017 Jin;16(6):425–434. 
Vernieri F, Paolucci M, Altamura C et al. Onabotulinumtoxin-A in chronic migraine: 
should timing and definition of non-responder status be revised? Suggestions from a real-
life Italian multicentre experience. Headache. 2019 Sep;59(8):1300–1309. 
Vijay V, Mollan SP, Mitchell JL et al. Utilising optical coherence tomography measures 
as surrogates for raised intracranial pressure in idiopathic intracranial hypertension. 
JAMA Opthalmology, 2020 Dec 1;138(12):1264-1271 
Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 
patients. Brain, 1991 Feb;114 (Pt 1A):155-80. 
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Wall M, Woodward KR, Brito CF. The effect of attention on conventional automated 
perimetry and luminance size threshold perimetry. Invest Ophthalmol Vis Sci. 2004. 
Jan;45(1):342-50.  
Wall M, Doyle CK, Zamba KD al. The Repeatability of Mean Defect with Size III and 
Size V Standard Automated Perimetry. Invest Ophthalmol Vis Sci 2013;54:1345–1351 
Wall M, McDermott MP, Kieburtz KD et al. Effect of acetazolamide on visual function 
in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic 
intracranial hypertension treatment trial JAMA 2014 Apr 23-30;311(16):1641-51  
Wall M, Johnson CA, Cello KE et al. Visual Field Outcomes for the Idiopathic 
Intracranial Hypertension Treatment Trial (IIHTT). Invest Ophthalmol Vis Sci. 2016 
Mar;57(3):805-812. 
Websky von K, Reichetzeder C, Hocher B. Physiology and pathophysiology of incretins 
in the kidney. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):54–60.  
Westgate CS, Botfield HF, Alimajstorovic Z et al. Systemic and adipocyte transcriptional 
and metabolic dysregulation in idiopathic intracranial hypertension. JCI insight 
2021:24;6(10). 
Weisberg LA, Chutorian AM. Pseudotumor cerebri of childhood. Am J Dis Child. 1977 
Nov;131(11):1243–8. 
White, I. R., Royston, P., & Wood, A. M. (2011). Multiple imputation using chained 
equations: issues and guidance for practice. Statistics in medicine, 30(4), 377-399. 
Wright BLC, Lai JTF, Sinclair AJ. Cerebrospinal fluid and lumbar puncture: a practical 
review. J Neurol. 2012 Aug;259(8):1530-45.  
Yiangou A, Mitchell JL, Fisher C et al. Erenumab for headaches in idiopathic intracranial 
hypertension: A prospective open-label evaluation. Headache. 2021 Jan;61(1):157-169. 
Yiangou A, Mitchell J, Markey KA et al. Therapeutic lumbar puncture for headache in 
idiopathic intracranial hypertension: Minimal gain, is it worth the pain? Cephalalgia. 
2019 Feb;39(2):245-253.  
Yri HM, Rönnbäck C, Wegener M, Hamann S, Jensen RH. The course of headache in 
idiopathic intracranial hypertension: A 12-month prospective follow-up study. Eur. J. 
Neurol. 2014 Dec;21(12):1458–1464. 
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Yri HM, Jensen RH. Idiopathic intracranial hypertension: Clinical nosography and field-
testing of the ICHD diagnostic criteria. A case-control study. Cephalalgia. 2015 
Jun;35(7):553-62. 
 
 
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17. 
APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-
301 
17.1. 
Appendix 1: LP SOP 
Diagnostic lumber puncture 
The diagnostic lumbar puncture (LP) is performed by the site as part of routine care to 
confirm the diagnosis of Idiopathic Intracranial Hypertension (IIH).  This is not a 
research LP. For the patient to be eligible for the IIH Evolve trial the diagnostic LP must 
have the opening pressure measured in the lateral decubitus position in line with the 
guidance below. The LP must be within 4 weeks of commencing screening. 
Research lumbar puncture 
A research LP is performed at the end of the Randomised Period/ Week 24/ Visit 10. This 
is the primary outcome for the trial. In the 4 weeks prior to visit 10, patients must not 
have missed more than one dose of trial medication and must have self-administered their 
final dose within 7 days of visit 10. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days. We 
recommend that the LP should be performed after visual  assessment. 
The LP should be performed by a trained clinician or health care professional according 
to local standard of care. The only mandatory requirement for the trial is that the 
measurement of LP opening pressure is conducted as per below.  
Procedure 
Suggested equipment required:  
• Antiseptic cleaned trolley; 
• Cleaning solution (Iodine or chlorhexidine) 
• 2 pairs of sterile gloves; 
• Sterile wound pack; 
• Lumbar puncture manometer (up to 3 should be available) with corresponding 3 
way valve stopcocks (should be included in pack); 
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• Needle point 20 gauge lumbar puncture needle; 
• 10ml syringe x 1; 
• Green syringe needle, blue syringe needle and orange syringe needle; 
• Gauze pads x 1; 
• 3 sterile universal pots; 
• Sterile dressing. 
Suggested technique 
For a standard (non-image guided) LP: 
• Ask the participant to lie in the lateral left position; they should be relaxed. 
• The legs must be flexed at the hip at a 90˚ angle (support may be need to maintain 
this position). 
• The L3/4 intervertebral space should be located using anatomical landmarks (the 
midline between the posterior superior iliac crests). If this is difficult, consider 
using ultrasound to identify the correct structures: IV space and spinous processes 
of L3 and L4. The space above or below may also be accessed if needed. 
• Mark the location of needle entry. 
• Clean a large circumference around the needle entry site using 70% alcohol or 
chlorhexidine using a sterile technique. 
• Infiltrate 1-2% lidocaine subcutaneously and into the vertebral ligaments. 
Aspirate prior to infiltration to avoid intravascular injection. No more than 
3mg/kg should be infiltrated (1% contains 10mg per 1ml). 
• Once the area is appropriately anaesthetised, insert the needle bevel up, 
horizontally to the marked area and towards the umbilicus.  
• Once a ‘give’ is felt, withdraw the stylet and ensure flow of CSF.  
LP opening pressure measurement (mandatory) 
• Pressure readings MUST be taken with the patient lying in the lateral left (or 
right) decubitus position. 
• Connect the manometer and record the opening pressure: 
o If the patient’s thighs are compressing their abdomen then very slowly 
extend the legs at the hip joint to ensure the abdomen is not compressed. 
o Ensure the patient is not speaking or breath holding (avoid valsalva)  
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o Allow time (sometimes around 5 minutes), for the pressure to become 
consistent (small fluctuations in the pressure with respiration should be 
seen) before a reading is taken 
• Collect a sample of CSF in sterile universal container (size typically 25-30ml), 
and collect a 3ml CSF sample for the research trial. This should immediately be 
stood upright in a wet ice bath until processing. Process should be within 30 
minutes of collection (see the Laboratory manual).  
• There is no need to record a closing pressure for the trial. 
• Replace the stylet, withdraw the needle and place a sterile dressing over the area. 
For an image guided-LP: 
This may be performed using guidance by ultrasound, x-ray or computerised tomography 
(CT). This should be performed by a suitability qualified health care professional (e.g. 
radiologist). The positioning for a patients undergoing an image guided LP vary 
internationally. For this trial the initial position for an image guided LP can be according 
to local expertise but the LP pressure measurement MUST be conducted in the lateral 
decubitus position as described above. This ensures standardisation across the trial. 
Post procedure advice: 
This should be in line with local hospital care pathways. We would suggest: 
• Lie flat for approximately 30 minutes (there is no evidence to support that lying 
flat for any duration reduces a post LP headache). Pragmatic advice on 
mobilisation when the patient has recovered is advised. 
• Simple analgesia may be prescribed and dispensed for post-procedure pain 
(headaches or back pain); 
• Oral fluids may help with post-procedure headache (non-evidenced based 
recommendation).  
• Remind the participant of the possible adverse effects. 
 
 
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17.2. 
Appendix 2: IIH Diagnostic criteria [Mollan, 2018] 
A. Papilloedema 
B. Normal neurological examination (except sixth cranial nerve palsy) 
C. Neuroimaging: normal brain parenchyma (no hydrocephalus, mass, structural 
lesion or meningeal enhancement). Venous thrombosis excluded in all. 
D. Normal CSF constituents (less than or equal to 7 white cells per mm3 with normal 
protein and glucose  
E. Elevated lumbar puncture pressure ≥ 25cm  CSF  
 
 
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17.3. 
Appendix 3: 36-item short from survey  
 
HEALTH 
. ' 
RAND > RAND Health > Surveys > RAND Medical Outcomes Study > 36-ltem Short Form Survey (SF-36) > 
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THERAPEUTlCS 
--
36-ltem Short Form Survey Instrument 
(SF-36) 
RAND 36-ltem Health Survey 1.0 Questionnaire Items 
Choose one option for each questionnaire item_ 
L In general, would you say your health is: 
n 1- Excellent 
,--.. 2 - Very good 
0 3-Good 
C} 4-Fair 
n 5-Poor 
2. Compared to one year ago, how would you rate your health in general now? 
0 
1- Much better now than one year ago 
0 2 - Somewhat better now than one year ago 
0 3 -About the same 
r'\ 4 - Somewhat worse now than one year ago 
r'\ s - Much worse now than one year ago 


 
 
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THERAPEUTlCS 
The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so, how much? 
Yes, 
Yes, 
No.not 
limited a 
limited a 
limited at 
lot 
little 
all 
3. Vigorous activities, such as running, lifting heavy objects, 
n
1 
n
2 
n
3 
participating in strenuous sports 
4. Moderate activities. such as moving a table. pushing a 
n
1 
0
2 
n
3 
vacuum cleaner, bowling. or playing golf 
s. Lifting or carrying groceries 
n
1 
0
2 
n
3 
6. Climbing several flights of stairs 
() l 
0
2 
0
3 
7. Climbing one flight of stairs 
n
1 
n
2 
n
3 
8. Bending, kneeling, or stooping 
0
1 
0
2 
0
3 
9. Walking more than a mile 
'] l 
n
2 
n
3 
10. Walking several blocks 
0
1 
0
2 
0
3 
n. Walking one block 
'] l 
n 
2 
n
3 
12. Bathing or dressing yourself 
C' l 
0
2 
0
3 


 
 
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THERAPEUTlCS 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
13. Cut down the amount of time you spent on work or other activities 
14. Accomplished less than you would like 
15. Were limited in the kind of work or other activities 
16. Had difficulty performing the work or other activities (for example, it took extra 
effort) 
Yes 
0 
r'\ 
0 
n 
No 
n 
2 
0 
2 
0 
2 
n 
2 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
Yes 
No 
17. Cut down the amount of time you spent on work or other activities O 1 0 2 
18. Accomplished less than you would like 
r'I 1 
0 
2 
19. Didn't do work or other activities as carefully as usual 
O 1 
0 2 
20. During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors, or 
groups? 
C' 1 - Nat at all 
r- 2 - Slightly 
0 
3 - Moderately 
ri 4 - Quite a bit 
,...._ 5 - Extremely 


 
 
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21. How much bodily pain have you had during the past 4 weeks? 
C' 1- None 
l"'I 2-Verymild 
r- 3-Mild 
0 4 - Moderate 
C' 5-Severe 
C 6 -Very severe 
22. During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
0 1 - Not at all 
C) 2-Alittlebit 
0 
3 - Moderately 
l"'I 4 - Quite a bit 
t) s - Extremely 
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THERAPEUTlCS 
These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question, please give the one answer that comes closest to the way 
you have been feeling. 
How much of the time during the past 4 weeks ... 
All of 
Most 
A good 
Some 
A little 
None 
the 
of the 
bit of the 
of the 
of the 
ofthe 
time 
time 
time 
time 
time 
time 
23. Did you feel full of pep? 
() 1 
O z 
0
3 
0
4 
C' 5 
O s 
24. Have you been a very nervous 
0
1 
n z 
1) 3 
(') 4 
r, 5 
n s 
person? 
25. Have you felt so down in the 
f' l 
O z 
n 3 
n 4 
n
5 
O s 
dumps that nothing could cheer you 
up? 
26. Have you felt calm and peaceful? 
(' l 
n 2 
(') 3 
(1 4 
r, 5 
n s 
27. Did you have a lot of energy? 
0
1 
O z 
I"") 3 
() 4 
r, 5 
n s 
28. Have you felt downhearted and 
(', l 
(") 2 
n 3 
("'1 4 
r'\ 5 
0
6 
blue? 
29. Did you feel worn out? 
0
1 
n z 
(') 3 
(') 4 
('I 5 
n s 
30. Have you been a happy person? 
C i 
O z 
Q
3 
0
4 
') 5 
O s 
31. Did you feel tired? 
(', l 
n z 
r') 3 
() 4 
(") 5 
n s 
32. During the past 4 weeks. how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
n 
1 - All of the time 
r, 2 - Most of the time 
r, 3-Some of the time 
r, 4 - A little of the time 
I"") 5- None of the time 


 
 
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THERAPEUTlCS 
How TRUE or FALSE is each of the following statements for you. 
Definitely 
Mostly 
Don't 
Mostly 
Definitely 
true 
true 
know 
false 
false 
33. I seem to get sick a little easier than 'J l 
') 2 
0
3 
') 4 
O s 
other people 
34. I am as healthy as anybody I know 
0 1 
') 2 
0
3 
') 4 
O s 
35. I expect my health to get worse 
n 1 
n 2 
(") 3 
r, 4 
n s 
36. My health is excellent 
n 1 
() 2 
(") 3 
,) 4 
n s 
ABOUT 
The RAND Corporation is a research organization that develops solutions to public policy challenges to help make 
communities throughout the world safer and more secure, healthier and more prosperous. RAND is nonprofit. nonpartisan. 
and committed to the public interest. 
II 
1776 Main Street 
Santo Monica, California 90401-3208 
RAND• is a registered trademark. Copyright© 1994-2016 RAND Corporation. 


 
 
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17.4. 
Appendix 4: EuroQol -5 dimension-5 level survey  
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THERAPEUTlCS 
UK (English) © 2009 EuroQof Group EQ-SDTM is a trade mark of the EuroQol Group 


 
 
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Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, hou 
leisure activities) 
I have no problems doing my usual 
I have slight problems doing my usu 
I have severe problems d 
lh 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
UK /English) © 2009 EuroQol Group EQ-5D'" is a trade mark of the EuroQol Group 
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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TOD 
• 
Now, please write the number you marked on the scale in the 
below. 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
vex 
THERAPEUTlCS 
The best health 
you can imagine 
100 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health 
you can imagine 


 
 
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17.5. 
Appendix 5: Headache Impact Test-6 
 
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THERAPEUTlCS 
HIT-6™ 
(VERSION 1.1) 
This questionnaire was designed to help you describe and communicate 
the way you feel and what you cannot do because of headaches. 
~HE 
\\fMTTESTN 
To complete, please circle one answer for each question. 
When you have headaches, how often is the pain severe? 
Never 
Rarely 
Sometimes 
How often do headaches limit your ability to do usual daily activities in 
work, work, school, or social activities? 
Never 
Rarely 
V When you have a headache, how often do yo 
Never 
Rarely 
In the past 4 weeks, how often have yo 
of your headaches? 
Never 
+ 
COLUMN 1 
COLUMN 2 
(6 points each) 
(8 points each) 
Sometimes 
COLUMN 3 
(10 points each) 
To score, add points for answers in each column. 
Please share your HIT-6 results with your doctor. 
llll·6" US(Er,glish)Versim1.1 
"2000, 2001 Oualilif',1etr~. In<. and Gl3lC0SmithKlin,G1oopofC001panits 
+ 
Always 
do work or daily activities because 
Very Often 
Very Often 
Very Often 
COLUMN 4 
(1 1 points each) 
+ 
Always 
Always 
Always 
COLUMN 5 
(13 points each) 
Total Score ,__I ___ 
__. 
Higher scores indicate 
greater impact on your life. 
Score range is 36-78. 


 
 
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THERAPEUTlCS 
HEADACHE 
IMPACT TEST™ 
What Does Your Score Mean? 
T 
If You Scored 60 or More 
Your headaches are having a very severe impact on your life. You may be experiencing disabli1 
are more severe than those of other headache sufferers. Don't let your headaches stop you fr 
your life, like family, work, school or social activities. 
Make an appoinunent today to discuss your HIT-6 results and your headaches with your d 
T 
If You Scored 56 - 59 
Your headaches are having a substantial impact on your life. As a result y 
symptoms, causing you to miss some time from family, work, school. or so 
Make an appointment today to discuss your HIT-6 results and y 
T 
If You Scored 50 - 55 
Your headaches seem to be having some impact on your 
work, school, or social activities. 
Make sure you discuss your HJT-6 results and ym 
T If You Scored 49 or 
Your headaches seem to be havin 
T 
T 
ur 
ecause research shows 1hat when doctors understand exactly how badly 
tients, 1hey are much more likely to provide a successful treatment program, which may 
et at www.headachctest.com. 
ou to print out a personal report of your results as well as a special detailed version for your doctor. 
gain or try the Internet version to continue to monitor your progress. 
The Headache Impact Test (HIT) is a tool used to measure the impact headaches have on your ability to function on the job, at 
school, at home and in social situations. Your score shows you the effect 1hat headaches have on normal daily life and your 
ability to functfon. HIT was developed by an international team of headache experts from neurology and primary care medicine 
in collaboration with the psychometricians who developed the SF-36,ii• health assessment tool. 
HIT is not intended to offer medical advice regarding medical diagnosis or treatment. You should talk to your healthcare 
provider for advice specific to your situation. 
SF-36° is a registered trademark of Medical Outcomes Trust and John E. Ware, Jr. 
HIT-6 Scoring lnterprelalion English Version I.I 
©2001 QualityMctric, Inc. and GlaxoSmithKline Group or Companies. All rights reserved. 


 
 
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CONFIDENTIAL 
Page 135 of 154 
 
17.6. 
Appendix 6: Visual Function Questionnaire-25 & 10-item 
Supplement 
 
 
National Eye institute 
Visual Functionin~J Questionnaire - 25 
(VFQ-25) 
PB/SA 
version 2000 
~(::• 
. :#" 
,# 
·•::;:hx.,·c. 
. .. 
& 
(, .... E--LF·-- DMIN•i· s··r·i::,.,E·o· F·o,R~llil·l-' •• . .,. 
-v 
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, .~ . .-.wr 
' :~ 
. 
I 
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-~. ~~fTu:'9p 
t' 
i.. 
•., 
k 
. 
w}' v:$':"" 
·- ,_ .. "(," 
~~''::;~ 
RAND hct"d)\f ~nm,.,
;.. . 
··•sio:1 tei U1iC
0w~~-
ionO~~stitute Visuol functioning C:uc:;tionnalre. 2S (Vf-Q-2£) 
JUii/ 1993, h•-n1::~:or· 
• .• 
fOli<Mhl\} (; 
'on:. whidl Sildll be d~ .• u.·r,,eO by c.lil to tifiVP. ti~~rl i41jt'~~d t(i as ... 
r.or'seq>Jerc~ of -t-::r.' 
)9 r1 
•• 
·s _it~cl' 
• : 
1. Ctm..tges to :her~ ... : •• a -2. • 
..; , -
.. be rm.-dc without the writtw pc,mlssi,:m .'.Jf RAtm. lfowcv.:,, all 
oiuch ct;_ 
e~ si1ali ;)e (!', ·~ !,r. 
1Hfi~ci as ;l~\il;1g iJeEcl• n~adt; by ihP. ret1p11,-1t 
··tis-
"•fu,1:. m:1 v:,· 
E . July 1996 i,cc,epte fU!I reeponeibi!iti•, one a~reee to hold RAt-J!J Mrmles!;, tor 1M 
·rac.y e;f any trar,s:lat:01 
t:,e NEJ VFQ-Zt kst Versl.1r. - July 1996 tntc ar.ott,cr :,mgua9c c',nd for JllY errors, 
liSSiori~:;~~-ttk> ·~::,t;~~- COli!'oequenc~s lhfl~(if. 
'~i!lis,.L•· 
·.Q.2•f·. JUiy 1995 3:c.epts !U!I r~~ponst!lility, J!ld a;:ir!!--M !O tlo!d RANU harml~ss, tcr any 
J~~Ces res1..lti 
.om l~e ;.ise .:if the NEI 'JFQ-2G. 
4. The- u~~r of ttl~ • 
• HJ-:li - . .July ·\~!1'3 •vi!I prnv!d~ "· creC'\fc line w!le-~ printing and cHstr!l,!J!ing th!s Oo~um'!nl 
.or in pi:~"W,esult~ or 1rna1ys-as !lase-don this ir.etrum~nt ac!<rtow!Mging that it 'A'M die•J~fop~d 3t RANO 
under t1,~•~sMp of tt.ec N;:iti;)r.a-1 E',i.e Institute. 
7,'29,'SC 
© RAND 1996 
vex 
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CONFIDENTIAL 
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vex 
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The following is a survey with statements about problems which involve your 
vision or feelings that you have about your vision condition. After each question 
please choose the response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
Please take as much time as you need to answer each question. 
answers are confidential. In order for this survey to improve our 
about vision problems and how they affect your quality of life, 
be as accurate as possible. Remember, if you wear glasses 
please answer all of the following questions as though you were_,,.,,,Iar< 
INSTRUCTIONS 
1. 
In general we would like to have people try to 
their own. If you find that you need a 
project staff and they will assist yo 
2. 
Please answer every question 
3. 
4. 
5. 
6. 
because they don't apply t 
u). 
ionn 
efore leaving the center and give it to 
Do not take it home . 
..ffloil"!S~~.olease feel free to ask a member of the project 
I be glaa to help you. 
would permit identification of any person who completed this 
e regarded as strictly confidential. Such information will be 
---."" purposes of this study and will not be disclosed or released for 
poses without prior consent, except as required by law. 
©RAND 1996 


 
 
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Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEAL TH AND VISION 
1. 
2. 
One) 
1 
2 
3 
4 
........................................ 5 
ou say your eyesight using both eyes (with 
ou wear them) is excellent. good, fair, 
u completely blind? 
(Circle One) 
Excellent ............................... 1 
Good ...................................... 2 
Fair ......................................... 3 
Poor ........................................ 4 
Very Poor .............................. 5 
Completely Blind ................ 6 
©RAND 1996 


 
 
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3. 
How much of the time do you worry about your eyesight? 
(Circle One) 
None of the time............................. 1 
A little of the time........................... 2 
Some of the time................. 
....... 3 
Most of the time............ 
. ........... . 
All of the time? ....................... .. 
4. 
How much pain or discomfort have you h 
(for example, burning, itching, or achin 
2 
3 
4 
5 
The next questions are a 
certain activi • 
for that activ 
. 
l!NiffliliCll difficulty, if any, you have doing 
or contact lenses if you use them 
5. 
have reading ordinary print in 
._,_._,.'Wl,,...,"'-'-9,l"''or'ould you say you have: 
(Circle One) 
ifficulty at all ................... ...................................... 1 
tie difficulty............................................................. 2 
3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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6. 
How much difficulty do you have doing work or hobbies that require 
you to ~e~~e!Lu_pg9.§.e., such as cooking, sewing, fixing things 
around the house, or using hand tools? Would you say: 
(Circle One) 
No difficulty at all ................... ...................................... 1 
.A. little difficulty .... ,. .. ",. .......................... , .... ,. ............. ,. .. 
Moderate difficulty ................................ , .... ,. .. , .... ,. ...... . 
Extremo d{fficuity .................................................. .. 
Stopped doing this because of your eyesigh 
Stopped doing this for other reasons or not 
interested in doing this .......................................... . 
7. 
Because ot your eyesight, how much 
something on a crowded shelf? 
8. 
No dil'ficulty at all ............. ..,_·.,-,.,-...,., 
A little difficulty.... .. . . ...... .. 
2 
3 
4 
5 
have rnadinq sb'eet signs or the names oi 
(Circle One) 
i/~ity at ;,II ........ .... ............. ,. ........... ............ 1 
le difficulty ............................................................. 2 
erate difficulty....................................................... 3 
4 
Stopped doing this becau;;e of your eyesight..... 5 
Stopped doing this for other reasons or not 
internsted in doing this ........................................... 6 
9. 
Beeausf, of your eyesight, how much difficulty de you have goinq 
down steps, s.ta!rs. er curbs in dim Hght or Ciit night? 
© RAND 1996 


 
 
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(Circle One) 
No difficulty at all ................... ...................................... 1 
A !ittl~ difficulty .......................................................................... 2 
Moderate difficult,•....................................................... 3 
Exireme di'fficuity ......................................................... 4 
Stopped doing this because of your eyesight ... .. 
Stopped doing this for other reasons or not 
interested in doing this. .......................... ..................... 6 
10. Because of your eyesight, how much diffi 
obrects off to the side while you are .w,.,""a'-"lk,.,_,in'-""'~~ 
No difficulty at all ............ .. 
A little difficulty ............. . 
3 
Extreme, difficulty . 
4 
Stopped doing this '4r'l~d"llif'I.. 
5 
Stopped 
intere•J:1111'1"1-,rn.;~,, .. 
'i1. 
Q"elil'll,i;ru..,:: 
w much ciifficuity do you have seeing 
say?' 
(Circle One) 
cu Hy at .. 11 ................... ...................................... 1 
•·tficuity............................................................. 2 
difficulty....................................................... 3 
me difficu!ty ..... .......... ... ..... ... ... .... ..... ............ 4 
,,,._...,_a;;,,,.~,ppecl doing !.hi':; because .of your eyesight..... 5 
Stopped doing this for other· reasons or not 
interested in doing UIis ........................................... 6 
© RAND 1996 


 
 
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12. Because of your eyesight, how much difficulty do you have g_ic_k[QQ..Q!ll 
,mcl matchinq_y9ur own clothes? 
(Circle One) 
No difficulty at all ................... ...................................... 1 
A little difficulty ........................... ., ............ , ..................... 2 
Moderate difficulty ........... ... .......... ................. ..... .. 
Extreme dilficu,ty ........................................................ . 
Stopped doing this because of your eyesight .· 
Stopped doing this for other reasons or not 
interested in doing this ........................................ . 
13. Because ot your eyesight, how much 
with eo le in their homes at arti 
No dil'ficulty at all ............. ..,_·.,-,.,._.,., 
A little difficulty.... .. . ........ . 
2 
3 
4 
5 
w much difficulty do you have going out 
, 
rts ·events? 
(Circie Ow~) 
ifficu!ty :at all .... ... ... ... ... ... ... .... .... ... 
1 
,,,,,,,__.,,,.,.,, ·Jttie difficulty ............................................................. 2 
i\/loderate difficulty....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of ycur eyesight. .. 5 
Stopped d,)ing this for other reasons c, not 
lnten:st;:?d in doing ti1is ............ ., ............................ 6 
15. J\m you ci:rrn-nt.!y driving. at least. once, in a •Nhile? 
©RAND 1996 


 
 
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(Circle One) 
Yes........................ 1 Skip TD Q 15c 
i'Jo ......................... 2 
15a. 
IF NO: Have you never driven a car or have you 
15b. 
griying? 
evesight, main!y_for 
g~sighia.nd..9theL..,,. ........ _... 
(Circle One) 
Never drove........ 1 
e of_your 
e of bot1Lvour 
·j 
Skip TD Part 3, Q 17 
,;;. Skip Tu A,rt 3, Q 17 
3 Skip Tu Part 3, 0 17 
TL Y DRl\/1!'\lG: How much difficulty do you have 
___ 
.. ,1.rio.9.the~f!Yti.!:mi.lnJfilI!illfil:.~~§? \/Vould you say 
••• 
a,~ 
(Circle One,l 
No difficulty at all................................. 1 
A little difficulty ........... . ,. ... ,. ... , ... ,,........ 
2 
Mochm ite difficulty............................... :t 
Extreme difficulty................................. 4 
© RAND 1996 


 
 
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CONFIDENTIAL 
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16.. 
How much difficulty do you have driving_at night? Would you say vou 
have: 
(Circle One) 
No difficulty at all....................................... 1 
A little difficulty ............ ""····· .. ···••"'"'''""''""'• 2 
Mod,er,, te· difficulty .. ,.... .............................. 3 
Extreme dift'iculty .......................... .. ....... 4 
Have you stopped doing this 
ause 
of your eyesight............. . .............. .. 
Have you stopped doing t 
reasons or are you not int 
doing this .................................. . 
16A. How much difficulty do you have ,,.d,_,ri_.,v~i ~
"'dc-"'-'-'-~~
~"-'-'~,>l,l.l"4-'s"'u"'-c"'-'h 
as in bad weather durin rush hou 
traffic? 
Would you say you have: 
2 
..................................... 3 
4 
u st,opped doing th!s because 
r eyesight .................................... 5 
ave you stopped doing this tor otiIer 
reasons or are you not interested in 
doing ,his................................................ 6 
© RAND 1996 


 
 
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PART 3· R.ESPONSES TO VISION PROBLEMS 
The next questions are about how things you do may be affected by your 
vision. For each one, please circle the number to indicate whether for you 
the statement is true for you all, most, some, a little, or none of the time. 
READ CATEGORIES: 
17. Do you accomplish les s 
than you would like· 
because of your vh,ion? 
18. P,re you !!mlted in how 
long you can \Nork nr de 
other act:vitie~-because of 
your vision? ...................... . 
19. Ho•N much does pain or 
discomfort i!!.O.Lfil:.Q!!Jl_g 
your eves, for 
burning, itchin 
aching, keep 
doing w 
be doi 
(Circle One On Each Line) 
Ali of 
Most of 
Some 
A 
None of 
the 
the 
the 
time 
time 
2 
3 
5 
2 
3 
4 
s 
© RAND 1996 


 
 
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CONFIDENTIAL 
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For each of the fo!lo1.'lling statements, please circle the number to indicate 
whether for you the statement is .-i~fini~l:!l _ 
__tr_ye, _111QsJ!y_Jme, .!TIQsJ!y_fa.l§e, 
or @fi.Di~ly_fru_s~ for you or you are n_o!_sYfe. 
(Circle One On Each Lme) 
Definitely 
Mostly 
i\lot 
True 
True 
Sme 
20.. 
! stay horn,) most of the-time 
because of my 0ye•sight. .... 
1 
21 
! feel frustrm_ejj_ a lot of the 
time because of my 
eyesight....... ............................... 
1 
22.. 
I have much less control 
over what I do, because of 
my eyesight. ......................... . 
23. Because of my eyesight, I 
have to rely too much on 
what other people teii me ... 
25. 
© RAND 1996 
3 
3 
2 
3 
2 
3 
4 
4 
4 
Definitely 
False 
5 
5 
5 
5 


 
 
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Appendix of Optional Additional Questions 
SUBSCALE: GENERAL HEALTH 
A1. How would you rate your overall health, on a scaie where 
bad as death and ·10 is beat possible heaHh? 
0 
Worst 
2 
SUBSCALE GENERAL VISION 
(Circle One) 
4 
5 
6 
A2. How would you rate your eyesi. 
on, if you wear them), on a sc 
worst possibie eyesight, as 
means the best possible 
means the 
, and 10 
0 
1/\Jorst 
SUBSCALE: 
A3. 
8 
9 
10 
Best 
ow 
h difficulty do you have r~c:!i_ngJ!le,,,§!!LaU 
ne boo~ on a medicine bottle.._9r on l~al forms? 
(Circle One) 
il'ficuiiy at all ................... ...................................... 1 
,,,__,-_.•~ little difficulty............................................................. 2 
Moderate difficulty ... ,. ........................ , ........ ..... ,............ 3 
Exfremc:o diffk u!ty .............................................................. 4 
Stopped doing this because of your eyes,ght ..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
© RAND 1996 


 
 
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CONFIDENTIAL 
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.A4. Because of your eyesight, how much difficulty do you have fi.lJJ!ri_ng 
out whether bills_you receive are accurate? 
(Circle One) 
No difficulty at all......................................................... 1 
.A little difficulty .... ........ .... .... ... ..... ................ ...... . 
Mod erate difficulty ....... ,. .............. , .............................. . 
Extreme d!'l'fic:uity .................................................. .. 
Stopped doing this because of your eyes,gh 
Stopped doing this for other reasons or not 
interested in doing this ......................................... .. 
A5. Because ot you 
• •• 
things I ike §S:!)h~ay_vJ.ruWm'.!!!!1J9-]c2ldlL!~IIO~!!(l;ll(!J!9J!!rf,t~i!.fil~',1 
No dil'fic 
A little di 
2 
3 
4 
5 
........................................... 6 
r eyesight, how much difficulty do you have 
le ou know from across a room? 
ing 
(Circle One) 
ii'ficuity at all ................... ...................................... 1 
little difficulty............................................................. 2 
Moderate difficulty ....................................................... 3 
Extreme d!fficu!ty ......................................................... 4 
Stopped doing this because of your eyeslght ..... 5 
Stopped doing this for other reasons or not 
interested in doing Ulis ........................................... 6 
© RAND 1996 


 
 
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Compound No.: Presendin 
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A7. Because of your eyesight, how much difficulty do you have mking_p.9[t 
in activesportsorother outcloor activities thaty_ou eniQY (like golf, 
bowling. jogging, or walking)? 
(Circle One) 
i\Jo difficulty at all......................................................... 1 
A little difficulty ............................................................. . 
Moderate difficulty ................. ...... ...... ....................... . 
Extreme di'l'fi·cuity ................................................. . 
Stopped doing this because of your eyesight ..... 
Stopped doing this for other reasons or not 
interested in doing this.............. . 
.. .................... 6 
AS. Because ot your eyesight, how much 
enjoying programs on TV? 
No dil'ficul-.y at all ............. ..,_·.,-,..-...,., 
A little difficulty.... .. . . ....... . 
2 
3 
4 
5 
r eyesight, how much ciifficuity do you have 
·•·1ch, .;me! fr,mil in our !1cmc? 
(Circle Or e) 
ifficu!ty c1t .:;ill ................... ........................... .,... 
1 
,,..,_,-,.;,...., ·aue difficulty............................................................. 2 
i\lloderate difficulty ....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stoppeci doing thi :;; for ,other reas,,.m:;; ex not 
lnten:st;:?d in doing ti1is ........................................... 6 
© RAND 1996 
and 


 
 
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SUBSCALE: DRIVING 
A10. [This item, "driving in difficult conditions", has been included as part 
of the base set of 25 items as item 16a.l 
SUBSCALE ROLE LiMiTATIONS 
A1 I. The next questions are about things you may do bev 
11islon. For each Hem, please cirde the number to ind,, 
you this is true for you all, most, Gome, a litde, or none oJ 
a. 
J;)Q__'!Q.!JJ]ave more ~lg 
from others because of 
your vision? ...... , .... , ...... .. 
b. Are 'lQU .limited i 
kinds of things yo::-:.."·--"=--"--
because of your vis1 
3 
3 
©RAND 1996 
4 
4 
Hone of 
the 
time 
5 
5 


 
 
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SUBSCALES WELL-BEING/DISTRESS (#A1 2) and DEPENDENCY (#A13) 
The next questions are about how you deal with your vision. For each 
statement, please circle the number to indicate whether for you it is 
definitely true, mostly true, mostly false, or definiteiy false for you or you 
don't know. 
Defi nitely 
Mcstiy 
Not 
True 
True 
Sur-:e 
A 12.1 am often irritable because 
of my eyesight....................... 
1 
2 
A 13.1 don't go out of my home 
alone, because of my 
eyesight. ............................... .. 
© RAND 1996 
5 


 
 
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10-ITEM NEU RO-OPHTHALMIC SUPPLEMENT TO THE NEI-VFQ-25 
The following are additional questions and statements about problems that involve your vision or 
feelings you may have about your vision condition. After each question, there will be a list of possible answers. 
Please choose the response that best describes your situation. 
Please answer all questions as if you were wearing your glasses or contact lenses (if any). Please take as much 
time as you need to answer each question. 
1. How much difficulty do you have performing tasks when your eyes are tired? 
/Circle One) 
None 
Mild 
2 
Moderate 
3 
Severe, or 
4 
Very severe? 
5 
2. Because of your vision, how much difficulty do you have ldenti~ 
sunlight? 
/Circle One) 
None 
Mild 
Moderate 
Severe, or 
Very severe? 
3. Because of your vision, how much difficult 
have 
• g a car? 
/Circle One) 
No difficulty at all 
A little difficulty 
2 
Moderate difficulty 
3 
Extreme difficulty 
4 
Stopped doing this because of our ey • 
5 
Stopped dmng th 
"-· _..._..,...~ 
r n 
rested 1n doing this 
6 
4. Because of y 
··.;-_.-.;J"" 
you have using a computer? 
/Circl 
N 
4 
5 
6 
I wing statement s, please indicate if it is definitely true, mostly true, mostly false, or 
definitely false for you or if you are not sure. 
5. I have a feeling that my two eyes see differently, even with correction {glasses or contact len ses). 
/Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
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6. 1 have a feeling that my eye or eyelid appearance is unusual. 
(Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
For each of the following, please indicate if it is true for you all, most, some, a little, or none of the time. 
7. My vision is blurry, not clear, or "fuzzy." 
(Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
8. I have trouble focusing on or following moving objects. 
(Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
9. I have double vision wittl both eyes open t 
t pres 
ther eye is covered. 
(Circle One) 
All of the time 
Mostofthe t1me 
Some of the time 
A little of the time 
None of the time 
4 
5 
1 
2 
3 
4 
5 
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Compound No.: Presendin 
Protocol 
Version: 5.0 for EU countries dated 
08Dec2022 
 
 
CONFIDENTIAL 
Page 153 of 154 
 
17.7. 
Appendix 7: Patient Global Impression of Change  
 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
Since the start of the study, my overall status is 
one box only: 
[1] 
Very much Improved 
[2] 
Much Improved 
[3] 
Minimally Improved 
[4] 
No change 
[5] 
Minimally Worse 
[6] D Much Worse 
[7] D Very much Worse 
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Compound No.: Presendin 
Protocol 
Version: 5.0 for EU countries dated 
08Dec2022 
 
 
CONFIDENTIAL 
Page 154 of 154 
 
17.8. 
Appendix 8: Contraception 
Birth control methods which may be considered as highly effective (that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are 
considered as highly effective birth control methods).  
Patients should be instructed not to take their oral contraceptive within 1 hour prior to 
administration of trial medication. 
Such methods include: 
• combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system ( IUS)  
• bilateral tubal occlusion  
• vasectomised partner 1 
• sexual abstinence 2 
 
1. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the trial participant.  
2. In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
 
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Compound No.: Presendin 
Protocol 
Version: 4.0 
 
Page 1 of 140 
 
CONFIDENTIAL 
 
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 
Effective Date: 
09-Jul-2022 
 
Short Title: A Phase III trial to determine the efficacy and safety of Presendin in 
IIH – IIH EVOLVE 
Abstract: 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 release 
formulation of exenatide (Presendin) in the reduction of intracranial pressure (ICP) in 
patients with IIH. The primary outcome will be determined by change in ICP, as 
measured by lumbar puncture (LP).  
Eligible, consenting patients will be randomised in a ratio of 1:1 to receive Presendin or 
placebo as a weekly dose for 24 weeks. 
 
Author  
Department 
Company 
Emma de Launay 
Clinical Operations 
Invex Therapeutics Ltd. 
 
 
 
 
The information contained in this document is the property of Invex Therapeutics and 
may not be produced, published or disclosed to others without written authorisation from 
Invex Therapeutics 
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Page 2 of 140 
 
CONFIDENTIAL 
Invex Therapeutics 
 
 
 
 
 
 
 
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Study Number: INVEX-CLIN-IIH-301 
Protocol 
SPONSOR SIGNATURE PAGE 
Sponsor Signatory: 
(}s; ,-JC{v ,;:_ 
Doctor Alexandra Sinclair 
MBChB, PhD, _FRCP 
Chief Scientific Officer 
Invex Therapeutics Ltd. 
 
 
 
 
CONFIDENTIAL 
. 1nvex 
THERAPEUTICS 
Com 
und No.: Presendin 
Version: 4.0 
z.1. (5 ·2022-
Datc 


 
 
Study Number: INVEX-CLIN-IIH-301 
Compound No.: Presendin 
Protocol 
Version: 4.0 
 
Page 4 of 140 
 
CONFIDENTIAL 
SPONSOR INFORMATION PAGE 
Role 
Name and 
Title 
Email Address 
Address 
Non-
Executive 
Chairman 
Dr Jason 
Loveridge 
 
Invex Therapeutics 
Ltd 
 
 
 
 
Medical 
Monitor 
(CRO) 
Premier 
Research 
Medical 
Monitor 
Premier Research 
3800 Paramount 
Parkway 
Suite 400 
Morrisville 
NC 27560 
USA 
Chief 
Operating 
Officer 
Carol 
Parish 
 
Invex Therapeutics 
Ltd 
 
 
 
Senior 
Clinical 
Trials 
Manager 
Emma de 
Launay 
 
Invex Therapeutics 
Ltd 
 
 
 
 
Sponsor Contact Information:   
Invex Therapeutics Ltd 
 
 
 
 
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Compound No.: Presendin 
Protocol 
Version: 4.0 
 
Page 5 of 140 
 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, have read and understood the protocol and am aware of my 
responsibilities as an Investigator. I agree to conduct the study in accordance with this 
protocol, the Trial Reference Manual and any subsequent amendments, the Declaration of 
Helsinki, ICH GCP guidelines, and the laws and regulations of the country in which the 
study is being conducted. 
 
Investigator Name and Qualifications: _____________________________________ 
 
 
 
Investigator Signature 
 
Date 
[Investigator Affiliation] 
 
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CONFIDENTIAL 
INVESTIGATOR INFORMATION PAGE 
Details will be provided in the Investigator Site File  
 
 
 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS .................................................................................................. 12 
PROTOCOL SUMMARY ........................................................................................ 14 
1. 
INTRODUCTION ............................................................................................. 26 
1.1. 
Background and Rational ............................................................................ 26 
1.1.1. 
Name and Description of the Investigational Product ................... 33 
1.1.2. 
Non-clinical Studies ..................................................................... 34 
1.1.3. 
Clinical Studies ............................................................................ 35 
1.1.4. 
Trial Conduct ............................................................................... 36 
1.2. 
Risk/Benefit Assessment ............................................................................ 36 
2. 
OBJECTIVES .................................................................................................. 37 
2.1. 
Primary Objective ....................................................................................... 37 
2.2. 
Secondary Objectives ................................................................................. 37 
2.3. 
Safety Objective.......................................................................................... 38 
2.4. 
Exploratory Objectives ................................................................................ 38 
3. 
ENDPOINTS ................................................................................................... 38 
3.1. 
Primary Endpoint ........................................................................................ 38 
3.2. 
Secondary Endpoints .................................................................................. 38 
3.3. 
Safety Endpoints ......................................................................................... 39 
3.4. 
Exploratory Endpoints ................................................................................. 39 
4. 
TRIAL DESIGN ............................................................................................... 40 
4.1. 
Summary of Trial Design ............................................................................ 40 
4.1.1. 
Trial Design ................................................................................. 40 
4.1.2. 
Randomisation and Blinding ........................................................ 42 
4.1.3. 
Duration of Patient Participation ................................................... 42 
4.2. 
Stopping Rules ........................................................................................... 42 
4.2.1. 
Trial Stopping Rules .................................................................... 42 
4.2.2. 
Individual Stopping Rules ............................................................ 43 
4.3. 
End of Trial ................................................................................................. 43 
5. 
TRIAL POPULATION ...................................................................................... 43 
5.1. 
Number of Patients ..................................................................................... 43 
5.2. 
Eligibility Criteria ......................................................................................... 43 
5.2.1. 
Inclusion Criteria .......................................................................... 43 
5.2.2. 
Exclusion Criteria ......................................................................... 44 
6. 
TRIAL ASSESSMENTS AND PROCEDURES ................................................ 47 
6.1. 
Procedures at Each Visit ............................................................................. 47 
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6.1.1. 
Visit 1 Screening .......................................................................... 47 
6.1.2. 
Visit 2 Baseline ............................................................................ 48 
6.1.3. 
Visit 3 Telephone call ................................................................... 50 
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits ............................................. 50 
6.1.5. 
Visit 10 ......................................................................................... 51 
6.1.6. 
Visit 11 Follow-Up ........................................................................ 53 
6.1.7. 
Unscheduled visit for repeat visual assessments ......................... 53 
6.2. 
Trial Procedures ......................................................................................... 54 
6.2.1. 
Screening Procedures ................................................................. 54 
6.2.1.1. 
Demographics ............................................................ 54 
6.2.1.2. 
Medical, Headache and Ophthalmic History ............... 54 
6.2.1.3. 
Reporting of Prior and Concomitant Medication .......... 54 
6.2.2. 
Safety Procedures ....................................................................... 55 
6.2.2.1. 
Physical Examination ................................................. 55 
6.2.2.2. 
Twelve- Lead Electrocardiogram ................................ 55 
6.2.2.3. 
Vital Signs .................................................................. 56 
6.2.2.4. 
Laboratory Assessments ............................................ 56 
6.2.2.4.1. 
Haematology .......................................... 56 
6.2.2.4.2. 
Clinical Chemistry ................................... 57 
6.2.2.4.3. 
Urinalysis ................................................ 57 
6.2.2.4.4. 
CSF ........................................................ 58 
6.2.2.4.5. 
Pregnancy .............................................. 58 
6.2.2.4.6. 
Pharmacokinetic sampling ...................... 58 
6.2.2.4.7. 
Anti-drug Antibodies sampling ................ 59 
6.2.2.5. 
Adverse Events .......................................................... 59 
6.3. 
Efficacy Procedures .................................................................................... 59 
6.3.1. 
Intracranial Pressure .................................................................... 59 
6.3.2. 
Visual Assessments ..................................................................... 59 
6.3.2.1. 
Frisén grade ............................................................... 59 
6.3.2.2. 
Optical Coherence Tomography ................................. 60 
6.3.2.3. 
Humphrey Visual Field ............................................... 60 
6.3.2.4. 
Visual Acuity ............................................................... 61 
6.3.3. 
Headache Assessments .............................................................. 61 
6.3.3.1. 
Headache Preventative Medication Review ................ 61 
6.3.4. 
Patient Reported Outcomes ......................................................... 61 
6.3.4.1. 
Visual related .............................................................. 61 
6.3.4.2. 
Health-related ............................................................. 61 
6.3.4.3. 
Headache related Quality of Life................................. 62 
6.3.4.4. 
Patient Global Impression of Change ......................... 62 
6.3.5. 
Body Weight and Body Mass Index ............................................. 62 
7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS ........................................ 63 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS ........................................... 67 
9. 
INVESTIGATIONAL PRODUCT ...................................................................... 67 
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9.1. 
Dosage and Administration ......................................................................... 67 
9.1.1. 
Randomised Period ..................................................................... 67 
9.2. 
Dose Rationale ........................................................................................... 68 
9.3. 
Maintaining the Blind .................................................................................. 68 
9.4. 
Treatment Assignment ................................................................................ 69 
9.5. 
Packaging and Labelling ............................................................................. 69 
9.6. 
Preparation ................................................................................................. 69 
9.7. 
Handling and Storage ................................................................................. 69 
9.8. 
Product Accountability and Assessment of Compliance .............................. 69 
9.9. 
Treatment of Investigational Product Overdose .......................................... 70 
9.10. 
Occupational Safety .................................................................................... 70 
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .................. 70 
10.1. 
Recording Prior and Concomitant Medication ............................................. 70 
10.1.1. 
Treatment Failure ........................................................................ 71 
10.1.1.1. Possible treatment failure ........................................... 71 
10.1.1.2. Definite treatment failure ............................................ 71 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive 
Visual Loss .................................................................................. 71 
10.1.2.1. Rescue Therapy for Headache ................................... 71 
10.2. 
Prohibited Medications ................................................................................ 72 
10.2.1. 
Prior to screening and randomisation ........................................... 72 
10.2.2. 
During the trial ............................................................................. 73 
11. PATIENT COMPLETION AND WITHDRAWAL ............................................... 73 
11.1. 
Patient Completion ..................................................................................... 73 
11.2. 
Patient Withdrawal ...................................................................................... 73 
11.2.1. 
Patient Withdrawal from Trial Treatment ...................................... 73 
11.3. 
Treatment after the End of the Trial ............................................................ 74 
11.4. 
Screen and Baseline Failures ..................................................................... 74 
12. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............................. 74 
12.1. 
Adverse Events........................................................................................... 74 
12.1.1. 
Causal Relationship ..................................................................... 74 
12.1.2. 
Severity Criteria ........................................................................... 75 
12.1.3. 
Reporting Adverse Events ........................................................... 75 
12.2. 
Serious Adverse Events .............................................................................. 76 
12.2.1. 
Suspected Unexpected Serious Adverse Reactions .................... 77 
12.2.2. 
Expected Adverse Events ............................................................ 77 
12.2.3. 
Reporting Serious Adverse Events .............................................. 77 
12.3. 
Reporting and Handling of Pregnancies ...................................................... 78 
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................ 79 
13.1. 
Hypotheses ................................................................................................. 79 
13.2. 
Trial Design Considerations ........................................................................ 79 
13.2.1. 
Sample Size Assumptions ........................................................... 79 
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13.2.1.1. Intracranial Pressure Power ....................................... 79 
13.2.1.1. Perimetric Mean Deviation Power ............................... 80 
13.2.2. 
Stratification ................................................................................. 81 
13.2.3. 
Sample Size Sensitivity ................................................................ 81 
13.2.3.1. Clinically Meaningful Effect Sizes ............................... 81 
13.2.4. 
Trial Stopping Criteria .................................................................. 82 
13.3. 
Data Analysis Considerations ..................................................................... 82 
13.3.1. 
Estimands .................................................................................... 83 
13.3.1.1. Outcome: Intracranial pressure (ICP) ......................... 83 
13.3.1.1.1. Intercurrent event: ICP-lowering 
medications ............................................ 83 
13.3.1.1.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 83 
13.3.1.1.3. Inter-current event: Dramatic 
weight-loss ............................................. 84 
13.3.1.2. Outcome: Perimetric Mean Deviation (PMD) .............. 84 
13.3.1.2.1. Intercurrent event: ICP-lowering 
medications ............................................ 84 
13.3.1.2.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 84 
13.3.1.2.3. Intercurrent event: Dramatic 
weight-loss ............................................. 85 
13.3.1.3. Outcome: Papilloedema measured by OCT 
(optic nerve head size, retinal nerve fibre layer) ......... 85 
13.3.1.3.1. Intercurrent event: ICP-lowering 
medications ............................................ 85 
13.3.1.3.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 85 
13.3.1.3.3. Intercurrent event: Dramatic 
weight-loss ............................................. 86 
13.3.1.4. Outcome: Monthly headache days (MHD) .................. 86 
13.3.1.4.1. Intercurrent event: Headache-
preventative medications ........................ 86 
13.3.1.4.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 87 
13.3.1.4.3. Intercurrent event: Dramatic 
weight-loss ............................................. 87 
13.3.1.4.4. Intercurrent event: ICP-lowering 
medications ............................................ 87 
13.3.1.5. Primary Estimand (Hypothetical assuming no 
concurrent procedures, irrespective of 
adherence to treatment) ............................................. 88 
13.3.1.6. Secondary Estimand (Hypothetical) ............................ 88 
13.3.2. 
Analysis Populations .................................................................... 88 
13.3.3. 
Treatment Comparisons .............................................................. 89 
13.3.4. 
Safety Analyses ........................................................................... 89 
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13.3.4.1. Adverse Events .......................................................... 90 
13.3.4.2. Clinical Laboratory Evaluations .................................. 90 
13.3.4.3. Vital Signs and Body Mass Index Evaluations ............ 90 
13.3.4.4. Electrocardiogram ...................................................... 91 
13.3.4.1. Other Safety Evaluations ............................................ 91 
13.3.5. 
Patient Reported Outcomes Analyses ......................................... 91 
13.3.6. 
Missing Data ................................................................................ 91 
13.3.7. 
Reporting Deviations from the Statistical Plan ............................. 91 
14. TRIAL ADMINISTRATION ............................................................................... 92 
14.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 92 
14.2. 
Trial Monitoring ........................................................................................... 92 
14.2.1. 
Access to Source Data ................................................................ 93 
14.2.2. 
Data Handling and Record Keeping ............................................. 93 
14.3. 
Provision of Trial Results and Information to Investigators and 
Publications ................................................................................................ 94 
14.4. 
Data Management ...................................................................................... 94 
14.5. 
Independent Adjudication Committee ......................................................... 95 
14.6. 
Data Safety Monitoring Committee ............................................................. 95 
14.7. 
Insurance, Indemnity and Finance .............................................................. 95 
15. REFERENCES ................................................................................................ 97 
16. APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-301 ....................... 106 
16.1. 
Appendix 1: LP SOP ................................................................................. 106 
16.2. 
Appendix 2: IIH Diagnostic criteria [Mollan, 2018] ..................................... 109 
16.3. 
Appendix 3: 36-item short from survey ...................................................... 110 
16.4. 
Appendix 4: EuroQol -5 dimension-5 level survey ..................................... 116 
16.5. 
Appendix 5: Headache Impact Test-6 ....................................................... 119 
16.6. 
Appendix 6: Visual Function Questionnaire-25 & 10-item 
Supplement .............................................................................................. 121 
16.7. 
Appendix 7: Patient Global Impression of Change .................................... 139 
16.8. 
Appendix 8: Contraception ........................................................................ 140 
 
 
 
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CONFIDENTIAL 
ABBREVIATIONS 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCRF 
Electronic Case Report Form 
BMI 
Body Mass Index 
CGRP 
Calcitonin Gene-Related Peptide 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DGM 
Data-Generating Models 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
GCL 
Ganglion Cell Layer 
GLP-1 
Glucagon Like Peptide-1 
HVF 
Humphrey Visual Field 
ICF 
Informed Consent Form 
ICP 
Intracranial Pressure 
IAC 
Independent Adjudication Committee 
ICH-GCP 
International Council of Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IIH 
Idiopathic Intracranial Hypertension 
ITT 
Intention-to-Treat 
LP 
Lumbar Puncture 
MAR 
Missing At Random 
MD 
Mean Deviation 
MHD 
Monthly Headache Days 
NRS 
Numeric Rating Scale 
OCT 
Optical Coherence Tomography 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QTcF 
QT Interval corrected according to Fridericia’s formula 
RNFL 
Retinal Nerve Fibre Layer 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SF-36 
36-item short form survey 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
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CONFIDENTIAL 
ULN 
VFQ-25-10 item  
Upper Limit of Normal 
Visual Function Questionnaire-25 and 10-item supplement 
 
 
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PROTOCOL SUMMARY 
Rationale 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends.  
IIH has significant associated morbidity and reduced quality of life. Elevated ICP causes 
papilloedema universally at disease onset and can lead to permanent visual loss. Visual 
loss occurs in greater than 90% of those with IIH [Wall 1991] and can be severe and 
permanent in between 5-25%. Besides risk of visual loss, the most disabling aspect for 
patients is severe chronic headaches driven by elevated ICP. Existing pharmacotherapies 
are limited. The most frequently used drug therapy, acetazolamide, is used off label and 
has been shown to have efficacy but due to side effects and treatment failures new drugs 
are needed. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but the failure rates are high and frequent complications and side 
effects occur. 
A modified release formulation of exenatide (Presendin) has been developed and this trial 
has been designed to evaluate the efficacy and safety of Presendin in IIH. The modified 
release formulation has been chosen to enable a once weekly dosing.  
Objectives 
Primary Objective 
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 lumbar 
puncture (LP) at baseline and at 24 weeks. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
Secondary Objectives 
To determine the effect of Presendin on change in: 
•
Perimetric Mean Deviation (PMD) as measured by the Humphrey Visual Field
analyser (24-2 SITA (Swedish Interactive Testing Algorithm)-Standard)
•
Papilloedema as measured by optical coherence tomography imaging (retinal nerve
fibre layer (RNFL) thickness and optic nerve head volume measurements)
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•
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
Safety Objectives 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
Exploratory Objectives 
To determine the effect of Presendin on: 
•
Macular ganglion cell layer/complex thickness
•
Headache responder rate: ≥30% reduction in monthly headache days
•
Headache responder rate: ≥30% reduction in moderate to severe monthly headache
days
•
Patient Reported Outcomes (PROs)
•
Body Mass Index (BMI)
•
Body Weight
•
Health Utilisation
Endpoints 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
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Secondary Endpoints 
• 
Perimetric Mean Deviation 
• 
Retinal nerve fibre layer 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 and 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.* 
*criteria defined in rescue therapy section 10.1.1 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs) 
• 
Resting 12-lead ECG 
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
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CONFIDENTIAL 
Exploratory Endpoints 
•
Macular ganglion cell layer/complex thickness
•
Responder rate monthly headache days (defined as ≥30%)
•
Responder rate moderate to severe monthly headache days (defined as ≥30%
reduction)
•
Patient Reported Outcomes:
•
Visual Function Questionnaire-25 and 10-item supplement (VFQ-25-10 item
supp)
•
Headache Impact Test -6 (HIT-6)
•
36-item short from survey (SF-36)
•
EuroQol -5 dimension -5 level (EQ-5D-5L) survey
•
Patient Global Impression of Change (PGIC)
•
Body Mass Index (BMI)
•
Body Weight
•
Health Utilisation
Trial Design 
This is a randomised, placebo-controlled, double-blind, multi-centre trial requiring 
240 adult randomised patients with IIH to determine the efficacy and safety of Presendin. 
Consenting patients with a diagnosis of IIH will enter a 1-week screening period, in 
which there will be no investigational treatment, to gather baseline measurements and to 
check eligibility. Although a headache diary is typically over 28 days, it was felt 
unethical to have patients off treatment for this more prolonged period due to the real risk 
of visual loss. Headache diaries designed to measure headache frequency have 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [Wall, 2014, Markey, 2017 and Mollan, 2021]. Hence the baseline 
headache frequency will be calculated over 1 week as has been done in other trials. 
At the screening visit, patients will be provided with training on the self-administration of 
the trial medication and provided with a leaflet to take home. Patients will be asked to 
self-administer one (1) dose of placebo during the screening visit to ensure they are 
comfortable with self-injection. Patients who are not comfortable with self-administration 
will be deemed a screen failure and will not be randomised into the trial. Eligible patients 
will then be randomised to receive either Presendin or matching placebo for 24 weeks in 
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a 1:1 ratio. After completion of the randomisation period 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 also be performed.  
The duration of the double-blind treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy over a 3-month time 
horizon. Additionally, an alternative off label drug used in IIH (acetazolamide) evaluated 
efficacy over a 6-month period. Hence efficacy is relevant over this time frame. A longer 
period of randomisation would not be ethical if patients were expected to remain on 
placebo for 12 months as this could place their overall health at risk. The duration of the 
trial for each patient will be up to 30 weeks, which includes a 1-week screening period, a 
24-week randomised double-blind treatment period, and a treatment follow-up period of 
5 weeks. 
Trial Population 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.2, Appendix 2), 
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 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  
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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 – see Section 16.8, Appendix 8 for 
further details) 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 
Patients must not be enrolled if they meet any of the following 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 
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Vision related exclusion criteria: 
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] 
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 apnoea­hypopnea 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 
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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 
 
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 – see section 10.1.2
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Trial Assessments 
Table 1: Time and Events 
 
 
SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Informed consent  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X  
(review) 
 
 
 
 
 
 
 
 
 
 
Demography (sex, age, 
ethnicity) 
X 
 
 
 
 
 
 
 
 
Medical & Ophthalmic 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Headache history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Headache preventative 
medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Train and dispense 
headache diary 
X 
 
 
 
 
 
 
 
 
 
 
 
Review headache diary1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Body weight and BMI 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examination 
(T = targeted) 
X  
(Full) 
X (T) 
 
 
 
X (T) 
 
X (T) 
X(T) 
X (T) 
 
(X) 
Pregnancy Test3 
X 
(Serum) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
OCT Imaging  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
Papilloedema Frisén 
grade4   
X 
X 
 
 
 
 
 
 
 
 
 
 
Perimetry  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visual Acuity Testing 
(LogMAR score) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
 
Patient Reported 
Outcomes 
(HIT-6, SF-36, EQ-5D-5L, 
VFQ-25 & 10-item supp) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Health Utilisation Form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC assessment 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments5  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Pharmacokinetic (PK) 
sampling6 
 
X7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-Drug Antibodies 
(ADA) sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Lumbar Puncture8 
 
 
 
 
 
 
 
 
 
X9 
 
 
Trial medication training10 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
Trial medication 
Dispensing  
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Trial medication 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
1 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Patients who do not meet the eligibility criteria based on diary review at 
randomisation/baseline (e.g., too few headache days or unacceptable concomitant medication use) will be considered screen failures; however, if the patient wishes and 
the Investigator is in agreement, he/she can be re-screened as a new patient. If the screening period exceeds 7 days, then eligibility will be based on the last 7 days of the 
screening period, i.e., the 7 days prior to randomisation visit. Trial site research team should review diaries remotely on a weekly basis to ensure compliance and follow 
up any patients with missing data 
2 
Vital signs to include: blood pressure and heart rate 
3 
Women of child-bearing potential. Serum pregnancy test to be conducted at screening, thereafter, highly sensitive urine pregnancy tests will be conducted. Visit 11 urine 
pregnancy test may be conducted at home 
4 
Frisén grade will be evaluated locally and the presence of papilloedema verified by the OCT Reading Centre at screening to confirm eligibility. Indeterminate cases 
should be referred to the IAC (and supplemented with fundus photography and ultrasound scan of the optic nerve) to confirm papilloedema prior to randomisation visit 
5 
Haematology, coagulation, biochemistry and urinalysis 
6 
All actual sampling times and dosing times will be recorded 
7 
Baseline Post-dose PK blood sample 
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8 
The diagnostic LP will be the baseline LP and must be performed in lateral decubitus position. Patients with ICP <25 cm  CSF at diagnosis will be excluded  
9 
Lumbar puncture to be performed after visual assessment. LP to be performed as per Appendix 1. CSF sample from visit 10 LP will be retained for future potential 
analysis 
10 
Patients will be provided with training on the self-administration of the trial medication. The patient will be asked to self-administer placebo at visit 1 to demonstrate 
ability to self-inject. Patients who are not comfortable to self-inject will be excluded 
11 
If patients discontinue in the randomised double-blind treatment period they will be encouraged to return for all trial visits up to visit 11. If a patient does not want to 
return for all visits then they will be asked to return at a minimum for visit 11 procedures for safety follow up 
12 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial medication and must have self-administered their final dose within 7 days of 
visit 10. Patients will be reminded by the trial site to self-administer trial medication weekly, to continue this until the completion of visit 10 and to bring their trial 
medication with them at visit 10 for return. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial medication has been missed in the previous 4 weeks. Visit 10 should be delayed no 
more than 14 days 
13 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients in whom there is concern about visual decline or who perform inadequately or where 
there is technical failure (more than 15% false positive responses or inadequate performance indicated by the Visual Field Reading Centre for HVF; or OCT imaging not 
of satisfactory quality as determined by the OCT Reading Centre) 
14 
In the event of any abnormal safety assessments identified at end of treatment, e.g., abnormal ECG, abnormal routine laboratory results or ongoing adverse events, this 
visit may be performed at the clinic to repeat or follow up safety assessments 
15 
Reporting of AEs/SAEs will continue up to the final follow up visit 11 
 
 
 
 
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1.
INTRODUCTION
1.1. 
Background and Rational 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing 
with rising obesity trends [Mollan, 2019a]. There is a high rate of repeat hospital 
admission in IIH (increased by 446% in last decade), reflected in escalating healthcare 
costs (in England £462 million/year predicted by 2030 [Mollan, 2019a] and more than 
$444 million in the USA [Friesner, 2011]). 
The cause of IIH is not fully understood. Recent research suggests that IIH is a disease of 
systemic metabolic dysregulation characterised by central adiposity [Hornby, 2017], 
double the risk of cardiovascular disease in excess to that mediated by obesity [Adderley, 
2019] and dysfunctional adipocyte metabolism primed for weight gain [Westgate, 2021]. 
Patients are also insulin resistant and have a unique hormone signature of androgen 
excess both systemically and in the cerebrospinal fluid.[O’Reilly, 2019] 
Morbidity in IIH is due to the elevated intracranial pressure which can cause severe 
papilloedema (swelling of the optic nerve) which can ultimately lead to blindness. The 
risk of permanent visual loss is a major concern in IIH. Visual loss occurs in greater than 
90% of those with IIH [Wall 1991] and can be severe and permanent in between 5-25%. 
Headache is an additional major disabler and affects the majority of IIH patients (over 
90%) [Yri, 2014; Markey, 2016; Mulla 2015] in the long term. Headaches significantly 
reducing quality of life [Mulla, 2015; Digre, 2015] are driven by raised intracranial 
pressure and often have a migraine- like phenotype (> 90%) [Mollan 2021a].  
Existing pharmacotherapies are limited. The most frequently used drug therapy, 
acetazolamide, is used off label and has been shown to have efficacy but due to side 
effects and treatment failures new drugs are needed. [Piper, 2015; Mollan, 2018; 
Hoffmann, 2018]. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but there is a high failure rate and frequent complications. The 
lack of licenced or targeted treatments in IIH perpetuates poor outcomes for patients. A 
priority setting exercise was run by patients with IIH (James Lind methodology) 
[Mollan, 2019c] establishing effective therapy was the top priority from the patient 
group. 
This trial will investigate an alternative therapeutic option for lowering ICP and thereby 
reducing papilloedema and consequently reducing the risk of visual loss. By reducing 
ICP it would also aim to improve headache, improving overall patient quality of life in 
IIH [Mollan 2021a]. 
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Gut neuropeptides are increasingly being recognised for their role in the central nervous 
system (CNS). A principal gut neuropeptide is glucagon like peptide-1 (GLP-1), which is 
known to stimulate insulin release, proliferation of pancreatic beta cells and control of 
glucose regulation in diabetes [Campbell, 2013]. Exenatide is a GLP-1 receptor agonist. 
It has also been shown to have some actions in the CNS; GLP-1 is involved in regulating 
satiety and weight through signalling at the hypothalamus [Astrup, 2009]. There is also 
evidence that GLP-1 may have a role in fluid secretion. In the renal proximal tubule 
GLP-1 acts to reduce sodium resorption to promote diuresis [Gutzwiller, 2004; 
Websky, 2014]. The choroid plexus is the fluid secreting structure within the brain 
producing the majority of CSF. The structure of the choroid plexus epithelial cells is 
analogous to an inverted renal proximal tubule with a similar mechanism of secretion and 
hence GLP-1 receptor agonists may also reduce CSF secretion in the brain, leading to a 
decrease in ICP in patients with IIH. 
Exenatide as well as other GLP-1 receptor agonists can lead to weight loss. In diabetic 
patients, weight loss of 2.8 - 4.4 kg has been reported over 6 months [Di Dalmazi 2020; 
Pujante 2012]. Whilst in non-diabetic overweight and obese patients exenatide caused 
sufficient weight loss between 2.0 – 5.1 kg [Moreno 2012]. In overweight and obese 
patients with polycystic ovarian syndrome exenatide led to 2kg more weight loss 
compared to placebo in over 12 weeks [Liu 2017]. Weight loss with exenatide therapy is 
increased in the setting of calorie restriction [Rosenstock 2010]. Weight loss is a 
desirable effect of exenatide as weight loss is therapeutic in IIH. Changes in body weight 
will be monitored during the trial and the impact on outcomes measures evaluated. 
Exenatide is the active ingredient in Byetta, an immediate-release (IR) formulation and 
Bydureon, an extended-release (ER) formulation. These have been licenced for use in 
adults with type-2 diabetes since 2005 and 2014, respectively. Therefore, there is a 
wealth of available safety data from both clinical trials and real-world experience. 
Exenatide has been identified as a potential candidate for the treatment of neurological 
conditions involving raised ICP and a polylactic-co-glycolic acid (PLGA) ER exenatide 
formulation under the name Presendin, has been developed by Invex Therapeutics for the 
treatment of IIH.  
Byetta has a known issue of rapid elimination of the product when given to humans, and 
because of this it needs to be administered twice daily to achieve its pharmacological 
effects. The data on file from the IIH Pressure trial has shown that in patients with IIH, 
exenatide administered twice daily was well tolerated and produced a positive effect on 
reducing CSF pressure. However, it is considered that the immediate release formulation 
of exenatide is not ideal for treating patients with IIH on a long-term basis. Presendin has 
been developed as an extended release formulation to allow for a reduction in dosing 
frequency to once weekly and more consistent therapeutic plasma levels. 
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This trial is designed to investigate the efficacy and safety of a modified release 
formulation of exenatide (Presendin) in patients with IIH.  
Intracranial pressure 
IIH is a debilitating condition characterised by raised ICP, which is clinically measured 
by LP [Mollan, 2018]. The units for measurement of LP are cm CSF and cm H2O and 
these should be thought of as interchangeable and reflect the measurement of the height 
of the CSF column at LP. The measurement must be taken in the lateral decubitus 
position. Lumbar puncture is conducted to make a diagnosis of IIH. Lumbar puncture 
may be conducted in a clinical setting during the disease course to both monitor and treat 
the condition. Frequent therapeutic LPs are no longer recommended by the International 
IIH guidelines [Mollan, 2018]. This is because LP can be traumatic for patients and can 
occasionally cause significant complications (meningitis, spinal haematoma, pain) 
[Wright, 2012]. Hence, unnecessary LP’s should be avoided. In some patients LP can 
alter other outcome measures, including measurements of papilloedema and headache 
[Yiangou, 2019]. Hence ideally, LP should be performed after these measures and 
symptoms have been assessed. Lumbar puncture can cause post-dural puncture 
headaches. The risk is 9-36% using a traumatic needle and 3-19% using an atraumatic 
needle [Wright, 2012]. Post-dural puncture headaches typically last less than a week but 
in some patients this can be longer [Yiangou, 2019]. Lumbar puncture pressure 
assessment of ICP reflects disease activity and is a useful and recognised outcome 
measure that has been utilised in other IIH trials [Markey 2020; Mollan 2021b]. 
Due to the invasive nature of LP, non-invasive measures of ICP are valuable. The 
majority of techniques historically evaluated as non-invasive surrogate measures of ICP 
lack sufficient quantification to be used clinically or in clinical trials.  Optical coherence 
tomography (OCT) measures of the optic nerve have been shown to provide a useful 
surrogate measure to quantify changes in ICP [Vijay, 2020]. For example, at 12 months, 
Vijay et al showed that a change in optic nerve head height of 50 µ predicted a 5 cm CSF 
change in ICP [Vijay, 2020]. 
Visual Function 
Perimetry is used to measure visual function in IIH clinical practice. This is assessed 
using a Humphrey Field Analyzer (program 24-2 SITA standard using a size III white 
stimulus) test. Patients are often unaware of their visual field loss until this becomes more 
severe and compromises daily activities. In patients with severe papilloedema optic 
atrophy can develop (measured objectively as loss of the macular ganglion cell layer on 
OCT imaging) and the loss of visual field becomes permanent. Patients at risk of rapidly 
progressive visual loss (also termed fulminant IIH) should receive emergency surgical 
intervention (most commonly a CSF shunt operation) [Mollan, 2018]. Patients requiring 
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emergency surgery will not be recruited into this trial. Medical therapy is used to treat 
those IIH patients not requiring emergency surgical intervention and will be included in 
this trial. But it is expected that approximately 5-10% will go on to need more aggressive 
intervention. 
Measuring visual function with perimetry has a number of challenges in IIH which need 
to be carefully considered. The visual field test is dependent on technician and patient 
performance and can be prone to variability and inaccuracy [Cello, 2016; Wall, 2016]. 
Patients can perform poorly on automated perimetry [Cello, 2016], and there is a learning 
effect [Kutzko, 2000; Wall, 2016]. There are further confounding factors when 
considering interpretation of automated visual field testing in IIH. The high prevalence of 
functional vision loss, presenting as non-organic visual fields results in this disease, may 
bias trial outcomes [Kutzko, 2000; Ney, 2009]. Additionally, impaired executive function 
and attention deficits have been noted in IIH [Sørensen, 1986], and have been shown to 
impair performance of visual field testing in IIH [Grech, 2021]. 
The protocol has been designed with these challenges in mind and visual field testing 
performance will be assessed at trial entry and throughout with opportunity for repeated 
assessment if there is performance failure (a performance failure is defined as a 
substantial worsening of the perimetric mean deviation due to human factors rather than 
visual damage) [Cello, 2016].. The visual fields will be assessed by the Visual Field 
Reading Centre. 
Papilloedema by change in optic nerve head size measured by OCT imaging. 
Papilloedema is a reliable sign of raised ICP [Dunn, 2002]. Change in papilloedema has 
been used by all the randomised control trials in IIH to date to determine clinical 
improvement [Ball, 2011; Wall, 2014; Mollan 2021b]. Change in papilloedema has been 
graded by experts using the Frisén classification, although it is more reliably measured by 
OCT imaging [Ball, 2011; Wall, 2014]. Professional bodies and the literature endorse the 
use of OCT imaging for monitoring papilloedema in IIH [Mollan, 2018]. 
 OCT imaging measures various aspects of the optic nerve. The retinal nerve fibre layer 
(RNFL) and optic nerve head volume  are measurements that both reflect swelling of the 
optic nerve and hence the extent of papilloedema. Measures of macular volume can 
quantify the ganglion cell layer (GCL) thickness which reflects axonal loss. Optic nerve 
head measures on OCT correlate with visual field sensitivity loss [Salgarello, 2001]. 
Analysis has shown that OCT measures of the RNFL significantly reflect changes in 
visual field perimetric mean deviation (MD) (for every 10µm increase in RNFL there was 
associated with a 0.6dB decrease in MD) [Rebolleda, 2009]. Optical coherence 
tomography measures of the macula volume have been shown to predict axonal loss of 
the optic nerve [Albrecht, 2017]. Most importantly, ganglion cell volume has been shown 
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to significantly correlate with the Humphrey visual field MD [Vijay, 2020]. This 
indicates that the GCL can be measured to reflect visual function. In other neurological 
diseases OCT has also been found to measure neuronal loss and correlated with visual 
loss [Petzold, 2010]. In summary, OCT assessment of the optic nerve and GCL represent 
objective measures of papilloedema and optic nerve axons which reflects visual function. 
The scan quality can be compromised if the automated software segmentation of the OCT 
is not accurate. This occurs particularly in those optic nerves with more pronounced 
papilloedema [Aojula, 2018]. Hence the quality and segmentation of all OCT scans will 
be assured by the OCT Reading Centre and scans will be repeated if of insufficient 
quality. 
Headache 
Headache is the predominant presenting feature in IIH [Mollan, 2019a]. Patient morbidity 
is high because of disabling headaches and they have been found to be the key driver for 
poor quality of life [Mulla, 2015; Digre, 2015]. Research into headache treatments were 
endorsed as clinically relevant by a priority setting partnership which included the 
opinions of the patients’ carers and physicians [Mollan, 2019c].  
It has been well documented that headache characteristics in IIH are typically migraine-
like (up to 90%) [Mollan, 2019b; Mollan 2021a]. The headache location can be halo-
cranial, frontal, temporal or parietal with features including nausea, throbbing pain, 
photophobia and phonophobia [Yri, 2015]. A Danish trial of 44 IIH patients noted that 
82% of patients had migraine-like attacks [Yri, 2014]. A prospective trial in 52 IIH 
patients in the UK characterised 80% of headaches as migraine-like [Yiangou, 2019]. As 
reported by the Idiopathic Intracranial Hypertension Treatment Trial, US, the headache 
phenotype was recorded as migraine or probable migraine in 68% of 144 patients with 
active IIH [Friedman, 2017]. A retrospective trial in Iran in 68 IIH patients characterised 
migraine-like headaches in 63% [Sina, 2017]. Other headache characteristics are typically 
tension-type or unclassified [Mollan, 2019b]. 
Hence whilst IIH headaches are not diagnostically the same as migraine according to the 
International Classification of Headache Disorders, 3rd edition Beta, they are very similar 
in character [Olesen, 2018]. The International Headache Society core outcomes for 
migraine are therefore applicable to IIH headaches [Tassorelli, 2018]. 
Headache in active IIH is driven by ICP. This is evidenced by the fact that removal of 
CSF fluid results in improved headache severity. In a prospective cohort study, headache 
severity improved in 71% following a standardised LP [Yiangou, 2019]. Ninety-five 
percent of IIH patients had improvement in headache symptoms at 1 month following 
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shunt placement [Daou, 2020]. Weight loss leading to reduction in ICP also significantly 
reduced headache [Sinclair, 2010].  
Medications that reduce ICP have been shown to modulate headache. In an open label 
trial using topiramate and acetazolamide, both of which are known to modulate ICP 
[Scotton, 2019], relief of headache was reported after a mean treatment period of 3.75 
months in the topiramate group and 3.3 months in the acetazolamide group [Çelebisoy, 
2007]. 
Importantly, headache measures (severity and monthly headache days) in IIH 
significantly correlate with changes in ICP [Mollan 2021a]. The IIH weight trial [Mollan, 
2021b], a randomised controlled parallel group multicentre trial in the United Kingdom, 
investigates weight management methods in IIH. Participants with active IIH (evidenced 
by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. The primary 
outcome was ICP as measured by LP opening pressure at 12 months, with secondary 
outcomes of ICP at 24 months and headache outcomes at 12 and 24 months. Headache 
severity was correlated with ICP at baseline; change in headache severity and monthly 
headache days correlated with change in ICP at 12 months. Importantly those with the 
greatest reduction in ICP over 12 months had the greatest reduction in headache 
frequency and severity. This implies that treatment of ICP should improve headache in 
IIH. 
The following headache outcomes are clinically relevant and are recommended by the 
American Headache Society [American Headache Society] and International Headache 
Society to identify patients who are benefiting from treatments. Headache outcomes are 
derived from a 28-day diagnostic headache diary. This is used in clinical trials to 
prospectively collect daily information on headache occurrence, severity, associated 
symptoms, and use of acute analgesic medications.  
Although a headache diary is typically over 28 days, for IIH headache it was felt 
unethical to have patients off treatment for this more prolonged period during screening 
due to the real risk of visual loss. Headache diaries designed to measure headache 
frequency have successfully utilised over shorter time periods in previous IIH trials and 
noted to be representative [Mollan 2021b]. Hence the baseline headache frequency will 
be calculated over 1 week as has been done in other trials. 
Monthly headache days  
Monthly headache days (MHD) will include all headache days, defined as those with an 
onset, continuation or recurrence, any severity or phenotype of headache and lasting at 
least 30 minutes or which require acute headache analgesia. This is the most relevant and 
objective measure of headache. 
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Moderate to severe monthly 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. This 
outcome captures the more disabling headaches. 
Moderate to severe MHD was recently reported as the primary endpoint in a prospective 
open label study providing evaluation of the effectiveness of erenumab, a calcitonin 
gene-related peptide (CGRP) monoclonal antibody, to treat headaches in IIH patients 
[Yiangou, 2021]. It is also used to measure headache in other secondary headache 
conditions such as persistent post traumatic headache [Aojula 2018; Ashina, 2020]. 
Headache responder rate (≥50% reduction in MHD) 
Headache responder rate (≥50% reduction in MHD) is the proportion of patients 
achieving at least 50% reduction in the mean number of MHD, of any intensity, from 
baseline to the defined trial end point. This criterion is clinically relevant as it is used as 
an empirical review for continuing or discontinuing headache therapy [Diener, 2020]. 
Responder rates can be used in meta-analyses of placebo controlled randomised 
controlled trials. 
Headache responder rate (≥50% reduction in moderate to severe MHD) 
Headache responder rate (≥50% reduction in moderate to severe MHD) is the proportion 
of patients achieving at least 50% reduction in the moderate to severe MHD from 
baseline to the defined trial end point. It is well recognized that 50% responder rates may 
not fully capture the benefits of treatment [Matharu, 2017]. For example, a patient may 
improve from a disabling 20 severe headache days per month to 11 moderate headache 
days per month. Despite this considerable clinical benefit, such a patient would not be 
considered a responder because headache days were not reduced by ≥50%, and as a result 
might lose access to beneficial treatment. Hence, responder rates of ≥30% are also 
important [Vernieri, 2019]. In IIH, a disorder of chronic severe headaches, a clinically 
meaningful treatment responder rate has not been definitively established, although the 
International Headache Society Clinical Trials Subcommittee has suggested the use of a 
≥30% reduction from baseline for chronic migraine.  
Headache severity 
Headache severity is an important measure and impacts quality of life. It is vital to 
consider some treatments which benefit headache may not reduce the MHD but if the 
severity is markedly improved this will lead to great overall functional benefit to the 
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patient and is clinically relevant [Silberstein, 2008]. Recording the decrease in intensity is 
an indicator of reduced disability, which is clinically meaningful. 
Monthly use of acute headache rescue medications 
Use of acute headache analgesics reflects a judgement of the inefficacy of the test 
treatment; hence it is a helpful secondary outcome. In Sinclair et al. reduction in 
analgesic days was significant and associated with clinical remission of IIH [Sinclair, 
2010]. Additionally, a high portion of IIH, up to 48% [Yiangou, 2021] have medication 
overuse and medication overuse headache, and reduction in analgesic days mitigates 
these. Reduction in monthly use of acute headache analgesic is an additional endpoint 
that contributes to clinically meaningful results. 
Quality of life in IIH 
IIH has a detrimental effect on all aspects of the patient’s quality of life; the majority of 
which is driven by headache [Kleinschmidt, 2000, Mulla, 2015; Daniels, 2007; Digre 
2015]. IIH also impacts visual function with PMD correlating with quality of life 
[Bruce 2016]. Patient reported outcomes in clinical trials are essential not only to permit 
health technology assessments and cost effectiveness analysis, but also as key outcomes 
for a therapy’s effectiveness [Deiner, 2019]. There is currently no IIH disease specific 
quality of life outcome measure. 
Whilst there are differences in the choice of the tools used in the trials, they all 
commonly used the short-form 36 health survey (SF-36) [Mollan, 2021, Wall, 2014, 
Digre, 2015; Bruce, 2016; Ball, 2011]. The physical component score of the SF-36 has 
been shown to correlate significantly with changes in ICP [Grech 2021]. The EuroQol –5 
dimension (EQ-5D-5L) [Euroqol, 1990] is typically employed for health technology 
assessments and cost effectiveness [Ottridge, 2017; Ball, 2011]. Using the EQ-5D-5L in 
isolation may lack sensitivity as compared to the SF-36 for IIH. The National Eye 
Institute Visual Function Questionnaire-25 and 10-item supplement [Mangione, 2001] 
has also been utilised to assess visual related quality of life in IIH and is associated with 
improvement in visual field [Bruce 2016; Mangione 1998; Raphael 2006]. The 10-Item 
neuro-ophthalmic supplement was found to be significantly discriminating in a previous 
IIH drug trial [Wall 2014].  
1.1.1. 
Name and Description of the Investigational Product 
Patients will receive active treatment, Presendin, or matching placebo.  
Presendin is a modified release formulation of exenatide. Exenatide is a GLP-1 receptor 
agonist currently used in the management of type 2 diabetes. Presendin consists of a drug 
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part (white or greyish white powder in a clear vial) and a diluent part (colourless liquid in 
a pre-filled syringe). The drug part is suspended in the diluent part solution and 
administered as a suspension. The patient or responsible person will be responsible for 
rehydrating the product for injection. Presendin is administered as a once weekly SC 
sustained-release injection containing 2.0 mg exenatide. Matching placebo will also be 
supplied as 2 parts, as visually identical vial and pre-filled 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. Placebo is administered once weekly as a SC 
injection. 
1.1.2. 
Non-clinical Studies 
Exenatide, the active ingredient of Presendin, has been previously developed and licensed 
as Byetta for the treatment of type 2 diabetes. A wealth of historical toxicological and 
pharmacological safety data is available in the public domain. Please see the 
Investigator’s brochure for data from rat and mouse studies which have investigated the 
Presendin formulation of exenatide. 
In vitro and in vivo data suggests that the choroid plexus, the CSF secreting structure in 
the brain, contains GLP-1 receptors [Ast 2020]. Preclinical studies in rodents demonstrate 
that GLP-1 agonists can regulate cerebrospinal fluid dynamics and reduce ICP [Botfield, 
2017]. 
Nonclinical pharmacology studies have shown that exenatide and GLP-1 agonists bind to 
and stimulate GLP-1 receptors equipotently. Due to the ability of exenatide to affect fluid 
homeostasis in the kidney, it was investigated for its potential to modulate CSF secretion 
and reduce ICP in rats. A single SC injection of exenatide rapidly (within 30 minutes) 
reduced ICP and maintained lower ICP for 6 days of dosing, suggesting that GLP-1 
receptor agonists could provide an alternative treatment for conditions with raised ICP 
[Botfield, 2017]. 
Exenatide was subjected to full toxicological assessments during its nonclinical 
development programme, details of which are publicly available in the Byetta® Product 
Monograph, 2019 and the FDA Pharmacology Review, June 2004 (Section 15). In 
summary, no lethality or serious toxicity was observed in mice, rats and monkeys 
following single doses up to 1500 µg/kg, 3000 µg/kg and 5000 µg/kg respectively. In 
repeat-dose toxicity studies decreased body weight gain and food consumption, a known 
pharmacological effect of exenatide, were observed in all studies. Exenatide caused no 
mortality or target organ toxicities in mice, rats and monkeys at doses up to 760μg/kg/day 
(182 days), 250 μg/kg/day (91 days), or 150 μg/kg/day (273 days) respectively. 
Reproductive toxicity data from animal studies showed that Byetta had a toxicological 
effect on foetal development at three times the human exposure levels in treatment of 
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diabetes. A summary of the findings of the exenatide toxicological assessment 
programme is presented in the Investigator Brochure for Presendin.  
1.1.3. 
Clinical Studies 
Exenatide has undergone extensive healthy volunteer studies and clinical trials for over 
15 years. It is licensed as a formulation for SC injection to be used in conjunction with 
diet and exercise to improve glycaemic control in adults with type 2 diabetes. Details of 
the trials conducted on exenatide, SC injection formulation, are presented in the Byetta 
Product Monograph (Section 15). Data from these studies are notable as the dose of 
exenatide to be used in the indication of IIH is intended to produce exposure levels not 
exceeding those experienced by patients receiving Byetta. It is anticipated that the 
proposed therapeutic dose of exenatide, in the modified release formulation Presendin, 
for treatment of IIH will be within the approved dose range of Byetta, achieving a level 
of total systemic exposure comparable with the immediate release Byetta formulation. 
Therefore, safety data available from the Byetta clinical development program are 
considered relevant and supportive of exenatide development in IIH.  
The efficacy of exenatide (Byetta) was evaluated in a Phase 2 randomised, placebo 
controlled, double-blind trial of exenatide in patients with active IIH (IIH:Pressure Trial). 
Sixteen patients with a diagnosis of active IIH (LP opening pressure >25 cm CSF and 
papilloedema) were identified and recruited to the trial. Participants had a telemetric ICP 
monitor implanted and were randomised to either exenatide (first dose was 2. 0 mcg 
followed by 10 mcg BD sub-cutaneous) or a matched placebo; allocation was 1:1. The 
treatment duration was 12 weeks. The trial was powered to seek significance to at least 
alpha < 0.1 and power at least 80% using equal group sizes. Data was analysed by 
hierarchical regression analysis. 16 participants were recruited, 15 were randomised and 
completed the study. At baseline the mean age was 28 ± 9 years, BMI 38.1 ± 6.2 kg/m2, 
ICP 23.5 ± 3.9 (equivalent to 32.0 ± 5.3 cm CSF). The primary outcome, change in 
intracranial pressure between arms, was significant: at 2.5 hours -4.2 ± 2.1 mmHg 
(equivalent to 5.7 ± 2.9 cm CSF), p=0.04, at 24 hours -4.7 ± 2.1 mmHg (equivalent to 6.4 
± 2.9 cm CSF), p=0.03, and at 12 weeks -4.1 ± 2.2 mmHg (equivalent to 5.6 ± 3.0 cm 
CSF), p=0.05. A significant reduction in monthly headache days was also observed 
amongst those on exenatide (-7.7 ± 9.2, p-0.069). LogMar visual acuity also significantly 
improved in the exenatide treated arm (-0.1 ± 0.05, p=0.036). No significant weight loss 
was observed in either arm and hence weight change is unlikely to have contributed to 
the reduction kin ICP observed. Exenatide was safe and well tolerated: no treatment 
related SAE’s were reported, 8 adverse events were reported in those taking exenatide. 
The most frequent adverse event, amongst those taking exenatide, was nausea (7 reports), 
the majority of these were mild and all reports were self-limiting. There were no patient 
withdrawals due to adverse events.  
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1.1.4. 
Trial Conduct 
This trial will be conducted in accordance with the requirements of this document (the 
Clinical Trial Protocol), the Trial Reference Manual and also in accordance with the 
following as per country specific requirements:  
• 
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013) 
• 
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016) 
• 
The United Kingdom Statutory Instrument 2004 No. 1031 and UKSI 2006 No.1928 
• 
European Union Directives 2001/20/EC and 2005/28/EC 
• 
United States Code of Federal Regulations Title 21 
• 
The Australian Therapeutic Goods Act, 1989, amended December 2020 and 
Therapeutic Goods Regulations, 1990, amended January 2021 
• 
Other country specific laws and regulations 
• 
Any amendments to these regulations  
1.2. 
Risk/Benefit Assessment 
Current treatments for IIH have limited efficacy and can cause disabling side effects. 
Acetazolamide, the most commonly used drug (off licence) has a high side effect profile 
(48% discontinued in a clinical trial due to intolerable side effects) [Ball, 2011]. 
Although IIH is a rare condition, incidence is rising with rising obesity trends. Improving 
IIH morbidity with new therapeutics is clearly an unmet need.  
Safety data for Presendin (exenatide) is based on the IB (Peptron Inc.). Warnings include 
pancreatitis, hypoglycaemia when used in combination with a sulfonylurea, renal 
impairment, severe gastrointestinal disease and hypersensitivity.  
Invex Therapeutics has considered these warnings and has defined eligibility criteria to 
ensure patient safety is paramount. As such patients with known contraindications to 
GLP-1 agonists, such as pancreatitis, ketoacidosis, severe gastrointestinal disease and 
renal impairment, will not be included. Additionally, diabetic patients receiving glucose 
lowering medication will be excluded. 
An Independent Adjudication Committee (IAC), as described in Section 14.5, will assist 
the Investigators (when required) with the eligibility criteria of the patients to be enrolled, 
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and also to determine treatment failures to ensure patient safety and the efficacy of the 
trial. 
The most common adverse reactions experienced with exenatide are nausea, 
hypoglycaemia (only when used with other glucose lowering drugs, but these patients are 
excluded from the trial), vomiting, diarrhoea, feeling jittery, dizziness, headache and 
dyspepsia. 
Patients receiving the active treatment during the randomised period may benefit by 
experiencing an improvement in their IIH symptoms, although this cannot be guaranteed. 
2.
OBJECTIVES
2.1. 
Primary Objective 
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. Week 24 LP to be performed as per Appendix 1. 
2.2. 
Secondary Objectives 
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
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2.3. 
Safety Objective 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
2.4. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Macular ganglion cell layer/complex thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes 
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. Week 24 LP to be performed as per Appendix 1. 
 
3.2. 
Secondary Endpoints 
• 
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. 
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•
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.*
*criteria defined in rescue therapy section 10.1.1
3.3. 
Safety Endpoints 
•
Vital Signs
•
Adverse events: Treatment-emergent adverse events (TEAEs), , serious adverse
events (SAEs)
•
Resting 12-lead electrocardiogram
•
Routine laboratory assessments (haematology, biochemistry and urinalysis)
3.4. 
Exploratory Endpoints 
•
Macular ganglion cell layer/complex thickness
•
Responder rate monthly headache days (defined as ≥30%)
•
Responder rate moderate to severe monthly headache days (defined as ≥30%
reduction)
•
Patient Reported Outcomes (PRO):
•
Visual Function Questionnaire-25 and 10-item supplement
•
Headache Impact Test-6
•
36-item short form survey
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•
EuroQol -5 dimension -5 level survey
•
Patient Global Impression of Change
•
Body Mass Index
•
Body Weight
•
Health Utilisation
4.
TRIAL DESIGN
4.1. 
Summary of Trial Design 
4.1.1. 
Trial Design 
This will be a randomised, placebo-controlled, double-blind, multi-centre clinical trial in 
approximately 240 randomised patients with IIH.  
The trial will begin with a 1-week screening period. Although a headache diary is 
typically over 28 days, it was felt unethical to have patients off treatment for this more 
prolonged period. Headache diaries designed to measure headache frequency have been 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [NORDIC, 2018; Mollan, 2021b]. Hence the baseline headache frequency 
will be calculated over 1 week. Patients will be provided with training on the self-
administration of the trial medication from the site trial coordinator and provided with a 
leaflet to take home at the screening visit. Patients will be asked to self-administer 
placebo during the screening visit to ensure they are comfortable with self-injection. 
Patients who are not comfortable with self-administration will be deemed screen failures, 
and not be randomised into the trial. The purpose of the screening period will be to 
establish baseline measurements and assess trial eligibility.  
The 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 SC dose of either Presendin 
(containing 2mg 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 that treatment visit, an end of trial 
safety follow-up telephone visit will be performed. In the event of any abnormal safety 
assessments or ongoing adverse event(s) identified at end of treatment; for example, an 
abnormal ECG or abnormal routine laboratory results, this visit may be performed at the 
clinic and a safety follow-up performed as appropriate.  
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The duration of the randomised treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy by 3 months. 
Additionally, an alternative off label drug used in IIH (acetazolamide) was evaluated over 
a 6-month period. Hence efficacy is relevant over this time frame. A longer period of 
randomisation would not be ethical if patients were expected to remain on placebo for 12 
months as this could place their overall health at risk. 
Assessments will be performed as outlined in Table 1. 
A schematic diagram of the trial can be seen in Figure 1. 
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Figure 1: Schematic Diagram 
 
 
4.1.2. 
Randomisation and Blinding 
At the end of the Screening period, eligible patients will be randomised to receive either 
Presendin or matching placebo in a 1:1 ratio using a computer system to generate 
randomisation codes. 
Investigators and other site personnel, patients, contract research organisation and 
Sponsor personnel will be blinded regarding the treatment during the randomised period. 
Only designated unblinded staff, not involved in the operational conduct of the trial, will 
be aware of the randomisation codes. 
The placebo will have the same appearance and reveal no differences, during 
administration, to either the Investigator or the patient. 
4.1.3. 
Duration of Patient Participation 
The duration of the trial for each patient will be up to 30 weeks, which includes a 1-week 
screening period, a 24-week randomised treatment period and a treatment follow-up 
period of 5 weeks.  
4.2. 
Stopping Rules 
4.2.1. 
Trial Stopping Rules 
There are no trial-specific stopping rules. The Sponsor maintains the right to stop the trial 
at any point. If this is done, then the Sponsor will provide the Investigators with the 
rationale for such early termination. 
1 week 
screening period 
,. 
-
.. 
/ 
"---T-reata
_ en_t __ 
----......... / 
Placebo 
24 weeks randomis,ed 
double-blind treatment 
period 
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4.2.2. 
Individual Stopping Rules 
Patients will be withdrawn from the trial medication if they are unable to tolerate the trial 
medication and will continue to attend trial visits as per protocol. See Section 11 for 
further details. A Data Safety Monitoring Committee (DSMC) will be involved in 
decisions for patient safety (Section 14.6). 
4.3. 
End of Trial 
The end of trial is defined as last patient last visit. 
5. 
TRIAL POPULATION 
5.1. 
Number of Patients 
It is anticipated that approximately 350 patients will be required to enter the screening 
phase for 240 patients to be randomised into the treatment phase. 
5.2. 
Eligibility Criteria 
5.2.1. 
Inclusion Criteria 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.2, Appendix 2), 
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’ 
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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 – see Section 16.8, Appendix 8 for 
further details) 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 
5.2.2. 
Exclusion Criteria 
Patients will not be enrolled if they meet any of the following 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), 
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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 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] 
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 apnoea­hypopnea 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  
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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
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 – see section 10.1.2
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6. 
TRIAL ASSESSMENTS AND PROCEDURES
6.1. 
Procedures at Each Visit
Trial procedures and timings are presented in the Time and Events Table, Table 1.
No procedures should be performed prior to obtaining informed consent. All visits (except 
telephone call visits) should be performed at the clinic. Should a clinic visit not be possible, 
due to a patient self-isolating, the visit will be conducted at the earliest opportunity and 
will not constitute a protocol deviation. 
6.1.1. 
Visit 1 Screening 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Visit 
procedures can be performed in a single visit or over a number of visits during the 
screening period. Ideally all screening procedures should be performed on the same day. 
•
Obtain patient’s written informed consent
•
Eligibility criteria
•
Including confirmation that diagnostic LP occurred within the last 4 weeks with
an opening pressure ≥ 25 cm CSF in lateral decubitus position
•
Demographics (sex, age and ethnicity)
•
Medical and ophthalmic history
•
Concomitant mediation history
•
Headache history (including family history of migraine (a first degree relative with
and migraine) and headache in the 7 days prior to diagnostic LP)
•
Headache preventative medication review
•
Headache diary dispensed and diary training – to be performed on first day of
screening.
•
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals)
•
Height, body weight and BMI
•
Full physical examination
•
Urine pregnancy test (for women of childbearing potential)
•
Electrocardiogram
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• 
Visual Assessments to both eyes 
• 
Frisén grading will be initially assessed by the site and then the presence of 
papilloedema verified by the OCT Reading Centre. Where there is uncertainty, 
fundus photos and or ultrasound scan (B scan) of the optic nerve may be 
conducted for evaluation by the IAC to confirm eligibility. 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site.  
• 
Humphrey Visual Field (24-2 SITA-Standard using a size III white stimulus)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay, and where there is uncertainty about 
eligibility this should be referred to the IAC. 
• 
Visual Acuity (LogMAR score) 
• 
Laboratory assessments 
• 
Trial medication training. Patients will be asked to self-administer 1 dose of placebo 
at the screening visit to ensure they are comfortable with self-injection. Patients who 
are not comfortable will be excluded 
6.1.2. 
Visit 2 Baseline 
• 
Review eligibility criteria 
• 
Concomitant medications review 
• 
Headache preventative medication review 
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• 
Review headache diary (Patient must meet required number of headache days as per 
inclusion criteria. If the headache diary exceeds 7 days, then eligibility will be based 
on the last 7 days of the screening period, i.e., the 7 days prior to randomisation visit) 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI 
• 
Adverse events review 
• 
Targeted physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
• 
Visual Assessments to both eyes 
• 
Frisén grading will be assessed by the site 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary 
• 
Health Utilisation Form 
• 
Laboratory assessments 
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• 
Anti-Drug Antibodies (ADA) blood sampling  
• 
Patient randomised  
• 
Trial medication training 
• 
Trial medication dispensed and first dose self-administered at clinic. Patients will 
then be instructed to administer subsequent doses once weekly. 
• 
Pharmacokinetic sampling (post-dose) 
6.1.3. 
Visit 3 Telephone call 
All patients will receive a telephone call at visit 3 to conduct headache preventative 
medication review, check for any AEs or changes in medication, procedures outside of 
protocol, health utilisation, to remind them to complete their diary and to answer any 
questions they may have on administration or storage of the trial medication.  
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI (not visit 4) 
• 
Adverse event review 
• 
Targeted physical examination (visit 6, 8 and 9 only) 
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload processes to the OCT Reading Centre, without delay. 
The OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
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• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary (not visit 4)  
• 
Health Utilisation Form 
• 
Laboratory assessments  
• 
Pharmacokinetic blood sampling  
• 
Anti-Drug Antibodies blood sampling  
• 
Trial medication dispensing (not Visit 4) and accountability - patients should be 
reminded by the trial site to self-administer the trial medication weekly and to return 
used and unused trial medication at clinic visits 
6.1.5. 
Visit 10 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial 
medication and must have self-administered their final dose within 7 days of visit 10. 
Patients will be reminded by the trial site to self-administer trial medication weekly, to 
continue this until the completion of visit 10 and to bring their trial medication with them 
at visit 10 for return.  
Where more than one dose has been missed during the 4 weeks preceding visit 10, visit 
10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial 
medication has been missed in the previous 4 weeks. Visit 10 should be delayed no more 
than 14 days. 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
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• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI  
• 
Adverse event review 
• 
Targeted physical examination  
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Lumbar puncture (within 7 days of last dose of trial medication) 
• 
Lumbar puncture to be performed ideally after visual assessments 
• 
Performed in the lateral decubitus position according to LP SOP Appendix 1 
• 
In some cases the lumbar puncture might be conducted using imaging guidance 
according to the preference of the individual and site. This could be using x-
rays, computer tomography or ultrasound guidance. 
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• 
If the procedure is not successfully performed it should be re-booked and 
repeated as soon as possible and the patient should remain on trial medication 
with the last dose within 7 days of the LP. 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary  
• 
Health Utilisation Form 
• 
Patient global impression of change question 
• 
Laboratory assessments 
• 
Pharmacokinetic blood sampling 
• 
Anti-drug antibodies blood sampling  
• 
Trial medication accountability 
Where it is not feasible to conduct all of visit 10 procedures on the same day, these could 
be split provided visual assessments are performed before the LP and the patient remains 
on trial medication with the last dose within 7 days of the LP. 
6.1.6. 
Visit 11 Follow-Up  
This visit will be performed as a telephone call to conduct headache preventative 
medication review and check for any AEs or changes in medication. In the event of any 
abnormal safety assessments identified at the end of treatment, e.g., abnormal ECG, 
abnormal routine laboratory results or ongoing adverse events, this visit may be 
performed at the clinic to repeat or follow up safety assessments. 
A urine pregnancy test (for women of childbearing potential) will be performed, this can 
be conducted at home if the visit is performed by telephone call. 
 
6.1.7. 
Unscheduled visit for repeat visual assessments 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients where 
there is concern about their visual decline or who perform inadequately or where there is 
technical failure (more than 15% false positive responses or inadequate performance 
indicated by the Visual Field Reading Centre for HVF; or OCT imaging not of 
satisfactory quality as determined by the OCT Reading Centre). Imaging only in the 
study eye(s). 
• 
Optical coherence tomography Imaging  
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 
Sites should initially check the scan quality. The OCT scan should go 
through the upload process to the OCT Reading Centre. The OCT scan will 
then be reviewed by the OCT Reading Centre for a full quality assessment. 
The report from the OCT Reading Centre will be sent to the site. Where the 
OCT is of insufficient quality it should be repeated as soon as possible at an 
unscheduled visit. Where the OCT processing is of insufficient quality it 
should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. Quality 
reports from the Visual Field Reading Centre will be received by the site. 
Where the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
 
6.2. 
Trial Procedures 
6.2.1. 
Screening Procedures 
6.2.1.1. 
Demographics 
The Investigator, or designee, should record the patient’s sex, ethnicity, age, height, body 
weight and BMI at screening. 
Ethnicity data will be collected in order to monitor any response differences in IIH 
disease progression/symptoms in different ethnicities. 
6.2.1.2. 
Medical, Headache and Ophthalmic History 
The Investigator, or designee, should record any ongoing co-morbidities and significant 
medical, headache and ophthalmic history along with the year in which such 
co-morbidities began (where known).  
6.2.1.3. 
Reporting of Prior and Concomitant Medication 
Concomitant treatment is any medication or therapeutic intervention being continued by 
the patient at trial entry and any new medication received during the trial. Prior treatment 
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includes previous medications, treatments and interventions received in the past but no 
longer ongoing. 
For this trial, only relevant prior concomitant medications within the last 4 months will 
be recorded. These include: 
•
Treatment to lower ICP (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)
•
Headache preventative medication (including oral or botulism toxin A or monoclonal
antibodies against CGRP or CGRP antagonists, or greater occipital nerve block)
•
GLP-1 receptor agonist
•
Warfarin
•
Glucose lowering medication
•
Recreational or illicit drugs
At every visit the Investigator or a qualified designee will ask the patient about relevant 
concomitant medication. 
No new medication should be started during the trial, unless medically necessary. The 
patient should be advised to consult the Investigator or designee before taking any 
prescribed or over-the-counter medications. In the case of headache preventative 
medications or ICP lowering medications please see details in the rescue therapy section. 
Acute headache analgesics are permitted and should be reported in the diary. 
6.2.2. 
Safety Procedures 
6.2.2.1. 
Physical Examination 
A full physical examination will be performed at the screening visit. At a minimum the 
following will be assessed: ear, nose and throat, cardiovascular system, pulmonary 
system, skin, abdomen and neurological system. At all other time points a targeted 
(symptom directed) examination will be performed at the Investigator’s discretion. 
6.2.2.2. 
Twelve- Lead Electrocardiogram 
Twelve lead ECGs should be performed at the times outlined in the Time and Events 
table (Table 1) in a standardized manner, i.e., after the patient has rested in the semi-
supine position for at least 10 minutes. Measurements will be made using an ECG 
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machine that automatically calculates the heart rate and measures PR, RR, QRS, and QT 
intervals.  
All ECG traces will be reviewed and signed by the Investigator or designee and any 
abnormalities will be marked as clinically significant or not clinically significant. 
6.2.2.3. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure and heart rate, will be 
measured at the time points specified in Table 1. 
Patients should rest in a supine position for 10 minutes before the vital signs are assessed. 
Three recordings will be taken and averaged.  
6.2.2.4. 
Laboratory Assessments 
Blood and urine samples will be processed at the site. Routine biochemistry and 
haematology samples will be evaluated at the trial appointed central laboratory. PK, ADA 
and CSF samples will be stored at the central laboratory and evaluated at a qualified 
international laboratory. Details of handling and shipping are described in the Laboratory 
Manual.  
6.2.2.4.1. Haematology 
Blood for the assessment of haematology parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
•
Total blood count; consisting of:
•
Red blood cells
•
Haematocrit
•
Mean cell volume
•
Mean cell haemoglobin
•
Mean cell haemoglobin concentration
•
Glycated haemoglobin (HbA1C)
•
Blood glucose (non-fasting)
•
Platelets
•
White blood cells
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•
Neutrophils
•
Lymphocytes
•
Monocytes
•
Eosinophils
•
Coagulation (prothrombin time, international normalised ratio, activated partial
thromboplastin time, thrombin time, fibrinogen)
•
Basophils
6.2.2.4.2. Clinical Chemistry 
Blood for the assessment of clinical chemistry parameters will be collected at the 
times outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
•
Sodium
•
Potassium
•
Chloride
•
Bicarbonate
•
Blood urea nitrogen
•
Creatinine
•
Total bilirubin
•
Total protein
•
Albumin
•
Alanine transaminase
•
Aspartate aminotransferase
•
Alkaline phosphatase
6.2.2.4.3. Urinalysis 
Urine samples will be collected at the times outlined in the Time and Events table (Table 1). 
The following parameters will be assessed at each time point: 
•
Glucose
•
Ketones
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•
Specific gravity
•
Blood
•
pH
•
Protein
•
Urobilinogen
6.2.2.4.4. CSF
CSF sample from visit 10 LP will be retained for future potential analysis of disease and 
drug related biomarkers. 
6.2.2.4.5. Pregnancy 
At screening blood will be collected to enable a serum pregnancy test to be performed. At 
visits thereafter, urine will be collected from female patients of childbearing potential at 
the times outlined in the Time and Events table (Table 1) to enable highly sensitive urine-
based pregnancy tests to be performed. Female patients who are identified as being 
pregnant during the trial will be withdrawn from further treatment but will continue to 
attend safety follow-up visits.  
The Investigator or designee should report any pregnancies in female patients to the 
Sponsor or designee, using the Pregnancy Report Form, within 24 hours. The contact 
details for reporting are: 
 
Female patients or partners of patients who become pregnant should be followed until 
delivery, stillbirth or termination. The outcome of the pregnancy and, if applicable, the 
health of the baby, should be reported to the Sponsor using the Pregnancy Report Form. 
6.2.2.4.6. Pharmacokinetic sampling 
Pharmacokinetic sampling is to characterize the pharmacokinetics of exenatide after once 
weekly subcutaneous administration of Presendin at the times outlined in the Time and 
Events table (Table 1). 
The primary purpose of the pharmacokinetic sampling is to characterize the steady state 
concentrations of exenatide. All actual sampling times and dosing times will be recorded. 
Sampling and processing will be performed as described in the Laboratory Manual. 
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6.2.2.4.7. Anti-drug Antibodies sampling 
Anti-drug antibodies sampling will be performed in all subjects at the times outlined in 
the Time and Events table (Table 1). 
Sampling and processing will be performed as described in the Laboratory Manual. 
6.2.2.5. 
Adverse Events 
Patients will be asked non-leading questions to assess how they are feeling at each clinic 
visit. Adverse events will be assessed and reported as outlined in Section 12. 
6.3. 
Efficacy Procedures 
6.3.1. 
Intracranial Pressure 
Assessment of ICP will be measured by LP in the lateral decubitus position. The 
diagnostic LP is performed by the clinical team prior to recruitment and the measurement 
must be made from the lateral decubitus position. The research LP will be performed 
according to LP standard operating procedure (SOP), Appendix 1. Lumbar puncture will 
ideally be performed after visual assessments as outlined in the Time and Events table 
(Table 1).  
In some cases the lumbar puncture might be conducted using imaging guidance according 
to the preference of the individual and site. This could be using x-rays, computer 
tomography or ultrasound guidance. 
Any additional LP procedures, outside of the protocol would constitute a protocol 
deviation and ideally should be discussed with the Investigator before the procedure is 
performed.  
Non-protocol LPs should be recorded in the Case Report Form. 
6.3.2. 
Visual Assessments 
Visual assessments should be performed on both eyes. All visual assessments should be 
uploaded without delay on the day of the visit to the OCT and Visual Field Reading 
Centres. In all cases the site is responsible for initial checks of the clinical data in the 
wider context of the patient’s disease, as well as a data quality check. 
6.3.2.1. 
Frisén grade  
At Screening (visit 1) Frisén grading (0 – 5) should initially be performed at the site 
through a dilated pupil. The presence of papilloedema  will be verified  by the OCT 
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Reading Centre at screening (visit 1) and a report sent to the site.  During screening, 
where there is uncertainty regarding the presence of papilloedema and / or Frisén grade a 
fundus photo and or ultrasound scan (B scan) of the optic nerve may be conducted (or 
may be requested by the OCT Reading Centre) and if uncertainty persists evaluated by 
the IAC. 
At Baseline (visit 2) sites will reconfirm the Frisén grade 
6.3.2.2. 
Optical Coherence Tomography 
Imaging may be acquired using Heidelberg Engineering or Cirrus platforms according to 
the OCT SOP. Key measures are RNFL, optic nerve head size, and macular ganglion cell 
layer/complex thickness.. 
• 
Sites should initially check the clinical interpretation of the OCT scan and scan 
quality. The OCT should then go through the upload processes to the OCT Reading 
Centre. The OCT will then be reviewed by the OCT Reading Centre for a full quality 
assessment. The report from the OCT Reading Centre will then be sent to the site. 
Where the OCT is of insufficient quality, it should be repeated as soon as possible. 
Where the OCT has not been processed correctly at the site the processing should be 
re-performed as soon as possible thereafter. Repeated or reprocessed images would 
then be again transmitted to the OCT Reading Centre for a full assessment. 
• 
If the site is concerned with the OCT findings, suggesting that the patient is a 
potential treatment failure and may require rescue therapy, the OCT Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
6.3.2.3. 
Humphrey Visual Field 
The visual field will be measured by Humphrey Visual Field analysis (24-2 SITA-
Standard) including standardised refraction as indicated, according to the Visual Field 
Centre SOP (Manual of Procedures).  
• 
At screening HVF will be reviewed by the Visual Field Reading Centre to confirm 
eligibility. 
• 
Inability to perform a reliable visual field examination as deemed by the Visual Field 
Reading Centre in study eyes (including >15% false positives), is an exclusion 
criterion. HVF can be repeated to obtain as assessment with reliable performance. 
• 
If the site is concerned with the HVF findings, suggesting that the patient is a 
treatment failure and may require rescue therapy, the Visual Field Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
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6.3.2.4. 
Visual Acuity  
Assessment of visual acuity will be recorded using a LogMAR chart (unaided, best 
corrected, and with pin hole). 
6.3.3. 
Headache Assessments 
Patients will be provided with an electronic/paper diary at screening to complete during 
the trial. Information collected will be used to assess the following headache parameters: 
• 
Monthly headache days 
• 
Monthly moderate to severe headache days 
• 
Responder rate 
• 
Monthly acute analgesic use 
• 
Headache severity (11-point NRS) 
 
6.3.3.1. 
Headache Preventative Medication Review 
A review of any headache preventative medications taken by the patient will be 
undertaken at each clinic visit. If the Investigator alters the headache preventative 
medication, this will be considered rescue medication (Section 10.1.1) and the IAC 
consulted. Use of headache preventative medication will be recorded at trial visits as 
outlined in the Time and Events table (Table 1). 
Patients will record their acute headache analgesic use in their trial diary. 
6.3.4. 
Patient Reported Outcomes 
6.3.4.1. 
Visual related 
Assessment of visual related quality of life will be derived from self-reported responses 
to the VFQ-25-10 item supp (see Section 16.6 Appendix 6). 
6.3.4.2. 
Health-related 
Assessment of health-related quality of life will be derived from self-reported responses 
using the following questionnaires: 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
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A Healthcare Utilisation Form will be completed by the trial site staff at clinic visits. 
All questionnaires can be found in Section 16, Appendix 3 for SF-36 and Appendix 4 for 
the EuroQoL- 5D-5L survey. 
6.3.4.3. 
Headache related Quality of Life 
Assessment of headache-related quality of life will be derived from self-reported 
responses to the Headache Impact Test-6 questionnaire and performed at time points as 
outlined in the Time and Events table (Table 1). A copy of this questionnaire can be 
found in Section 16.5, Appendix 5. 
6.3.4.4. 
Patient Global Impression of Change  
The Patient Global Impression of Change will be conducted at visit 10, as outlined in the 
Time and Events table (Table 1).  
It is a single item questionnaire using a seven-point verbal response scale to assess 
overall change in the patient’s status since taking trial medication. A copy of this 
questionnaire can be found in Section 16.7, Appendix 7 
6.3.5. 
Body Weight and Body Mass Index 
The patient’s body weight and BMI will be measured at the time points as outlined in the 
Time and Events table (Table 1).  
The patient’s height will be measured at Screening (shoes off).  
 
 
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7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS
The COVID-19 global pandemic presents numerous challenges to the conduct of ongoing 
clinical trials. In line with the FDA and European Medicines Agency's Guidance on the 
Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic 
(EMA, 2021), the following protocol considerations are provided to ensure patients 
safety is maintained and adequate benefit/risk analyses are applied relative to the 
completion of study procedures and maintaining the investigational product supply chain.  
Other unforeseen global crises may occur during the conduct of the study, similar to the 
COVID-19 global pandemic, in which case the following protocol considerations may 
also be applied. 
Recognizing the flexibility required to manage the impact of the pandemic (or other 
global crisis) on this clinical study, additional details will be added to respective study 
manuals, project plan documents, and communicated to the investigative sites as needed.  
For any additional questions, the investigator should confer with the sponsor. 
Number of Trial Patients 
The evolving situation of the pandemic (or other global crisis) may result in a substantial 
number of patients’ early withdrawal from the study, which could affect the data integrity 
of the study.  Because of this risk, the sponsor may decide to recruit additional patients in 
the study, beyond the expected number, to mitigate such risk. 
Study Visits 
There are a number of on-site visits that would be required to ensure study validity.  If 
there are local travel restrictions, isolation requirements, or the investigator determines it 
to be unsafe for patients to attend their scheduled study visits, the site staff may conduct 
certain visits via telemedicine (phone or video calls) to minimize patient risk as follows. 
Screening Period 
The following visit must be performed in person: 
•
Screening/Visit 1
Note:  To minimize direct, in-person contact between site personnel and patients,
certain screening procedures may be performed remotely via telemedicine.  All
other procedures should be done in-person while the subject is on-site.
Specifically, the following procedures may be done remotely:
o
Informed consent (where applicable, per approved IRB/IEC process)
o
Demography
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o Medical and ophthalmic history 
o Concomitant medication history 
o Headache history 
o Headache preventative medication review 
o Train and dispense headache diary 
o Trial medication training 
Randomised period 
• Baseline (Visit 2) 
There are essential aspects to the baseline visit which must be performed in 
person. 
If the baseline visit is delayed the headache diary should utilise the preceding 7 
days data. Where the visit is delayed by more than 10 days due to a global crisis 
the patient will be considered to have failed screening.  Patients who screen failed 
due to the pandemic (or other global crisis) may be rescreened at a later time, if 
feasible. 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 4, 5, 6, 7, and 8 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
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o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 10 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
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o Lumbar puncture* 
 
* Lumbar puncture to be ideally performed after visual assessments. In the 4 weeks prior 
to visit 10, patients must not have missed more than one dose of trial medication and 
must have self-administered their final dose within 7 days of visit 10. Patients will be 
reminded by the trial site to self-administer trial medication weekly, to continue this until 
the completion of visit 10 and to bring their trial medication with them at visit 10 for 
return.  
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days, if 
possible, but this can be extended according to local government policy if a patient is 
unable to attend (for example if a patient is self-isolating) as long as medication use is 
maintained as above. 
 
• Follow up/ Visit 11 
This should be performed as a telephone visit unless clinical contact is necessary, as 
per protocol. Where face to face contact is required, this should be conducted at the 
earliest available opportunity.  
 
Study Drug Dispensation and Distribution 
If a patient is not able to attend a clinic visit, to ensure the continuity of providing 
patients’ study drug within the constraints imposed by the pandemic (or other global 
crisis), the site staff may decide to supply study drug to patient as follows: 
o Adequate supplies of study drug can be shipped to the patient by the study staff 
using a third-party service with approval from the patient.  The third-party vendor 
will be agreed upon with the sponsor. 
o The patient may request, with prior arrangement/agreement with the site, an 
authorized individual (a relative or delegate) to retrieve the study drug from the 
study site if the patient is unable to personally to do so. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed; however, the site monitor will continue to 
employ off-site monitoring practices such as routine communication methods (e.g., phone 
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calls, emails, video visits) with the sites to get information on study progress, patient 
status, and information on issue resolution as detailed in the Data Monitoring Guidelines, 
Remote source data verification. 
If the trial site monitor cannot be on-site to carry out the final drug accountability for 
reconciliation purposes, and the operation cannot be postponed, it may be carried out by a 
pharmacist from the site pharmacy or by the study coordinator/data manager with suitable 
training. The study drug can be returned to the sponsor by the site pharmacy directly, or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 
Direct Contracts with Third Parties/Specialized Service Companies 
If necessary, direct contracts can be established with third-party local physicians to 
conduct activities related to the clinical management of patient for whom the investigator 
is responsible and maintains oversight.  In such situations, the investigator is required to 
provide the local physician with a delegation letter listing all delegated activities.  The 
sponsor, through the study investigator or institution, will reimburse the local physician 
for the test/procedures conducted outside of the standard of care. 
Clinic visits should take place to the extent possible and usual protocol requirements 
adopted for all subjects as soon as the crisis-related limitations permit. 
All safety data that are possible to obtain locally should be collected at a remote visit. 
These measurements may include the use of local practitioners and resources. 
Exceptional measures taken in response to a crisis (e.g., COVID-19) and their impact on 
study results, such as tests done in a local laboratory, will be explained, assessed and 
reported in the clinical study report following ICH E3 guidance. 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS
Patients will receive lifestyle advice as per routine care from their treating physician. 
9. 
INVESTIGATIONAL PRODUCT
9.1. 
Dosage and Administration
9.1.1. 
Randomised Period
During the 24-week randomised treatment period (Figure 1) patients will be randomised 
in a 1:1 ratio to receive active treatment or placebo. 
Either 
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Presendin (2.0mg exenatide) as a SC injection, self-administered once weekly. 
Presendin is supplied as 2 parts, one vial consisting of a drug part (white or grayish 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 as a 
suspension.  
or 
Placebo as a SC injection, self-administered once weekly. 
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 as a suspension. 
9.2. 
Dose Rationale 
The proposed 2mg weekly dose was based on the pharmacokinetic performance of the 
Peptron formulation (PT320). Pharmacokinetic profiles obtained after repeated once 
weekly dosing of 2mg of PT320 s.c. (as specified in the Presendin IB phase 2 clinical 
study in patients with type 2 diabetes) were comparable to those predicted by the 
population PK model developed for weekly s.c. administration of the recommended dose 
of the 2mg Bydureon extended-release formulation [Cirincione 2017],with time to reach 
the steady state slightly shorter for PT320 than for Bydureon (7-8 weeks vs 8-10 weeks) 
and with steady state plasma concentrations remaining within a comparable range for 
both products. Based on the same molecule and dose, comparable plasma concentrations 
for PT320 and Bydureon and the established safety profile of Bydureon a similarly 
acceptable safety and tolerability profile for PT320 is expected. 
9.3. 
Maintaining the Blind 
This is a double-blind trial. 
A computer/website system will be used to maintain the blind for this trial. The site will 
be provided with website login details for the system. If the Investigator needs to unblind 
a patient’s treatment, due to a medical emergency, the website should be accessed to 
unblind for that patient. . 
The responsibility to break the treatment code in emergency situations resides solely with 
the investigator. 
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9.4. 
Treatment Assignment 
Patients will be randomised in a ratio of 1:1 to receive active treatment (Presendin) or 
placebo. A computer/website system will be used to randomly assign each patient to a 
treatment arm.  
9.5. 
Packaging and Labelling 
Individual supplies of trial medication will be provided to the sites in a double-blind 
format. The labels will contain all information required to meet the applicable local 
regulatory requirements. 
Further information on packaging, labelling and dispensing are included in the Pharmacy 
Manual. 
9.6. 
Preparation 
Each dose of trial medication is provided as two parts, a single use vial and a pre-filled 
syringe of diluent. Patients will receive training and be provided with an instruction sheet 
with details, on how to store, prepare, self-administer and discard/keep used trial 
medication.  
9.7. 
Handling and Storage 
Presendin, the active trial medication, contains the active ingredient, exenatide, which is 
hygroscopic and light sensitive and must be protected from light during storage. Prior to 
use, all trial medication should be stored refrigerated at 2-8ºC.  
9.8. 
Product Accountability and Assessment of Compliance 
In accordance with International Council of Harmonisation – Good Clinical Practice 
(ICH-GCP), each trial centre will account for all supplies of trial medication. Details of 
receipt, storage, assembly, and return will be recorded. The unit of accountability will be 
one single active or placebo vial. Needles will be disposed of in a sharps box. 
All unused supplies will either be destroyed or returned to the trial Sponsor at the end of 
the trial in accordance with instruction by the Sponsor. 
All trial medication will be self-administered by the patients. If a dose is not administered 
as planned, patients will record the missed dose in their electronic/paper diaries and it 
will be documented in the electronic case report form (eCRF). 
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9.9. 
Treatment of Investigational Product Overdose 
Definition of Overdose: More than 1 (one) dose in 24 hours. 
In the event a patient overdoses on trial medication the Investigator should be notified as 
soon as possible. If symptoms appear, the Investigator will treat the patient according to 
their clinical judgement depending on the type of clinical signs and symptoms exhibited 
by the patient. The Sponsor should be notified in writing within 24 hours of the 
Investigator becoming aware. 
Effects of overdose that may be seen include severe nausea, severe vomiting and rapidly 
declining blood glucose concentrations. 
9.10. 
Occupational Safety 
There are no known occupational safety risks to staff. The Material Safety Data Sheet 
will be made available where required by local regulations. 
10.
CONCOMITANT MEDICATIONS AND NON-DRUG
THERAPIES
10.1. 
Recording Prior and Concomitant Medication
All relevant medication taken within 4 months of screening should be recorded in the 
eCRF along with all relevant medication taken from the start of the screening period until 
the final follow-up visit (Section 6.2.1.3). 
At a minimum the following information will be collected: 
•
Generic name
•
Dose
•
Frequency
•
Date started
•
If ongoing (or if not, then the date stopped will be recorded)
•
Reason for taking the medication
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10.1.1. 
Treatment Failure 
Rescue therapy can be initiated when there is a treatment failure. Since perimetric 
variability increases with increasing visual field damage, a two-tiered approach is used 
[Wall, 2013].  
10.1.1.1. 
Possible treatment failure 
Possible treatment failure is defined as those with baseline PMD between -2 and -3.5dB 
who experience a decline of > or equal to 2dB. In those with a baseline PMD between -
3.5 and -7 dB, those who experience a decline of  > or equal to 3 dB.  
When a possible treatment failure is identified, perimetry, and if needed, other visual 
tests, should be repeated at an unscheduled visit. 
10.1.1.2. 
Definite treatment failure 
A definite treatment failure occurs when a patient with baseline PMD between -2 and -
3.5dB experiences a decline of  > or equal to 2dB which remains after repeat perimetry. 
Or in those with a baseline PMD between -3.5 and -7 dB who experience a decline of > 
or equal to 3 dB which remains after repeat perimetry.  
These cases should be reviewed without delayby the IAC (who will review all visual and 
clinical data) to confirm or refute a definite treatment failure. 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive Visual Loss 
When a treatment failure occurs, rescue therapy can be initiated, in addition to study 
treatment, based on the medical judgement of the Investigator. Decisions should always 
be discussed with the IAC without delay and if possible before any action is taken, unless 
in the opinion of the Investigator there is no time to do so as it is judged to be a medical 
emergency. In all cases the final decision lies with the Investigator. 
Patients showing progressive visual loss will be considered for rescue therapy with 
acetazolamide or an alternative diuretic. In cases where the visual loss is severe and 
“rapid”, and believed by the Investigator to necessitate surgical intervention, the 
intervention will be conducted in accordance with local emergency practice. 
10.1.2.1. Rescue Therapy for Headache 
If the Investigator wishes to alter the headache preventative medication (any drug can be 
considered), this decision should always be discussed with the IAC before any action is 
taken, unless in the opinion of the Investigator there is no time to do so as it is judged to 
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be a medical emergency. Use of headache preventative medication will be recorded at 
trial visits. 
Use of acute headache analgesics is not considered as rescue medication and is permitted 
but must be documented in the headache diary (monthly analgesic use). 
10.2. 
Prohibited Medications 
10.2.1. 
Prior to screening and randomisation 
•
Treatment to lower ICP within 1 week prior to screening (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).
•
Exposure to fluoroquinolones, lithium, vitamin A, or tetracyclines within 2 months of 
diagnostic LP
•
Glucagon like peptide-1 receptor agonist within last 4 weeks prior to screening
•
Warfarin
•
Glucose-lowering medicationCOVID-19 vaccine within 2 weeks prior to screening
•
Recreational or illicit drugs during screening period
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 – see section 10.1.2.
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10.2.2. 
During the trial 
• 
Treatment to lower ICP (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). These will all be considered rescue medication (Section 10.1.2) and the 
IAC consulted. Use will be considered a protocol deviation. 
• 
If the Investigator alters the headache preventative medication (including oral or 
botulism toxin A or monoclonal antibodies against CGRP or CGRP antagonists, or 
greater occipital nerve block) this will be considered headache rescue medication 
(Section 10.1.2) and the IAC consulted.  
• 
Glucagon like peptide-1 receptor agonists 
• 
Recreational or illicit drugs  
• 
Warfarin 
• 
Glucose-lowering medication 
• 
Regarding COVID-19 vaccination, the risks of receiving or not receiving the 
vaccination have been considered in relation to the IMP and no additional risks are 
envisaged. Hence patients may choose to have or not have COVID-19 vaccination or 
booster during this trial. 
The investigator should follow the cautions and guidance on the management of other 
concomitant medication or DDIs as detailed in section 9.2.5.2 (Drug-Drug Interactions) 
of the IB. 
 
11. 
PATIENT COMPLETION AND WITHDRAWAL 
11.1. 
Patient Completion 
Patients will be classed as having completed the trial once they have completed all 
required trial visits. See Section 11.2.1 for early discontinuations. 
11.2. 
Patient Withdrawal 
11.2.1. 
Patient Withdrawal from Trial Treatment 
A patient will be withdrawn from treatment for any of the following reasons: 
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• 
Withdrawal of consent to continue in the trial. The reason for this will be 
documented if provided 
• 
The Investigator or Sponsor, for any reason, decides the patient should be withdrawn 
from the treatment 
• 
Lack of compliance with the trial medication is classified as <75% or >125% of 
scheduled doses over the course of the trial, excluding supply issues 
• 
Adverse events, which cannot be tolerated by the patient 
• 
Pregnancy during the treatment period 
Patients will be encouraged to continue in the trial to the end of the randomised treatment 
period even if they stop trial medication so that data can be collected for the Intention-
To-Treat (ITT) population.  
If a patient is withdrawn from treatment during the randomised treatment period, they 
will be encouraged to return for all trial visits up to visit 10. If a patient does not want to 
return then at a minimum they should be encouraged to attend for visit 11 procedures as a 
safety follow-up visit.  
11.3. 
Treatment after the End of the Trial 
Patients will not be provided with trial medication following the end of the trial. 
11.4. 
Screen and Baseline Failures 
Information will be collected on all patients who sign the Informed Consent Form (ICF). 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
12.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
12.1.1. 
Causal Relationship 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs. To promote consistency, the following guidelines should be taken into consideration 
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along with good clinical and scientific judgment when determining the relationship of drug 
treatments to an AE: 
•
Probable relationship: event occurs in a plausible time relationship to the medication
administration and cannot be explained by concurrent disease or other drugs or
chemicals; the response to the withdrawal of the drug should be clinically plausible
•
Possible relationship: event occurs with a reasonable time sequence to the medication
administration, but could also be explained by concurrent disease or other drugs or
chemicals; information on the drug withdrawal may be lacking or unclear
•
Unlikely relationship: event occurs with little temporal relationship to the medication
administration and other factors such as drugs, chemicals or underlying disease
provide plausible explanations
•
Not related: event has no temporal relationship to the medication administration or
there is a definite alternative aetiology
12.1.2. 
Severity Criteria 
An assessment of severity grade will be made using the following categorical descriptors: 
•
Grade 1 means a relatively minor side effect
•
Grade 2 means a moderate side-effect
•
Grade 3 means a severe or medically significant but not immediately life-threatening
side-effect
•
Grade 4 means life-threatening consequences
•
Grade 5 death related to AE
The exact definition of each number in the scale depends on the particular side effect 
according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
[CTCAE].  
The Investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the patient (e.g., laboratory abnormalities). 
Adverse events occurring as a result of LP should be specifically recorded. Occurrence of 
post lumbar headache will be specifically reported. 
12.1.3. 
Reporting Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated informed consent form is obtained until completion of 
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the patient's final safety follow-up visit. The Sponsor will evaluate any safety information 
that is spontaneously reported by an Investigator beyond the time frame specified in the 
protocol. Adverse events reported after dosing will be classed as treatment emergent AEs. 
All AEs, regardless of seriousness, severity, or presumed relationship to trial therapy, must 
be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common 
aetiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the source 
documents and the eCRF their opinion concerning the relationship of the AE to trial 
therapy. All measures required for AE management must be recorded in the source 
document and reported according to Sponsor instructions. 
The patient must be provided, on the first day of trial medication (Day 1), with a "patient 
card" indicating the following: 
• Patient number 
• Name of the investigational product 
• Investigator's name and 24-hour contact information 
• Statement that the patient is participating in a clinical trial 
12.2. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
Medical and scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not reach the 
above definition but may jeopardise the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive or malignant 
cancers, intensive treatment in an accident and emergency department or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse. 
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Deterioration of IIH necessitating CSF shunting or optic nerve sheath fenestration or 
dural venous sinus stenting will be recorded as an SAE and reported. 
Deterioration of IIH necessitating hospital admission will be recorded as an SAE and 
reported. 
Pre-defined exclusions: 
•
Hospitalisation for unrelated elective procedures
•
Post LP headache
12.2.1. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to be 
related to the trial medication and are both unexpected (i.e., the nature or severity is not 
expected from the information provided in the Investigator Brochure) and serious. 
12.2.2. 
Expected Adverse Events 
Perceived deterioration of IIH necessitating attendance or admission to hospital will not 
be reported as an SAE, but these events will be reported and recorded at follow-up. Non-
protocol LPs will be reported at follow-up. 
12.2.3. 
Reporting Serious Adverse Events 
All SAEs occurring during clinical studies must be reported to the appropriate Sponsor 
designee (contract research organisation) within 24 hours of their knowledge of the event. 
SAEs will be reported from the time a signed and dated informed consent form is obtained 
until completion of the patient's final safety follow-up visit.  
Information regarding SAEs will be transmitted to the Sponsor’s safety contact using the 
SAE Form, which must be completed and signed by the Investigator, and transmitted to 
the Sponsor’s safety contact within 24 hours.  
The contact details are: 
 
The Sponsor assumes responsibility for appropriate reporting of SAEs or SUSARs to the 
regulatory authorities. The Investigator (or Sponsor where required) must report these 
events to the appropriate Independent Ethics Committee (IEC) that approved the protocol 
unless otherwise required and documented by the IEC. 
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An annual safety report will be submitted to the Institutional Review Board once a year via 
the Investigator. 
12.3. 
Reporting and Handling of Pregnancies 
Pregnant patients will be withdrawn from the trial. 
Female patients will be instructed to notify the Investigator immediately if they become 
pregnant during the trial and up to 12 weeks after discontinuation/completion of trial 
medication. Pregnant patients will be withdrawn from further trial treatment. The patients 
will also be instructed to report pregnancies discovered after the last visit, if they believe 
that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the trial medication 
has interfered with the efficiency of any contraceptive measures. The Investigator should 
report all pregnancies to the Sponsor contact or designee within 24 hours of being 
informed of them. The pregnancy report form should be used instead of the SAE form. 
The pregnant patients will be followed until the end of the pregnancy. Any complication 
during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, 
stillbirth, birth defect/congenital anomaly, death, or other serious infant condition must be 
reported and followed up as an SAE. 
Patients will give consent on enrolment that the Investigator will report any pregnancy to 
the Sponsor and that further information will be collected until delivery. 
 
 
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13. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will be finalised prior to database lock providing 
detailed methods for the analyses outlined below. 
13.1. 
Hypotheses 
This trial compares outcomes in IIH patients under Presendin and matched placebo. The 
primary hypothesis that will be tested is: 
• 
The ICP measurement in the Presendin group is equal to the ICP measurement in the 
placebo group at Week 24; against the alternative that the outcomes differ 
13.2. 
Trial Design Considerations 
13.2.1. 
Sample Size Assumptions 
The target sample size for the trial is 240 randomised patients, i.e., 120 patients per arm. 
We justify this figure in the following sections. The two outcomes for which we sought to 
power the study are ICP and PMD.  
13.2.1.1. Intracranial Pressure Power 
The most difficult parameters to specify for a sample size calculation pertain to the 
variability of outcomes. We present a brief summary of the literature. Baseline standard 
deviations (SD) of ICP in previous trials were: 5.4 (n=10) and 6.3 (n=17) in the Drug 
Trial [Markey, 2017]; 5.0 (n=16) (data on file); and 5.7 (n=32) and 5.3 (n=30) in the 
Weight Trial [Ottridge, 2017]. Post-baseline standard deviations were slightly lower (and 
less than 6.0) in three of these five arms; and increased slightly in one (but remained less 
than 6.0). The post-baseline standard deviation however increased to over 8.0 in the 
surgery arm of the Weight Trial because the surgical intervention dramatically impacted 
ICP in some patients.  In the NORDIC trial [Wall, 2014] however, the standard deviation 
of baseline ICP was much higher, at 9.4 in the treatment arm (n=86). Seeking to avoid 
underpowering the study, we elected to proceed with the SD estimate for the NORDIC 
trial as this is the most similar trial population to the planned IIH EVOLVE trial (both 
recruiting acute IIH). We assume that control arm baseline and 24-week ICP SD equals 
9.4, Presendin baseline ICP SD equals 9.4, and Presendin 24-week ICP SD equals 10.4. 
These values assume the variability of ICP measures in untreated patients is as high as 
has been seen in the NORDIC trial and assumes that the variability in treated patients is 
slightly higher still. We anticipate that the standard deviation will be slightly higher in the 
experimental arm as treatment effects will potentially manifest changes in ICP. However, 
we do not expect such variability to be as inflated in this trial relative to control as it was 
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in the Weight Trial because of the likely difference in treatment effect between surgical 
and drug interventions.  
Under this parameterisation, when testing for a difference between arms at 24-weeks of 5 
CSF (justified below) using a total sample size of 240, assuming that up to 50% of 
observations are missing (i.e. 60 final LPs are completed in each arm), using a 5% 
significance level by Analysis of Covariance (ANCOVA) adjusted for baseline ICP, the 
two stratification variables, and treatment arm, we expect to have approximately 85% 
power. If 40% of observations are missing (i.e. 72 final LPs are completed in each arm), 
we expect power to be 91%. These figures have been inferred by computer simulation. Of 
the 165 patients in IIHTT [Wall, 2014] it was reported that “only 85 participants (47 
[55%] in the [treated] group and 38 [48%] in the placebo group) agreed to a lumbar 
puncture at month 6.” 
We expect a high rate of missing data because lumbar puncture is an invasive procedure 
that patients can find painful and traumatising [Scotton, 2018]. If patients have an 
unpleasant experience at the diagnostic LP they are also more likely to decline the LP at 
trial outcome. If patients do decline the final LP, logically it will be because of the 
baseline experience rather than their prevailing ICP. If data for the LP at 24 weeks is 
missing, the reason will be recorded. 
Outcomes from previous trials show that baseline and post-baseline distributions of ICP 
show central tendency with approximate symmetry, so we conclude that normality is a 
reasonable assumption and therefore ANCOVA is a defensible analysis method. 
13.2.1.1. Perimetric Mean Deviation Power 
We summarise here the estimated power for detecting differences between arms in the 
PMD outcome measure. In the NORDIC trial [Wall, 2014], the authors observed that the 
improvement from baseline to 6-months in PMD was 0.71dB greater in the experimental 
arm than the control arm. Cross-sectional SD of PMD was 1.1-1.2 at baseline. Table 2 in 
their publication shows that the standard error of mean PMD is higher at 6m than at 
baseline, likely reflecting a combined effect of missing data at 6-months and greater 
variability of post-baseline measures. We plan to take repeated measures of PMD at 
baseline, 2 weeks, 1-month (m), 2m, 3 m, 4m, 5m and 6m. Assuming that the overall SD 
of PMD scores is 1.8, thus introducing some reasonable inflation on Wall et al.’s baseline 
variability parameter for the reasons identified, using the formula given on p.31 of 
Diggle, Liang & Zeger (1994) we would expect to require 142 patients in total to detect a 
difference of 0.71dB (justified below) with 90% power at a 5% significance level, if the 
serial correlation between repeated measures is 0.4 (and we expect a value in this region) 
[Diggle, 1994]. If the serial correlation parameter is as low as 0.3, the required sample 
size increases to 166.  
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Note that the method used above assumes full follow-up and data collection. Although 
every effort will be made to collect all outcomes, naturally some missing data is 
expected. If we inflate the maximum sample size identified above by up to 30% to 
account for some data loss, we require up to 166 / 0.7 = 237 patients. The assumed 30% 
missing data rate was adjudged to be realistic by the Sponsor based on previous trials in 
IIH. Thus, we expect to be able to cover the impact of missing data using the extra 
patients necessitated by the sample size calculation for ICP. 
The above assumes only one eye is measured per patient. In actuality, some patients may 
provide outcomes for both eyes because any eye that satisfies the eligibility criteria (see 
Section 5.2) will be enlisted in the study. Put another way, all patients will provide 
outcomes in at least one eye, and some will provide outcomes in two. Second eyes will 
naturally be highly correlated with first eyes. From a sample size perspective, this means 
the additional information in second eyes will be of modest value. Nevertheless, 
outcomes on second eyes will contain some additional information and should be 
included in the analysis in the interest of efficiency. When estimating sample size, for the 
sake of simplicity and because of uncertainty in the rate of eligibility in second eyes, we 
have assumed that each patient yields outcomes from only one eye. Eligible second eyes 
will be included in the analysis with appropriate model terms to handle the within-patient 
correlation (further details are included in the SAP). As such we expect outcomes from 
second eyes to provide a modest uplift in power to the scenarios presented here. 
This section assumes a longitudinal analysis method such as hierarchical regression. 
 
13.2.2. 
Stratification 
At the outset, it is expected that markers of disease severity will be prognostic of 
potential efficacy. For this reason, it is proposed to stratify randomisation by, baseline 
ICP (<35cm or ≥35 cm), baseline body mass index (< 30 kg/m2 or ≥30 kg/m2) and 
baseline PMD (worse than or equal to -3.5dB or better than -3.5dB).   
13.2.3. 
Sample Size Sensitivity 
13.2.3.1. Clinically Meaningful Effect Sizes 
Minimally relevant effect sizes have not been fully determined in IIH given it is a rare 
disease with relatively few previous trials.  
The ICP diagnostic threshold in IIH is 25 cm CSF [Mollan, 2018]. However, it is not 
necessary to reduce ICP <25 cm CSF to achieve remission from signs and symptoms of 
IIH in all patients [Sinclair, 2010]. The clinical importance of a particular change in ICP 
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will vary depending on the starting ICP and the impact this pressure has on vision and 
headache. Changes in ICP of 5 cm CSF are generally considered meaningful when 
treating IIH patients. For example, in a clinical study evaluating the benefits of weight 
loss in IIH patients, a 16.5% (6.2 cm CSF) reduction in ICP resulted in a statistically 
significant improvement in headache and vision measures as well as quality of life 
[Sinclair, 2010]. In the IIH Treatment trail (n=165), a study evaluating the drug treatment 
acetazolamide against placebo, a reduction of -5.9 cm CSF was seen in association with 
significant improvement in PMD, OCT measures of papilloedema and quality of life 
measures [Wall, 2014]. 
The minimally clinically important change in the perimetric mean deviation adopted into 
clinical practice was stablished by the Neuro-Ophthalmology Research Disease 
Investigator Consortium (NORDIC) group and the IIH Treatment Trial (IIHTT). The 
investigators found a 0.71dB difference in the PMD between the two trial arms 
(comparing acetazolamide with placebo) that was clinically meaningful. The change of 
0.71dB was interpreted as clinically meaningful as this was accompanied by significant 
changes in LP opening pressure, papilloedema (measured by OCT), general quality of life 
and visual related quality of life [Wall, 2014, Bruce, 2016].  
The clinically meaningful effect size for MHD reflects that for a phenotypically similar 
headache, chronic migraine. Recent randomised trials in patients with chronic migraine 
[Tepper, 2017; Silberstein, 2017], episodic migraine [Goadsby, 2017], or both 
[Camporeale, 2018] have shown in post-baseline months 1–3, odds of migraine relative 
to baseline of 0.5–0.8 with placebo and 0.5–0.3 with experimental drugs. Decreases in 
MHD relative to baseline grew in time, and placebo responses were stronger in chronic 
migraine than episodic migraine. In the three placebo-controlled, blinded trials, these 
equated to odds-ratios of migraine compared with placebo of 0.8–0.6, or absolute 
differences of 1.5–2.5 MHD [Sinclair, 2010; Tepper 2017; Silberstein, 2017; 
Goadsby, 2017].  
 
13.2.4. 
Trial Stopping Criteria 
There are no trial-specific stopping rules.  
13.3. 
Data Analysis Considerations 
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13.3.1. 
Estimands 
We have specified intercurrent events that are material to the measurement of our 
primary and secondary outcomes, and unbiased estimation of treatment effects 
attributable to Presendin. 
ICP-lowering medication include:  acetazolamide, topiramate, diuretics, glucocorticoids 
(oral dexamethasone and oral prednisolone). Headache-preventative medications include: 
amitriptyline, topiramate, nortriptyline, beta blockers, candesartan, sodium valproate, 
pizotifen, botox, CGRP-therapy. 
13.3.1.1. Outcome: Intracranial pressure (ICP) 
13.3.1.1.1. Intercurrent event: ICP-lowering medications 
All patients are expected to have elevated ICP because it is a defining characteristic of 
the disease. ICP is a physiological variable that is unlikely to show spontaneous 
improvement without treatment. For these reasons, we expect ICP-lowering medication 
use to be greater in the placebo arm. If a patient takes medication that is intended to 
reduce their ICP, it is logical to expect that their ICP will be reduced. Outcomes from 
patients that take ICP-lowering medications will confound the estimation of the causal 
treatment effect of Presendin. We have no data to estimate the length of effects of ICP-
lowering medications. For these reasons, we propose to remove 24-week ICP outcomes 
from all patients that have used ICP-lowering medications and replace these observations 
with arm-specific imputations. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. Patients will consent at enrolment to forgo 
the use of ICP-lowering medications and be informed that taking ICP-lowering 
medications during the trial would constitute rescue therapy and a treatment failure and 
be a protocol deviation. 
13.3.1.1.2. Intercurrent event: Off-protocol lumbar punctures 
Lumbar punctures are commonly conducted to reduce intracranial pressure [Weisberg, 
1977; Johnston, 1981; De Simone, 2005]. In some centres, they are given routinely 
although this has now been advised against in the International IIH Guidelines (Soler, 
1998; Mollan, 2018). As such, they remain a material therapeutic option. LP is expected 
to reduce ICP mean opening pressure 32 (28-37) cm CSF to 19 (17-21) cm CSF post LP 
[Yiangou, 2019]. Beneficial effects dissipate with time and whilst there has been no 
longitudinal assessment to quantify change in ICP after an LP, it is expected that effects 
in the majority of change would have dissipated completely within two months [Yiangou, 
2019]. Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove 24-week ICP outcomes from all patients that have had an off-protocol LP within 
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two months of the protocol-scheduled 24-week LP and replace these observations with 
arm-specific imputations. Where patients require off-protocol LP this would be a protocol 
deviation. 
13.3.1.1.3. Inter-current event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in ICP [Sinclair, 2010]., Sudden dramatic weight loss, 
e.g. arising from a surgical procedure will likely yield material changes to IIH symptoms. 
This will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove 24-week ICP outcomes from all patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure and 
replace with arm-specific imputations. Patients will be ineligible for the trial if they have 
had a surgical weight-loss procedure within 3 months of randomisation or fail to confirm 
that they do not intend to undertake such a procedure during the trial. They will also be 
informed at enrolment that undergoing a surgical weight-loss procedure would be a 
protocol deviation. 
13.3.1.2. Outcome: Perimetric Mean Deviation (PMD) 
13.3.1.2.1. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication (rescue medication due to treatment failure ), it is 
logical to expect that their ICP will decrease and that papilloedema will reduce as a 
result, allowing visual fields to improve. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the PMD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
13.3.1.2.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema, allowing visual fields to improve. Patients that have LPs are expected to 
experience less pressure on the optic nerve, less papilloedema, and have better chances of 
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their visual fields improving. Beneficial effects dissipate with time and whilst there has 
been no longitudinal assessment to quantify papilloedema after an LP the consensus of 
clinicians would predict that effects of the LP on papilloedema and therefore visual fields 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
PMD outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove PMD outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.2.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including improvements in visual fields [Sinclair, 2010]. Sudden dramatic 
weight loss, e.g. arising from a surgical procedure will likely yield material changes to 
IIH symptoms. This will confound the estimation of the causal treatment effect of 
Presendin. For these reasons, we propose to remove PMD outcomes of patients that 
experience weight loss exceeding 10% of baseline weight after a surgical weight-loss 
procedure from the date of procedure. These outcomes will be replaced with patient-
within-arm imputations generated by a method suitable for longitudinal data imputation. 
13.3.1.3. Outcome: Papilloedema measured by OCT (optic nerve head size, 
retinal nerve fibre layer) 
13.3.1.3.1. Intercurrent event: ICP-lowering medications 
All patients will suffer from papilloedema at enrolment as it is the hallmark feature of the 
disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient takes ICP-lowering 
medication, it is logical to expect that their ICP will decrease and that the papilloedema 
will reduce in turn. As stated, we expect ICP-lowering medication use to be greater in the 
placebo arm. Outcomes from patients that take these medications will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove the OCT outcomes following the administration of ICP-lowering medications and 
replace these observations with imputations generated by a method suitable for 
longitudinal data imputation. Outcomes recorded at the unscheduled visit when the 
treatment failure is confirmed (and just prior to starting ICP lowering medication) will be 
defined as the last analysed visit. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. 
13.3.1.3.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
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associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema. Patients that have LPs are expected to experience less pressure on the optic 
nerve and therefore relatively less papilloedema. Beneficial effects dissipate with time 
and whilst there has been no longitudinal assessment to quantify papilloedema after an 
LP the consensus of clinicians would predict that effects of the LP on papilloedema 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
OCT outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove OCT outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.3.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in papilloedema [Sinclair, 2010]. Sudden dramatic weight 
loss, e.g. arising from a surgical procedure will likely yield material changes to IIH 
symptoms. This will confound the estimation of the causal treatment effect of Presendin. 
For these reasons, we propose to remove OCT outcomes of patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure from 
the date of procedure. These outcomes will be replaced with patient-within-arm 
imputations generated by a method suitable for longitudinal data imputation. 
13.3.1.4. Outcome: Monthly headache days (MHD)  
13.3.1.4.1. Intercurrent event: Headache-preventative medications 
The great majority of patients are expected to suffer from headache because it is a 
common symptom of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient 
takes medication that is intended to prevent headache, it is logical to expect that their 
headache burden will be decreased. Despite the widely-observed short-term placebo-
effect observed in headache outcomes, we expect headache-preventative medication use 
to be greater in the placebo arm. Outcomes from patients that take headache-preventative 
medications will confound the estimation of the causal treatment effect of Presendin 
(more so with botulinum toxin A and CGRP therapies). For these reasons, we propose to 
remove the headache outcomes following the administration of headache-preventative 
medications and replace these observations with imputations generated by a method 
suitable for longitudinal data imputation. This will allow estimation of the treatment 
effect that is purely and causally attributable to Presendin. Patients who require a change 
to their headache preventative medications will do this through consultation with the IAC 
and such a change would be regarded as headache rescue therapy. 
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13.3.1.4.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing the frequency and intensity of 
headache. Beneficial effects dissipate with time. Prospective data documents alterations 
in headache for at least 7 days and whilst there is no prospective longitudinal data over a 
longer time period consensus amongst clinicians would widely acknowledge that 
headache in some individuals can be influenced for up to a month [Yiangou, 2019]. 
Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. MHD outcomes will be recorded 
daily via diaries. For the reasons stated, we propose to remove MHD outcomes recorded 
in the 4-weeks following each off-protocol LP and replace these observations with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in headache frequency and severity [Sinclair, 2010]. 
Sudden dramatic weight loss, e.g. arising from a surgical procedure will likely yield 
material changes to IIH symptoms. This will confound the estimation of the causal 
treatment effect of Presendin. For these reasons, we propose to remove MHD outcomes 
of patients that experience weight loss exceeding 10% of baseline weight after a surgical 
weight-loss procedure from the date of procedure. These outcomes will be replaced with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4.4. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication, it is logical to expect that their ICP will decrease 
and that headache will reduce as a result. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the MHD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
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13.3.1.5. Primary Estimand (Hypothetical assuming no concurrent procedures, 
irrespective of adherence to treatment) 
The primary estimand is defined as the following for the primary endpoint: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect ICP. 
The primary estimand for the initial secondary endpoint will be handled similarly to the 
primary endpoint using the “Hypothetical” approach. The initial secondary endpoint is 
defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect PMD. 
 
13.3.1.6. Secondary Estimand (Hypothetical) 
The secondary estimand for the primary endpoint is defined as follows: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, if all patients adhered to 
treatment, where patients did not have medications or procedures likely to materially 
affect ICP. 
The secondary estimand for the initial secondary endpoint will be defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, if all patients adhered to treatment, 
where patients did not have medications or procedures likely to materially affect 
PMD. 
All details will be defined in the SAP. 
 
13.3.2. 
Analysis Populations 
The following analysis populations are planned for this trial:  
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•
Safety Population: The Safety population includes all patients randomised to
treatment who receive at least one dose of trial medication. This will be the
population used for all safety analyses unless otherwise specified.
•
Intent-To-Treat Population (ITT): The ITT population includes all patients
randomised to treatment. This will be the main population for all efficacy analyses
unless otherwise specified.
•
Per Protocol (PP): The PP population includes all patients randomised to treatment
without important non-evaluable protocol deviations. Only protocol deviations with
the potential to affect the trial results significantly, or to invalidate the interpretation
of the data obtained, will lead to exclusion of patients from the PP population.
Protocol deviations to be considered will include (but will not be limited to):
•
Failure to meet inclusion/exclusion criteria
•
Wrong treatment or incorrect volume of drug administration
•
Prohibited concomitant medications
•
Compliance of less than 75% or>125% with trial drug administration
•
Use of rescue procedures, including, off-protocol LPs, LP shunts or bariatric
surgery
Assignment of patients to populations will be confirmed at a blinded data review meeting 
to be held before the trial database is locked. 
If a patient is randomised incorrectly or is administered the incorrect trial medication, 
analyses of the ITT will be based on the assigned treatment, whereas all other analyses 
will be based on the actual treatment received. 
13.3.3. 
Treatment Comparisons 
Treatment comparisons will be undertaken between active and control groups. The 
primary outcome will be analysed as described in Section 13.2.1.  
13.3.4. 
Safety Analyses 
Safety will be evaluated from reported AEs, changes in clinical laboratory values, 
changes in vital signs, and ECG results. 
All safety analyses will be performed on the Safety population. 
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13.3.4.1. Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (the most recent 
version before starting the trial will be used).  
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of trial medication. 
The number and percentage of patients reporting TEAEs, grouped by MedDRA system 
organ class and preferred term will be tabulated by treatment group. Summaries will be 
presented for all TEAEs, TEAEs by severity and TEAEs by relationship to trial 
medication. 
In the AE data listings, all AEs will be displayed. Adverse events that are not treatment-
emergent will be flagged. The observation period in which an AE started will also be 
provided. 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm. Treatment failures will be displayed by trial arm. 
13.3.4.2. Clinical Laboratory Evaluations  
Laboratory test results for each biochemistry and haematology parameter will be 
summarized descriptively by treatment group and time point as both observed values and 
change from baseline values. 
The number of patients with clinical laboratory (biochemistry, haematology, and 
urinalysis) values categorized as below, within, or above the normal ranges (or as either 
normal or abnormal for urinalysis variables that do not have quantitative ranges), will be 
tabulated in relation to baseline (shift tables), for each clinical laboratory analyte by 
treatment group and time point. 
Laboratory values will be displayed in the data listings and those that are outside the 
reference ranges will be flagged, along with corresponding normal ranges. Any patients 
with any markedly abnormal laboratory results will also be provided in a listing. 
Pregnancy test results including reason, if not performed, will be listed. 
13.3.4.3. Vital Signs and Body Mass Index Evaluations 
Descriptive summaries of observed values and changes from baseline will be calculated 
for systolic blood pressure, diastolic blood pressure and heart rate by treatment group and 
time point.  
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Body mass index will be derived at Screening, Baseline and Weeks 4, 8, 16, 24, 32 and 
48 using height captured at Screening and weight at the respective assessment. Body 
mass index and weight will be summarized descriptively by treatment group and time 
point as both observed values and change from baseline values for Safety and ITT 
populations. 
13.3.4.4. Electrocardiogram 
Descriptive statistics of observed values and change from baseline will be presented for 
ECG measures of PR interval, QRS interval, QT interval, QT interval corrected 
according to Fridericia’s formula (QTcF). These summaries will be presented by 
treatment and time point for the Safety population.  
The number and percentage of patients with values beyond clinically important limits 
will be summarised including those with an increase in QTcF >30 msec increase from 
baseline and >60 msec increase from baseline or those with an absolute QTcF value of 
>450 msec (male patients) or >470 msec (female patients). 
13.3.4.1. Other Safety Evaluations 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm.  
13.3.5. 
Patient Reported Outcomes Analyses 
All patient reported outcome endpoints (VFQ-25, HIT-6, SF-36, EQ-5D-5L) will be 
analysed as observed and presented with change from baseline in a descriptive summary 
of treatment and visit  
The number and percentages of PGIC responses will be tabulated by treatment and visit. 
13.3.6. 
Missing Data 
Although every effort will be made to collect responses from all patients at all scheduled 
time points, there undoubtedly will be some missing data.  The SAP describes in detail 
steps for dealing with missing data using relevant imputation strategies for specific 
endpoints that adjust for treatment arm, centre, baseline value, and stratification 
variables. 
13.3.7. 
Reporting Deviations from the Statistical Plan 
Any deviations from the planned analyses will be described and justified in the final 
clinical trial report. 
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14. 
TRIAL ADMINISTRATION 
14.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Before initiation of a trial site, the Sponsor will obtain approval from the appropriate 
regulatory agency to conduct the trial in accordance with ICH-GCP and applicable 
country-specific regulatory requirements. 
The trial will be conducted in accordance with all applicable regulatory requirements. 
The trial will be conducted in accordance with the EU Clinical Trial Regulation 
536/2014, ICH-GCP, all applicable patient privacy requirements and the ethical 
principles that are outlined in the Declaration of Helsinki 2013, including, but not limited 
to: 
• 
An IEC/Institutional Review Board review and approval of trial protocol and any 
subsequent amendments and all ICFs or other information given to the patient 
• 
Patient informed consent 
• 
Investigator reporting requirements 
The Sponsor will provide full details of the above procedures, either verbally, in writing, 
or both. 
Written informed consent must be obtained from each patient before participation in the 
trial. Written informed consent will be collected following a review of the patient’s 
information leaflet by the potential patient and a discussion between the patient and the 
Investigator or suitably qualified designee. 
The Investigator will cooperate with all regulatory inspections and will notify the 
Sponsor as soon as they are aware of an inspection which may involve this trial. With the 
exception of statutory regulatory authority inspections, the Sponsor will be consulted in 
the event of inspection of the clinical site(s) by an outside authority before the Inspectors 
are permitted access to any of the trial records or the trial areas. 
14.2. 
Trial Monitoring 
In accordance with applicable regulations, ICH-GCP, the monitoring plan and the 
Sponsor’s and/or delegate procedures, monitors will contact the site before the start of the 
trial to review with the site staff the protocol, trial requirements, and their responsibilities 
to satisfy regulatory, ethical, and the Sponsor’s requirements. When reviewing data 
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collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. 
The Sponsor and or delegated monitors will perform risk-based monitoring during the 
conduct of the trial to ensure that: 
• 
The data are authentic, accurate and complete 
• 
The patient’s safety and rights are being protected 
• 
The trial is conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH-GCP and all applicable regulatory requirements 
14.2.1. 
Access to Source Data 
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor, Sponsor-appointed auditors and regulatory inspectors direct access to 
all relevant documents. 
14.2.2. 
Data Handling and Record Keeping 
Following closure of the trial, the Investigator or head of the medical institution (where 
applicable) must maintain all site trial records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
Investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The Investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
The Sponsor will inform the Investigator of the time period for retaining the site records 
in order to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, the Sponsor SOPs and/or institutional requirements. 
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
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ownership of the records in the event that the Investigator is no longer associated with the 
site. 
14.3. 
Provision of Trial Results and Information to Investigators 
and Publications 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical trial report. The Investigator will be provided 
reasonable access to statistical tables, figures and relevant reports and will have the 
opportunity to review the complete trial results at a mutually agreeable location. 
The Sponsor will also provide the Investigator with the full summary of the trial results. 
The Investigator is encouraged to share the summary results with the trial patients, as 
appropriate. 
If the Sponsor decides to publish the results, then they will provide the Investigator with 
an opportunity to review the manuscript. If the Investigator wishes to publish anything 
related to the trial, then they must provide the Sponsor with the draft publication and 
allow them no less than 14 days to review the document. The Investigator cannot publish 
without written authorisation from the Sponsor. 
14.4. 
Data Management 
For this trial, patient data will be collected using an eCRF and combined with data 
provided from other sources in a validated data system. Patient’s identifiable data (e.g., 
name, initials, address etc.) will not be collected in the eCRF or transferred to Invex 
Therapeutics. Clinical data management will be performed with the objective of 
removing errors and inconsistencies in the data which would otherwise impact on the 
statistical analysis or the credibility of the Clinical Study Report. Original CRFs will be 
retained by Invex Therapeutics; the Investigator will also retain a copy. 
Management of clinical data will be performed in accordance with the applicable Sponsor 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using the Medical Dictionary for Regulatory Affairs and World Health 
Organisation Drug dictionary.  
When using electronic trial data handling and/or remote electronic trial data systems, the 
Sponsor or designee will:  
a. 
Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation) 
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b. Maintain SOPs for using these systems 
c. 
Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail) 
d. Maintain a security system that prevents unauthorised access to the data 
e. 
Maintain a list of the individuals who are authorised to make data changes 
f. 
Maintain adequate backup of the data 
g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing) 
Training on the use of the electronic data collection system will be provided to all 
relevant trial site staff. 
14.5. 
Independent Adjudication Committee 
The IAC will consist of  international medical experts in neurology or ophthalmology 
who are independent of the Sponsor team. 
The role of the IAC will be: 
• 
To support the Investigators with opinions on the eligibility of potential patients 
• 
To provide opinions regarding treatment failure and need for rescue medications 
required during the trial 
Further details on the composition, activities and responsibilities of the IAC can be found 
in the IAC charter. 
14.6. 
Data Safety Monitoring Committee 
Details on the composition, activities and responsibilities of the DSMC can be found in 
the DSMC charter. 
14.7. 
Insurance, Indemnity and Finance 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
The Sponsor will indemnify all Investigators participating in this trial against future 
claims by trial patients; the terms of this will be detailed within a separate letter of 
indemnification. The indemnity will only apply where all trial procedures have been 
carried out according to this protocol. 
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The financial aspects of the trial are addressed in a separate agreement. 
 
 
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Kutzko KE, Brito CF, Wall M. Effect of instructions on conventional automated 
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Liu X, Zhang Y, Zheng SY et al. Efficacy of exenatide on weight loss, metabolic 
parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin 
Endocrinol (Oxf). 2017 Dec;87(6):767-774. 
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16. 
APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-
301 
16.1. 
Appendix 1: LP SOP 
Diagnostic lumber puncture 
The diagnostic lumbar puncture (LP) is performed by the site as part of routine care to 
confirm the diagnosis of Idiopathic Intracranial Hypertension (IIH).  This is not a 
research LP. For the patient to be eligible for the IIH Evolve trial the diagnostic LP must 
have the opening pressure measured in the lateral decubitus position in line with the 
guidance below. The LP must be within 4 weeks of commencing screening. 
Research lumbar puncture 
A research LP is performed at the end of the Randomised Period/ Week 24/ Visit 10. This 
is the primary outcome for the trial. In the 4 weeks prior to visit 10, patients must not 
have missed more than one dose of trial medication and must have self-administered their 
final dose within 7 days of visit 10. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days. We 
recommend that the LP should be performed after visual  assessment. 
The LP should be performed by a trained clinician or health care professional according 
to local standard of care. The only mandatory requirement for the trial is that the 
measurement of LP opening pressure is conducted as per below.  
Procedure 
Suggested equipment required:  
• Antiseptic cleaned trolley; 
• Cleaning solution (Iodine or chlorhexidine) 
• 2 pairs of sterile gloves; 
• Sterile wound pack; 
• Lumbar puncture manometer (up to 3 should be available) with corresponding 3 
way valve stopcocks (should be included in pack); 
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• Needle point 20 gauge lumbar puncture needle; 
• 10ml syringe x 1; 
• Green syringe needle, blue syringe needle and orange syringe needle; 
• Gauze pads x 1; 
• 3 sterile universal pots; 
• Sterile dressing. 
Suggested technique 
For a standard (non-image guided) LP: 
• Ask the participant to lie in the lateral left position; they should be relaxed. 
• The legs must be flexed at the hip at a 90˚ angle (support may be need to maintain 
this position). 
• The L3/4 intervertebral space should be located using anatomical landmarks (the 
midline between the posterior superior iliac crests). If this is difficult, consider 
using ultrasound to identify the correct structures: IV space and spinous processes 
of L3 and L4. The space above or below may also be accessed if needed. 
• Mark the location of needle entry. 
• Clean a large circumference around the needle entry site using 70% alcohol or 
chlorhexidine using a sterile technique. 
• Infiltrate 1-2% lidocaine subcutaneously and into the vertebral ligaments. 
Aspirate prior to infiltration to avoid intravascular injection. No more than 
3mg/kg should be infiltrated (1% contains 10mg per 1ml). 
• Once the area is appropriately anaesthetised, insert the needle bevel up, 
horizontally to the marked area and towards the umbilicus.  
• Once a ‘give’ is felt, withdraw the stylet and ensure flow of CSF.  
LP opening pressure measurement (mandatory) 
• Pressure readings MUST be taken with the patient lying in the lateral left (or 
right) decubitus position. 
• Connect the manometer and record the opening pressure: 
o If the patient’s thighs are compressing their abdomen then very slowly 
extend the legs at the hip joint to ensure the abdomen is not compressed. 
o Ensure the patient is not speaking or breath holding (avoid valsalva)  
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o Allow time (sometimes around 5 minutes), for the pressure to become 
consistent (small fluctuations in the pressure with respiration should be 
seen) before a reading is taken 
• Collect a sample of CSF in sterile universal container (size typically 25-30ml), 
and collect a 3ml CSF sample for the research trial. This should immediately be 
stood upright in a wet ice bath until processing. Process should be within 30 
minutes of collection (see the Laboratory manual).  
• There is no need to record a closing pressure for the trial. 
• Replace the stylet, withdraw the needle and place a sterile dressing over the area. 
For an image guided-LP: 
This may be performed using guidance by ultrasound, x-ray or computerised tomography 
(CT). This should be performed by a suitability qualified health care professional (e.g. 
radiologist). The positioning for a patients undergoing an image guided LP vary 
internationally. For this trial the initial position for an image guided LP can be according 
to local expertise but the LP pressure measurement MUST be conducted in the lateral 
decubitus position as described above. This ensures standardisation across the trial. 
Post procedure advice: 
This should be in line with local hospital care pathways. We would suggest: 
• Lie flat for approximately 30 minutes (there is no evidence to support that lying 
flat for any duration reduces a post LP headache). Pragmatic advice on 
mobilisation when the patient has recovered is advised. 
• Simple analgesia may be prescribed and dispensed for post-procedure pain 
(headaches or back pain); 
• Oral fluids may help with post-procedure headache (non-evidenced based 
recommendation).  
• Remind the participant of the possible adverse effects. 
 
 
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16.2. 
Appendix 2: IIH Diagnostic criteria [Mollan, 2018] 
A. Papilloedema 
B. Normal neurological examination (except sixth cranial nerve palsy) 
C. Neuroimaging: normal brain parenchyma (no hydrocephalus, mass, structural 
lesion or meningeal enhancement). Venous thrombosis excluded in all. 
D. Normal CSF constituents (less than or equal to 7 white cells per mm3 with normal 
protein and glucose  
E. Elevated lumbar puncture pressure ≥ 25cm  CSF  
 
 
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16.3. 
Appendix 3: 36-item short from survey  
 
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HEALTH 
. ' 
--
RAND > RAND Health > Surveys > RAND Medical Outcomes Study > 36-ltem Short Form Survey (SF-36) > 
36-ltem Short Form Survey Instrument 
(SF-36) 
RAND 36-ltem Health Survey 1.0 Questionnaire Items 
Choose one option for each questionnaire item_ 
L In general, would you say your health is: 
n 1- Excellent 
', 2 - Very good 
0 3 - Good 
C 4-Fair 
n 5-Poor 
2. Compared to one year ago, how would you rate your health in general now? 
n 1- Much better now than one year ago 
0 2 - Somewhat better now than one year ago 
0 3 -About the same 
n 4 - Somewhat worse now than one year ago 
n s - Much worse now than one year ago 


 
 
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V X 
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The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so, how much? 
Yes, 
Yes, 
No.not 
limited a 
limited a 
limited at 
lot 
little 
all 
3. Vigorous activities, such as running, lifting heavy objects, 
n
1 
0
2 
n
3 
participating in strenuous sports 
4. Moderate activities, such as moving a table, pushing a 
r, l 
0
2 
n
3 
vacuum cleaner, bowling, or playing golf 
s. Lifting or carrying groceries 
'1 1 
Ch 
n
3 
6. Climbing several flights of stairs 
0 l 
0
2 
0
3 
1. Climbing one flight of stairs 
I"'\ l 
n
2 
n
3 
8. Bending, kneeling, or stooping 
0
1 
0
2 
Q
3 
9. Walking more than a mile 
n
1 
n
2 
n
3 
10. Walking several blocks 
0
1 
0
2 
Q
3 
11. Walking one block 
n
1 
n
2 
n
3 
12. Bathing or dressing yourself 
0
1 
0
2 
Q
3 


 
 
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V X 
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During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
13. Cut down the amount of time you spent on work or other activities 
14. Accomplished less than you would like 
1s. Were limited in the kind of work or other activities 
16. Had difficulty performing the work or other activities (for example, it took extra 
effort) 
Yes 
No 
0 
0 
2 
C) 
0 
2 
r, 
0 
2 
r, 
n 
2 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
Yes 
No 
17. Cut down the amount of time you spent on work or other activities O 1 
Q 2 
18. Accomplished less than you would like 
,) 1 
r, 2 
19. Didn't do work or other activities as carefully as usual 
O 1 
0 2 
20. During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors, or 
groups? 
C' 1 - Not at all 
r,, 2-Slightly 
0 3 - Moderately 
{") 4 - Quite a bit 
0 5 - Extremely 


 
 
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21. How much bodily pain have you had during the past 4 weeks? 
0 1- None 
-:::) 2-Verymild 
t' 3-Mild 
0 4 - Moderate 
0 5-Severe 
0 6 -Very severe 
22. During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
0 1-Notatall 
I) 2-Alittlebit 
r:: 3 - Moderately 
r"\ 4 - Quite a bit 
{') s - Extremely 
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These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question, please give the one answer that comes closest to the way 
you have been feeling. 
How much of the time during the past 4 weeks ... 
All of 
Most 
A good 
Some 
A little 
None 
the 
of the 
bit of the 
of the 
ofthe 
ofthe 
time 
time 
time 
time 
time 
time 
23. Did you feel full of pep? 
(; l 
0
2 
0
3 
0
4 
0 s 
O
s 
24. Have you been a very nervous 
0
1 
n
2 
'J 3 
(') 4 
1""1 5 
O
s 
person? 
25. Have you felt so down in the 
(' l 
0
2 
0
3 
0
4 
O s 
O
s 
dumps that nothing could cheer you 
up? 
26. Have you felt calm and peaceful? 
('\ l 
n
2 
n 3 
() 4 
f'""\ 5 
n
s 
27- Did you have a lot of energy? 
0
1 
0
2 
tJ 3 
Q
4 
O s 
O
s 
28. Have you felt downhearted and 
('\ l 
n 2 
c\ 3 
n 4 
n s 
() s 
blue? 
29. Did you feel worn out? 
('\ l 
n 
2 
(') 3 
(') 4 
n s 
n
s 
30. Have you been a happy person? 
C i 
0
2 
Q
3 
0
4 
C' 5 
O
s 
31. Did you feel tired? 
0
1 n 2 
'J 3 
n 4 
n s 
() 6 
32. During the past 4 weeks. how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
0 l - All of the time 
0 2 - Most of the time 
f""I 3 - Some of the time 
f""I 4 - A little of the time 
n s-Noneofthetime 


 
 
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How TRUE or FALSE is each of the following statements for you. 
Definitely 
Mostly 
Don't 
Mostly 
Definitely 
true 
true 
know 
false 
false 
33. I seem to get sick a little easier than 
0
1 
0
2 
0
3 
') 4 
O s 
other people 
34- I am as healthy as anybody I know 
0
1 
0
2 
0
3 
') 4 
O s 
35. I expect my health to get worse 
r, 1 
n 2 
n 3 
{) 4 
(") 5 
36. My health is excellent 
r'l 1 
() 2 
() 3 
'J 4 
r'l 5 
ABOUT 
The RAND Corporation is a research organization that develops solutions to public policy challenges to help make 
communities throughout the world safer and more secure. healthier and more prosperous. RAND is nonprofit. nonpartisan. 
and committed to the public interest. 
II 
1776 Main Street 
Santo Monico, California 90401-3208 
RAND• is a registered trademark. Copyright© 1994-2016 RAND Corporation. 


 
 
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16.4. 
Appendix 4: EuroQol -5 dimension-5 level survey  
 
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UK (English} © 2009 EuroQof Group EQ-5O'" is a trade mark of/he EuroQol Group 


 
 
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Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, hou 
leisure activities) 
I have no problems doing my usual 
I have slight problems doing my usu 
I have severe problems d 
lh 
s or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
UK /English) © 2009 EuroQol Group EQ-5O'" is a trade mark of the EuroQol Group 
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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TOD 
• 
Now, please write the number you marked on the scale in the 
below. 
UK (English) © 2009 EuroQo/ Group EQ-5D™ is a trade mark of the EuroQo/ Group 
X 
THERAPEUTICS 
The best health 
you can imagine 
100 
The worst health 
you can imagine 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 


 
 
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Version: 4.0 
 
 
CONFIDENTIAL 
Page 119 of 140 
 
16.5. 
Appendix 5: Headache Impact Test-6 
 
V X 
THERAPEUTICS 
HIT-6™ 
(VERSION 1.1) 
~HE 
This questionnaire was designed to help you describe and communicate 
the way you feel and what you cannot do because of headaches. \ 'J'MT TESTN 
To complete, please circle one answer for each question. 
When you have headaches, how often is the pain severe? 
Never 
Rarely 
Sometimes 
"V" How often do headaches limit your ability to do usual daily activities in 
T work, work, school, or social activities? 
Never 
Rarely 
V When you have a headache, how often do yo 
Never 
Rarely 
In the past 4 weeks, how often have yo 
of your headaches? 
Never 
+ 
COLUMN 1 
COLUMN 2 
(6 points each) 
(8 poin ts each) 
Sometimes 
COLUMN 3 
(10 points each) 
To score, add points for answers in each column. 
Please share your HIT-6 results with your doctor. 
llll-6"US([nglish)V,rs011.1 
"2000,2001 OualityMctrit,lnc.andGlaxoSm~hKlitw:Gro;p<XCompani,s 
+ 
Always 
do work or daily activities because 
Very Often 
Very Often 
Very Often 
COLUMN 4 
(1 1 poin ts each) 
+ 
Always 
Always 
Always 
COLUMN 5 
(13 points each) 
Total Score ._I ___ 
__. 
Higher scores indicate 
greater impact on your life. 
Score range is 36-78. 


 
 
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CONFIDENTIAL 
Page 120 of 140 
 
 
 
X 
THERAPEUTICS 
ffl 
HEADACHE 
IMPACT TEST™ 
What Does Your Score Mean? 
T If You Scored 60 or More 
Your headaches are having a very severe impact on your life. You may be experiencing disabli1 
are more severe than those of other headache sufferers. Don't let your headaches stop you fr 
your life, like family, work, school or social activities. 
Make an appointment today to discuss your HIT-6 results and your headaches with your d 
T If You Scored 56 - 59 
Your headaches are having a substantial impact on your life. As a result y 
symptoms, causing you to miss some time from family, work, school, or so 
Make an appointment today to discuss your HIT-6 results and y 
T If You Scored 50 - 55 
Your headaches seem to be having some impact on your 
work, school, or social activities. 
Make sure you discuss your HJT-6 results and ym 
T If You Scored 49 or 
Your headaches seem to be havin 
T 
T 
ur 
ecause research shows that when doctors understand exactly how badly 
ients, they are much more likely to provide a successful treatment program, which may 
et at www.headachetest.com. 
ou to print out a personal report of your results as well as a special detailed version for your doctor. 
gain or try the Internet version to continue to monitor your progress. 
The Headache Impact Test (HIT) is a tool used to measure the impact headaches have on your ability to function on the job, at 
school, at home and in social situations. Your score shows you the effect that headaches have on normal daily life and your 
ability to function. HIT was developed by an international team of headache experts from neurology and primary care medicine 
in collaboration with the psychometricians who developed the SF-36®* health assessment tool. 
HIT is not intended to offer medical advice regarding medical diagnosis or treatment. You should talk to your healthcare 
provider for advice specific to your situation. 
SF-36® is a registered trademark of Medical Outcomes Trust and John E. Ware, Jr. 
HIT-6 Scoring lnterprelalion English Version I.I 
©2001 QualilyMetric, Inc. and GlaxoSmithKline Group of Companies. All rights reserved. 


 
 
Study Number: INVEX-CLIN-IIH-301 
Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
CONFIDENTIAL 
Page 121 of 140 
 
16.6. 
Appendix 6: Visual Function Questionnaire-25 & 10-item 
Supplement 
 
 
National Eye institute 
Visual FunctioninrJ QuE)stionnaire - 25 
{VFQ-25) 
version 2000 
PB/SA 
,1/)-
-::t: ... ftfr 
( ...... E-LF--
DMIN• 1S·-r·i::r-.E·o- F-o,R~" 8xl / 
r\ 
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1--:'"'-
l\:16, 
) 
""•'•.,.._ 
.v.v"f' 
_, _ 
~,;¼JV 
.-:~t:,. 
.6 
41t=' 1 ·<~¥•' 
t~:i~-
-~-~~·Tu,,9p 
r' 
i-. 
., 
k 
. 
w).' -.-:$':... 
·· ,, .. r 
--~-:-:-:-~ 
~;-. . 
-~
: -
RAND hcrd>\f ~rnn,···sio:1 tei ui.c th
0~1onal EV.! lr.stitutt Visuol Fune;tioning C:uc:;tionnalre. 2-S (Vf-Q-2£) 
July i:993, ht fiCj:or·, 
• • . -
•• foli<Mill!) (; 
~c,ns Whidl Sildll '1e d:i,iUroleO by di! to t1fiVe ti~~Hl i41jte~d t(, as d 
r.onser.p;enc~ of w::r. 
)9 r1 
·s _it~cl'! 
: 
1. Ctm11ges to :her~ ... :~ .0-2_ 
Y, -
.: be made without the writtw permissioil .'.>f RAtm. lfowcve,, all 
oiUCh ch_ J~~- e~ !iilali be~ 
!)': 
filfi£:-ci as t'l~Vhlg bel?U m.tdt; by ih~ tetlpil!•lt. 
"•tis 
"•ftn1::. f-Jf l v:,· 
S - July 1996 accept~ fu!I re~pon~tbl!U~•. and lgree~ to hold RAr-m harmlt£!;, tor 1hca 
·rac.y <;f any trar.i.:Jat:01 
"." t:,e NEJ VFQ-ZC. k st Version - July 1996 tnto ,mott,cr :,mguc.gc ~nd for ,lily errors, 
liSSic,n~:;~~-tio:> ·~::-<./ COJi!'oP.(IUeJi(!l!"S lhHE:-(if. 
·~tnts,.L
00 -.Q.£€° . JUiy 1995 lt.:Ce-pts !U!I re~ponsi-.!Jility, J!ld a;irn-~s ~o t!O!d RANU harml::!SS, tcr any 
J~:W;Ces Hosulti 
om lhe..ise of the NEI 'JFQ-2G. 
4. The IJ~~r of ttlt: • 
• HJ-:li - .July ·\~iiJ •vl!I pro>nd~ cl. crectit line w!lE'n printing tJ.nd cHstr!l,!l!ing th!s Oor::ument 
,::,r in pu~W,esultt or Jria11s-es Mse-d en this inetrum2-nt ac!<r'tOW\Mging tt!Jt it W.:l$ de•Jetop~-d .lt RA.NO 
unocr u,~·~Sh:p of tt.c N.itl.or.c.l Eve Institute. 
1:w:sc 
@ HAND 1996 
X 
THERAPEUTICS 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
CONFIDENTIAL 
Page 122 of 140 
 
 
X 
THERAPEUTICS 
- 1 -
version 2000 
The following is a survey with statements about problems which involve your 
vision or feelings that you have about your vision condition. After each question 
please choose the response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
Please take as much time as you need to answer each question. 
answers are confidential. In order for this survey to improve our 
about vision problems and how they affect your quality of life, 
be as accurate as possible. Remember, if you wear glasses 
please answer all of the following questions as though you were"°"'~~ 
INSTRUCTIONS 
1. 
In general we would like to have people try to 
their own. If you find that you need a 
project staff and they will assist yo 
2. 
Please answer every question 
3. 
4. 
5. 
6. 
because they don't apply t 
u). 
ionn 
efore leaving the center and give it to 
Do not take it home . 
.ni.ll"!s~~.olease feel free to ask a member of the project 
I be glad to help you. 
would permit identification of any person who completed this 
e regarded as strictly confidential. Such information will be 
---."" purposes of this study and will not be disclosed or released for 
poses without prior consent, except as required by law. 
©RAND 1996 


 
 
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Version: 4.0 
 
 
CONFIDENTIAL 
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X 
THERAPEUTICS 
- 1 -
version 2000 
Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEAL TH AND VISION 
1. 
2. 
One) 
1 
2 
3 
4 
........................................ 5 
ou say your eyesight using both eyes (with 
ou wear them) is excellent. good, fair, 
u completely blind? 
(Circle One) 
Excellent ............................... 1 
Good ...................................... 2 
Fair ......................................... 3 
Poor ........................................ 4 
Very Poor .............................. 5 
Completely Blind ................ 6 
©RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
THERAPEUTICS 
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3. 
How much of the time do you worry about your eyesight? 
(Circle One) 
None of the time............................. 1 
A little of the time........................... 2 
Some of the time................. 
.. .... . 
Most of the time ............ 
. ........... . 
4. 
How much pain or discomfort have you h 
(for example, burning, itching, or achin 
2 
3 
4 
5 
The next questions are a 
certain activi • 
for that activ 
. 
ffloli"III~ difficulty, if any, you have doing 
or contact lenses if you use them 
5. 
(Circle One) 
ifficulty at all ................... ...................................... 1 
tie difficulty............................................................. 2 
3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
THERAPEUTICS 
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version 2000 
6. 
How much difficulty do you have doing work or hobbies that require 
you to see well up close, such as cooking, sewing, fixing things 
around the house, or using hand tools? Would you say: 
(Circle One) 
No difficulty at all ................... ...................................... 1 
.A little difficulty ........................................... ,. ............ ,, .. . 
Moderate difficulty ....... ., ........ ...................................... . 
Extreme dlfficuity ................................................... . 
Stopped doing this because of your eyesigh 
Stopped doing this for other reasons or not 
interested in doing this ......................................... .. 
7. 
Because ot your eyesight, how much 
someihing on a crowded shelf? 
No dii'ficulty at all ............. ..,_·.,....,,.,-...,.. 
A little difficulty.... .. .. ...... .. 
2 
3 
.
.. ., 
.. ., .. 4 
eyes,ght ..... 5 
have ,·eading stteet signs or ihv names oi 
(Circle Ona) 
. Hy ,'11 ;JII ..................... ., ......... .... ............ .,.. 1 
difficulty ............................................................. 2 
ate difficulty....................................................... 3 
4 
Stepper! doing this because of ycm eyasight..... 5 
Stopped doing this for other reasons c, not 
internsted in doing this ........................................... 6 
9. 
Be,~ausc, c.f your eyesight, how much dlfficu!ty de you hz,ve goinq 
down steps. st airs er curbs in dim Hght or ell night? 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
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(Circle One) 
No difficulty at all ................... ...................................... 1 
A !ittl~ difficulty.................................................................... 2 
Moderate difficult:,,....................................................... 3 
Extreme di'fficuity ................... ...................................... 4 
Stopped doing this because of your eyesight ... .. 
Stopped doing this for other reasons or not 
interested in doing this ............................ ........
....... 6 
10. Because of your eyesight, how much diffi 
'i1. 
objects off to the side while you are .w
,.,,_.a,.,,lk"'i,_,n'!:1'!111::.-::= 
No difficulty at all ............. . 
A little difficulty ............. . 
Extreme difficulty . . 
Stoppe ··• 
• • • 
Stopp 
int 
3 
4 
5 
w much ciifficuity do you have seeing 
say?' 
(Circle One) 
culiy at all ................... ...................................... 1 
··tficulty............................................................. 2 
difficulty ....................................................... 3 
me difficulty ..... .............. .. ... ... ... .... ... . . ..... ....... 4 
.,.._.....,...,....,.~,pped doing '.chi<; because of ycur eyesight..... 5 
• Stopped doing this for other reasons er not 
interested in doing this ........................................... 6 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
THERAPEUTICS 
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12. Because of your eyesight, how much difficulty do you have u_icJ5J11.q.21u 
and matchino your own clothes? 
(Circle One) 
No difficulty at all ................... ...................................... 1 
A little difficulty., ....................... ........ , ..... , ..... , ...................... 2 
Mede rate difficulty ............... .... ............... ..... .... ..... .. 
Extreme di'fficuity ............................................. .......... .. 
Stopped doing this because of your eyesight .· 
Stopped doing this for other reasons or not 
interested in doing this ........................................ . 
13. Because ot your eyesight, how much 
with eo le in their homes at arti 
No dii'ficulty at all ............. ..,_·.,...,.,-...,.. 
A little difficulty.... .. . . ...... .. 
2 
3 
-
.......... 4 
eyes,ght ..... 5 
w much difficulty do you have going out 
, 
rts ·evcen!s? 
(Circ!e One) 
ifficulty :at all .... .... .... ... ... ... .... .... .... ... 
1 
.,..,_...,..,,,...tr itUe difficulty ............................................................. 2 
fvloderate difficulty ................. ...................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your eyesight . ... 5 
Stopped dr)ing this for other reasons <.r, not 
lnten:sfod in doing tilis: .............. , ............................. 6 
15.. 
,~re you currn-nt!y driving . .at least. once in a •Nh!le? 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
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X 
THERAPEUTICS 
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version 2000 
(Circle One) 
Yes........................ 1 Skip To Q 15c 
1·Jo ......................... 2 
15a. 
IF NO: Have you never driven a car or have you 
15b. 
griying? 
eyesight, mainly_for 
g~s!ghia_nd..9t!J.eL..,,. ..... ..,_.., 
(Circle One) 
Never drove........ 1 
e of_your 
e of bot1Lvoyr 
·j 
Skip To Pa,t 3, Q 17 
£. Skip To P;:,,t 3, Q 17 
.. , Skip Tu Pc:,rt 3, 0 17 
TL Y DR!\/lf\lG: Hovv much difficulty do you have 
___ . .1,.rio.9.th!t,_gr!YtilmlirLffilililll!!'..~~§? \I\Jould you sav 
--- -
a,~ 
(Circle One.l 
No difficulty at all................................. 1 
A little difficulty ........... . ,....................... 2 
Mochmite di-!ficulty ............................... 3 
Extreme difficulty................................. 4 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
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16. How much difficulty do you have drivjng_ainioht? Would you say vou 
have: 
(Circle One) 
No difficulty at all....................................... 1 
A little difficulty .... ,. ...................... ,................ 2 
Moc:lern,te difficuHy .. ,................................... 3 
Extreme dift'iculty .......................... .. ....... 4 
Have you stopped doing this 
ause 
of your eyesight............. . .............. .. 
Have you stopped doing t 
reasons or are you not int 
doing this .................................. . 
16A. How much difficulty do you have ,,.d'--'ri_.,vi.Ji lll:l/"',¼-"'-'--'~~ '--"""--'--'~,1111.l/14-'s"'u.._c,,,_,h 
as in bad weather durin rush hou 
traffic? 
Would you say you have: 
2 
..................................... 3 
4 
u sklpped doing this because 
r eye:,,;ight .................................... 5 
ave you stopped doing this 1'or otiIer 
reasons or are you not interested in 
doing ,his................................................ 6 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
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version 2000 
PART 3· R.ESPONSES TO VISI ON PROBLEMS 
The next questions are about how things you do may be affected by your 
vision. For each one, please circle the number to indicate whether for you 
the statement is true for you all, most, some, a little, or none of the time. 
READ CATEGORIES: 
17. Do vou accomplish less 
than you would tike 
bccciuse of yo-ur vk,ion? 
18. P,re you !lmlted in how 
long you czn \Nork or do 
other act.ivitie~-because of 
your vision? ........ ,.. .......... ., 
19. Ho1N much does pain or 
discomfort i!lOLfil:.Q!!J"l_g 
your eves, for 
burning, itchin 
aching, keep y 
doing w 
be doi 
(Circle One On Each Line) 
Ali of 
Most of 
Some 
A •• 
None of 
the 
the 
the 
time 
time 
2 
3 
5 
.2 
3 
4 
s 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
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version 2000 
For each of the fo!lm'lling statements, please circle the number to indicate 
whether for you the statement is definitely true, mostlv true, mostlv false, 
or @fiDi~ly_f<!l.s~ for you or you are n_o!_sYf~. 
(Circle One On Each Lme) 
Definitely 
Mostly 
i\lot 
True 
True; 
Sui"e 
20. ! stay horn,) most of the· time 
because of my eyesight. .... 
1 
21 
! feel frustrated a lot of the 
time because of my 
eyesight. ·········••"·••·····•···•········· 
1 
22.. 
I have much less c:ontrcit 
over what I do, because of 
my eyesight. ......................... . 
23. Because ot my eyesight, I 
have to rely too much on 
what other people teii me ... 
25. 
© RAND 1996 
2 
3 
3 
2 
3 
2 
3 
4 
4 
4 
Definitely 
False 
5 
5 
5 
5 


 
 
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X 
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version 2000 
Appendix of Optional Additional Questions 
SUBSCALE: GENERAL HEALTH 
A1. How would you rate your overall health, on a scaie where 
bad as death and ·10 is be;.t po;.sible heaHh? 
0 
Worst 
2 
SUBSCALE GENERAL VISION 
(Circle One) 
4 
5 
6 
.., 
A2. How would you rate your eyesi. 
on, if you wear them), on a sc 
worst possibie eyesight, as •• ad 
means the 
, and 10 
means the best possible 
• •• ht'? 
0 
1/\Jorst 
8 
9 
rn 
Best 
SUBSCALE: 
A3. 
ow 
h difficulty do you have r~,c:!i_rig_the,,§!llilH 
ne boo!s., on a medicine bottle.._9r on l~al forms? 
(Circle One) 
ifficuliy at all ................... ...................................... 1 
.-...,-,...•~ little difficulty............................................................. 2 
Moderate difficulty .............................................................. 3 
Exi:remci diffkuity .... .,....................................................... 4 
Stopped doing this because of your eyes,ght ..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
CONFIDENTIAL 
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X 
THERAPEUTICS 
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version 2000 
.A4. Because of your eyesight, how much difficulty do you have fi_g_y_ri.ng 
out whether bills_you receive are accurate? 
(Circle One) 
No difficulty at all ................... .......................... ............ 1 
.A l.ittle difficulty .... .... .... .... .... .................... .... ...... . 
Moderate diff1culty ......... ,. ......... .... ., .............. , ......... , ........ . 
Extreme dl"l'ficuity .................................................. .. 
Stopped doing this because of your eyes1gh 
Stopped doing this for other reasons or not 
interested in doing this ......................................... .. 
A5. Because ot you 
• •• 
things I ike §s:!)h~ay_vJ..ruw!!YJM!B..]cQ!dlL!:~IO~!!l?l~!9J.:!:~~~',1 
No dii'fic 
A little di 
2 
3 
........... 4 
eyes,ght ..... 5 
r eyesight, how much difficuity do you have 
le ou know from across a room? 
ing 
(Circle One) 
il'ficuity at all ................... ...................................... 1 
little difficulty............................................................. 2 
Moderate difficulty ........ ,. ..................... ., ........ .,............ 3 
Extreme d!fficu!ty ..... ....................................... ............ 4 
Stepped doing this bacause of ycur eyesight..... 5 
Stopped doing this tor other reasons or not 
interested in doing ti'lis ........................................... 6 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
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X 
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version 2000 
A7. Because of your eyesight, how much difficulty do you have Ylkin9.-DJU1 
i11 active sports or other outdoor activities that you eniQY (like golf, 
bowling. jogging, or walking)? 
(Circle One) 
i\lo difficulty at all ..................... ,. .......... ,. .............. ,,,..... 1 
A little difficulty .................. ....................... ,. ... ........... . 
Moderate difficulty ................. ..... ...... ....................... . 
Extreme d:'ffi·cuity ................................................ .. 
Stopped doing this because of your eyesight ..... 
Stopped doing this for other reasons or not 
interested in doing this.............. . 
.. .................... 6 
AS. Because ot your eyesight, how much 
enjoying programs on TV? 
No dii'ficulty at all ............. ..,_·.,....,,.,-...,.. 
A little difficulty.... .. . . ....... . 
2 
3 
........... 4 
eyes,ght ..... 5 
,-, eyesight, how much cilfficuity do you have 
''las ,md t.,mil in our heme? 
(Circle Or e) 
ifficu!ty c1t ,:,ill ..... ,.......................................... 
1 
.,..,_......,......, itUe difficulty ............................................................. 2 
Moderate difficulty ....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your ei1esight ..... 5 
Stoppeti d,oing this for ,other reas,ons er not 
lnten:sfod in doing tilis: ........................................... 6 
© RAND 1996 
and 


 
 
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Compound No.: Presendin™ 
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Version: 4.0 
 
 
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X 
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SUBSCALE: DRIVING 
A10. [This item, "driving in difficult conditions", has been included as part 
of the base set of 25 items as item 16a.I 
SUBSCALE ROLE LIMITATIONS 
A1 I. The next questions are about things you may do be,:; 
·. islon. For each Hem, please cird e the number to ind,· 
you this is true for you all, mosl , 5ome, a littie, m nom, m 
a. 
J;)Q...yQ! 1J:iave more MIQ 
from others because of 
your v.ision? ........................ . 
b. Are~u .limited i 
kinds of things yo'""'"'"'·.-:-...-... 
because of your vis1 
3 
3 
© RAND 1996 
4 
4 
Hone of 
the 
time 
5 
5 


 
 
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SUBSCALES WELL-BEING/DISTRESS (#A1 2) and DEPENDENCY (#A13) 
The next questions are about how you deal with your vision. For each 
statement, please circle the number to indicate whether for you it is 
definiteiy true, mostly true, mostly false, or definitely false for you or you 
don't know. 
Defi niialy 
Mcstiy 
f~ot 
True 
True 
Sur-:e 
A 12. I am often irritable because 
of my eyesight....................... 
1 
2 
A 13.1 don't go out of my home 
alone, because of my 
eyesight. ............................... .. 
© RAND 1996 
5 


 
 
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10-ITEM NEURO-OPHTHALMIC SUPPLEMENT TO THE NEI-VFQ-25 
The following are additional questions and statements about problems that involve your vision or 
feelings you may have about your vision condition. After each question, there will be a list of possible answers. 
Please choose the response that best describes your situation. 
Please answer all questions as if you were wearing your glasses or contact lenses (if any). Please take as much 
time as you need to answer each question. 
1. How much difficulty do you have performing tasks when your eyes are tired? 
/Circle One) 
None 
Mild 
2 
Moderate 
3 
Severe, or 
4 
Very severe? 
5 
2. Because of your vision, haw much difficulty do you have identi~ 
sunlight? 
{Circle One) 
None 
Mild 
Moderate 
Severe, or 
Very severe? 
3. Because of your vision, how much difficult 
have 
• g a car? 
/Circle One) 
Na difficulty at all 
A little difficulty 
2 
Moderate difficulty 
3 
Extreme difficulty 
4 
Stopped doing this because of our ey • 
5 
Stopped dmng th 
"-· _..._..,..... 
r n 
rested 1n doing this 
6 
4. Because of y 
··:,;_,.-.;-,.:: 
you have using a computer? 
/Circl 
N 
4 
5 
6 
I wing statements, please indicate if it is definitely true, mostly true, mostly false, or 
definitely false for you or if you are not sure. 
5. I have a feeling that my two eyes see differently, even with correction {glasses or contact lenses). 
{Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
X 
THERAPEUTICS 


 
 
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Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
CONFIDENTIAL 
Page 138 of 140 
 
 
6. I have a feeling that my eye or eyelid appearance i, unusual. 
(Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
For each of the following, please indicate if it is true fo r you all, most, some, a little, or none of the time. 
7. My vision is blurry, not clear, or "fuzzy." 
(Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
8. I have trouble focusing on or following moving objects. 
(Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
9. I have double vision wittl both eyes open t 
t pres 
ther eye is covered. 
(Circle One) 
All of the time 
Most ofthe t1me 
Some of the time 
A little of the time 
None of the time 
4 
5 
1 
2 
3 
4 
5 
X 
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Compound No.: Presendin™ 
Protocol 
Version: 4.0 
 
 
CONFIDENTIAL 
Page 139 of 140 
 
16.7. 
Appendix 7: Patient Global Impression of Change  
 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
Since the start of the study, my overall status is 
one box only: 
[1] 
Very much Improved 
[2] 
Much Improved 
[3] D Minimally Improved 
[4] 
No change 
[5] 
Minimally Worse 
[6] D Much Worse 
[7] D Very much Worse 
X 
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Version: 4.0 
 
 
CONFIDENTIAL 
Page 140 of 140 
 
16.8. 
Appendix 8: Contraception 
Birth control methods which may be considered as highly effective (that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are 
considered as highly effective birth control methods).  
Patients should be instructed not to take their oral contraceptive within 1 hour prior to 
administration of trial medication. 
Such methods include: 
• combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system ( IUS)  
• bilateral tubal occlusion  
• vasectomised partner 1 
• sexual abstinence 2 
 
1. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the trial participant.  
2. In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
 
V X 
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Version: 3.0 
 
Page 1 of 137 
 
CONFIDENTIAL 
 
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 
Effective Date: 
08-Jun-2022 
 
Short Title: A Phase III trial to determine the efficacy and safety of Presendin in 
IIH – IIH EVOLVE 
Abstract: 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 release 
formulation of exenatide (Presendin) in the reduction of intracranial pressure (ICP) in 
patients with IIH. The primary outcome will be determined by change in ICP, as 
measured by lumbar puncture (LP).  
Eligible, consenting patients will be randomised in a ratio of 1:1 to receive Presendin or 
placebo as a weekly dose for 24 weeks. 
 
Author  
Department 
Company 
Emma de Launay 
Clinical Operations 
Invex Therapeutics Ltd. 
 
 
 
 
The information contained in this document is the property of Invex Therapeutics and 
may not be produced, published or disclosed to others without written authorisation from 
Invex Therapeutics 
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Version: 3.0 
 
Page 2 of 137 
 
CONFIDENTIAL 
Invex Therapeutics 
 
 
 
 
 
 
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Study Number: INVEX-CLIN-IIH-301 
Protocol 
SPONSOR SIGNATURE PAGE 
Sponsor Signatory: 
Doctor Alexandra Sinclair 
MBChB, PhD, FRCP 
Chief Scientific Officer 
Invex Therapeutics Ltd. 
 
 
 
 
CONFIDENTIAL 
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Com 
und No.: Presendin 
Version: 3.0 
Date 
Pege 3of 137 


 
 
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Compound No.: Presendin 
Protocol 
Version: 3.0 
 
Page 4 of 137 
 
CONFIDENTIAL 
SPONSOR INFORMATION PAGE 
Role 
Name and 
Title 
Email Address 
Address 
Non-
Executive 
Chairman 
Dr Jason 
Loveridge 
 
Invex Therapeutics 
Ltd 
 
 
 
Medical 
Monitor 
(CRO) 
Premier 
Research 
Medical 
Monitor 
Premier Research 
3800 Paramount 
Parkway 
Suite 400 
Morrisville 
NC 27560 
USA 
Head of 
Clinical 
Operations 
Carol 
Parish 
 
Invex Therapeutics 
Ltd 
 
 
 
Senior 
Clinical 
Trials 
Manager 
Emma de 
Launay 
 
Invex Therapeutics 
Ltd 
 
 
 
 
Sponsor Contact Information:   
Invex Therapeutics Ltd 
 
 
 
 
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Compound No.: Presendin 
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Version: 3.0 
 
Page 5 of 137 
 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, have read and understood the protocol and am aware of my 
responsibilities as an Investigator. I agree to conduct the study in accordance with this 
protocol, the Trial Reference Manual and any subsequent amendments, the Declaration of 
Helsinki, ICH GCP guidelines, and the laws and regulations of the country in which the 
study is being conducted. 
 
Investigator Name and Qualifications: _____________________________________ 
 
 
 
Investigator Signature 
 
Date 
[Investigator Affiliation] 
 
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CONFIDENTIAL 
INVESTIGATOR INFORMATION PAGE 
Details will be provided in the Investigator Site File  
 
 
 
 
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Compound No.: Presendin 
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Version: 3.0 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS .................................................................................................... 12 
PROTOCOL SUMMARY .......................................................................................... 14 
1. 
INTRODUCTION .............................................................................................. 26 
1.1. 
Background and Rational ............................................................................. 26 
1.1.1. 
Name and Description of the Investigational Product ................... 33 
1.1.2. 
Non-clinical Studies ...................................................................... 34 
1.1.3. 
Clinical Studies ............................................................................. 35 
1.1.4. 
Trial Conduct ................................................................................. 36 
1.2. 
Risk/Benefit Assessment .............................................................................. 36 
2. 
OBJECTIVES .................................................................................................... 37 
2.1. 
Primary Objective ......................................................................................... 37 
2.2. 
Secondary Objectives .................................................................................. 37 
2.3. 
Safety Objective ........................................................................................... 38 
2.4. 
Exploratory Objectives ................................................................................. 38 
3. 
ENDPOINTS ..................................................................................................... 38 
3.1. 
Primary Endpoint .......................................................................................... 38 
3.2. 
Secondary Endpoints ................................................................................... 38 
3.3. 
Safety Endpoints .......................................................................................... 39 
3.4. 
Exploratory Endpoints .................................................................................. 39 
4. 
TRIAL DESIGN ................................................................................................. 40 
4.1. 
Summary of Trial Design .............................................................................. 40 
4.1.1. 
Trial Design ................................................................................... 40 
4.1.2. 
Randomisation and Blinding ......................................................... 42 
4.1.3. 
Duration of Patient Participation ................................................... 42 
4.2. 
Stopping Rules ............................................................................................. 42 
4.2.1. 
Trial Stopping Rules ...................................................................... 42 
4.2.2. 
Individual Stopping Rules ............................................................. 43 
4.3. 
End of Trial ................................................................................................... 43 
5. 
TRIAL POPULATION ........................................................................................ 43 
5.1. 
Number of Patients....................................................................................... 43 
5.2. 
Eligibility Criteria ........................................................................................... 43 
5.2.1. 
Inclusion Criteria ........................................................................... 43 
5.2.2. 
Exclusion Criteria .......................................................................... 44 
6. 
TRIAL ASSESSMENTS AND PROCEDURES ................................................. 47 
6.1. 
Procedures at Each Visit .............................................................................. 47 
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6.1.1. 
Visit 1 Screening ........................................................................... 47 
6.1.2. 
Visit 2 Baseline ............................................................................. 48 
6.1.3. 
Visit 3 Telephone call .................................................................... 50 
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits .............................................. 50 
6.1.5. 
Visit 10 .......................................................................................... 51 
6.1.6. 
Visit 11 Follow-Up ......................................................................... 53 
6.1.7. 
Unscheduled visit for repeat visual assessments ......................... 53 
6.2. 
Trial Procedures ........................................................................................... 54 
6.2.1. 
Screening Procedures .................................................................. 54 
6.2.1.1. 
Demographics ............................................................. 54 
6.2.1.2. 
Medical, Headache and Ophthalmic History ............... 54 
6.2.1.3. 
Reporting of Prior and Concomitant Medication .......... 54 
6.2.2. 
Safety Procedures ........................................................................ 55 
6.2.2.1. 
Physical Examination .................................................. 55 
6.2.2.2. 
Twelve- Lead Electrocardiogram ................................. 55 
6.2.2.3. 
Vital Signs ................................................................... 56 
6.2.2.4. 
Laboratory Assessments ............................................. 56 
6.2.2.4.1. 
Haematology ........................................... 56 
6.2.2.4.2. 
Clinical Chemistry ................................... 57 
6.2.2.4.3. 
Urinalysis................................................. 57 
6.2.2.4.4. 
CSF ......................................................... 58 
6.2.2.4.5. 
Pregnancy ............................................... 58 
6.2.2.4.6. 
Pharmacokinetic sampling ...................... 58 
6.2.2.4.7. 
Anti-drug Antibodies sampling ................ 59 
6.2.2.5. 
Adverse Events ........................................................... 59 
6.3. 
Efficacy Procedures ..................................................................................... 59 
6.3.1. 
Intracranial Pressure ..................................................................... 59 
6.3.2. 
Visual Assessments ...................................................................... 59 
6.3.2.1. 
Frisén grade ................................................................ 59 
6.3.2.2. 
Optical Coherence Tomography ................................. 60 
6.3.2.3. 
Humphrey Visual Field ................................................ 60 
6.3.2.4. 
Visual Acuity ................................................................ 61 
6.3.3. 
Headache Assessments ............................................................... 61 
6.3.3.1. 
Headache Preventative Medication Review ................ 61 
6.3.4. 
Patient Reported Outcomes .......................................................... 61 
6.3.4.1. 
Visual related ............................................................... 61 
6.3.4.2. 
Health-related .............................................................. 61 
6.3.4.3. 
Headache related Quality of Life ................................. 62 
6.3.4.4. 
Patient Global Impression of Change .......................... 62 
6.3.5. 
Body Weight and Body Mass Index .............................................. 62 
7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS ......................................... 63 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS ............................................ 67 
9. 
INVESTIGATIONAL PRODUCT ....................................................................... 67 
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9.1. 
Dosage and Administration .......................................................................... 67 
9.1.1. 
Randomised Period ...................................................................... 67 
9.2. 
Dose Rationale ............................................................................................. 68 
9.3. 
Maintaining the Blind .................................................................................... 68 
9.4. 
Treatment Assignment ................................................................................. 69 
9.5. 
Packaging and Labelling .............................................................................. 69 
9.6. 
Preparation ................................................................................................... 69 
9.7. 
Handling and Storage................................................................................... 69 
9.8. 
Product Accountability and Assessment of Compliance .............................. 69 
9.9. 
Treatment of Investigational Product Overdose ........................................... 70 
9.10. 
Occupational Safety ..................................................................................... 70 
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................... 70 
10.1. 
Recording Prior and Concomitant Medication .............................................. 70 
10.1.1. 
Treatment Failure .......................................................................... 71 
10.1.1.1. Possible treatment failure ............................................ 71 
10.1.1.2. Definite treatment failure ............................................. 71 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive 
Visual Loss .................................................................................... 71 
10.1.2.1. Rescue Therapy for Headache ................................... 71 
10.2. 
Prohibited Medications ................................................................................. 72 
10.2.1. 
Prior to screening and randomisation ........................................... 72 
10.2.2. 
During the trial ............................................................................... 73 
11. PATIENT COMPLETION AND WITHDRAWAL ................................................ 73 
11.1. 
Patient Completion ....................................................................................... 73 
11.2. 
Patient Withdrawal ....................................................................................... 73 
11.2.1. 
Patient Withdrawal from Trial Treatment ...................................... 73 
11.3. 
Treatment after the End of the Trial ............................................................. 74 
11.4. 
Screen and Baseline Failures ...................................................................... 74 
12. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............................. 74 
12.1. 
Adverse Events ............................................................................................ 74 
12.1.1. 
Causal Relationship ...................................................................... 74 
12.1.2. 
Severity Criteria ............................................................................ 75 
12.1.3. 
Reporting Adverse Events ............................................................ 75 
12.2. 
Serious Adverse Events ............................................................................... 76 
12.2.1. 
Suspected Unexpected Serious Adverse Reactions .................... 77 
12.2.2. 
Expected Adverse Events ............................................................. 77 
12.2.3. 
Reporting Serious Adverse Events ............................................... 77 
12.3. 
Reporting and Handling of Pregnancies ....................................................... 78 
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................ 79 
13.1. 
Hypotheses .................................................................................................. 79 
13.2. 
Trial Design Considerations ......................................................................... 79 
13.2.1. 
Sample Size Assumptions ............................................................ 79 
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13.2.1.1. Intracranial Pressure Power ........................................ 79 
13.2.1.1. Perimetric Mean Deviation Power ............................... 80 
13.2.2. 
Stratification .................................................................................. 81 
13.2.3. 
Sample Size Sensitivity ................................................................. 81 
13.2.3.1. Clinically Meaningful Effect Sizes ................................ 81 
13.2.4. 
Trial Stopping Criteria ................................................................... 82 
13.3. 
Data Analysis Considerations ...................................................................... 82 
13.3.1. 
Estimands ..................................................................................... 83 
13.3.1.1. Outcome: Intracranial pressure (ICP) .......................... 83 
13.3.1.1.1. Intercurrent event: ICP-lowering 
medications ............................................. 83 
13.3.1.1.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 83 
13.3.1.1.3. Inter-current event: Dramatic 
weight-loss .............................................. 84 
13.3.1.2. Outcome: Perimetric Mean Deviation (PMD) .............. 84 
13.3.1.2.1. Intercurrent event: ICP-lowering 
medications ............................................. 84 
13.3.1.2.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 84 
13.3.1.2.3. Intercurrent event: Dramatic 
weight-loss .............................................. 85 
13.3.1.3. Outcome: Papilloedema measured by OCT 
(optic nerve head size, retinal nerve fibre layer) ......... 85 
13.3.1.3.1. Intercurrent event: ICP-lowering 
medications ............................................. 85 
13.3.1.3.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 85 
13.3.1.3.3. Intercurrent event: Dramatic 
weight-loss .............................................. 86 
13.3.1.4. Outcome: Monthly headache days (MHD) .................. 86 
13.3.1.4.1. Intercurrent event: Headache-
preventative medications ........................ 86 
13.3.1.4.2. Intercurrent event: Off-protocol 
lumbar punctures .................................... 87 
13.3.1.4.3. Intercurrent event: Dramatic 
weight-loss .............................................. 87 
13.3.1.4.4. Intercurrent event: ICP-lowering 
medications ............................................. 87 
13.3.1.5. Primary Estimand (Hypothetical assuming no 
concurrent procedures, irrespective of 
adherence to treatment) .............................................. 88 
13.3.1.6. Secondary Estimand (Hypothetical) ............................ 88 
13.3.2. 
Analysis Populations ..................................................................... 88 
13.3.3. 
Treatment Comparisons ............................................................... 89 
13.3.4. 
Safety Analyses ............................................................................ 89 
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13.3.4.1. Adverse Events ........................................................... 90 
13.3.4.2. Clinical Laboratory Evaluations ................................... 90 
13.3.4.3. Vital Signs and Body Mass Index Evaluations ............ 90 
13.3.4.4. Electrocardiogram ....................................................... 91 
13.3.4.1. Other Safety Evaluations ............................................. 91 
13.3.5. 
Patient Reported Outcomes Analyses .......................................... 91 
13.3.6. 
Missing Data ................................................................................. 91 
13.3.7. 
Reporting Deviations from the Statistical Plan .............................. 91 
14. TRIAL ADMINISTRATION ................................................................................ 92 
14.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process .......................................................................................... 92 
14.2. 
Trial Monitoring ............................................................................................ 92 
14.2.1. 
Access to Source Data ................................................................. 93 
14.2.2. 
Data Handling and Record Keeping ............................................. 93 
14.3. 
Provision of Trial Results and Information to Investigators and 
Publications .................................................................................................. 94 
14.4. 
Data Management ........................................................................................ 94 
14.5. 
Independent Adjudication Committee .......................................................... 95 
14.6. 
Data Safety Monitoring Committee .............................................................. 95 
14.7. 
Insurance, Indemnity and Finance ............................................................... 95 
15. REFERENCES ................................................................................................. 97 
16. APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-301 ....................... 106 
16.1. 
Appendix 1: IIH Diagnostic criteria [Mollan, 2018] ...................................... 106 
16.2. 
Appendix 2: 36-item short from survey ....................................................... 107 
16.3. 
Appendix 3: EuroQol -5 dimension-5 level survey ..................................... 113 
16.4. 
Appendix 4: Headache Impact Test-6 ........................................................ 116 
16.5. 
Appendix 5: Visual Function Questionnaire-25 & 10-item 
Supplement ................................................................................................ 118 
16.6. 
Appendix 6: Patient Global Impression of Change ..................................... 136 
16.7. 
Appendix 7: Contraception ......................................................................... 137 
 
 
 
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CONFIDENTIAL 
ABBREVIATIONS 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCRF 
Electronic Case Report Form 
BMI 
Body Mass Index 
CGRP 
Calcitonin Gene-Related Peptide 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DGM 
Data-Generating Models 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
GCL 
Ganglion Cell Layer 
GLP-1 
Glucagon Like Peptide-1 
HVF 
Humphrey Visual Field 
ICF 
Informed Consent Form 
ICP 
Intracranial Pressure 
IAC 
Independent Adjudication Committee 
ICH-GCP 
International Council of Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IIH 
Idiopathic Intracranial Hypertension 
ITT 
Intention-to-Treat 
LP 
Lumbar Puncture 
MAR 
Missing At Random 
MD 
Mean Deviation 
MHD 
Monthly Headache Days 
NRS 
Numeric Rating Scale 
OCT 
Optical Coherence Tomography 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QTcF 
QT Interval corrected according to Fridericia’s formula 
RNFL 
Retinal Nerve Fibre Layer 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SF-36 
36-item short form survey 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
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CONFIDENTIAL 
ULN 
VFQ-25-10 item  
Upper Limit of Normal 
Visual Function Questionnaire-25 and 10-item supplement 
 
 
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PROTOCOL SUMMARY 
Rationale 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends.  
IIH has significant associated morbidity and reduced quality of life. Elevated ICP causes 
papilloedema universally at disease onset and can lead to permanent visual loss. Visual 
loss occurs in greater than 90% of those with IIH [Wall 1991] and can be severe and 
permanent in between 5-25%. Besides risk of visual loss, the most disabling aspect for 
patients is severe chronic headaches driven by elevated ICP. Existing pharmacotherapies 
are limited. The most frequently used drug therapy, acetazolamide, is used off label and 
has been shown to have efficacy but due to side effects and treatment failures new drugs 
are needed. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but the failure rates are high and frequent complications and side 
effects occur. 
A modified release formulation of exenatide (Presendin) has been developed and this trial 
has been designed to evaluate the efficacy and safety of Presendin in IIH. The modified 
release formulation has been chosen to enable a once weekly dosing.  
Objectives 
Primary Objective 
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 lumbar 
puncture (LP) at baseline and at 24 weeks. 
The baseline LP is the diagnostic LP. 
Secondary Objectives 
To determine the effect of Presendin on change in: 
• 
Perimetric Mean Deviation (PMD) as measured by the Humphrey Visual Field 
analyser (24-2 SITA (Swedish Interactive Testing Algorithm)-Standard) 
• 
Papilloedema as measured by optical coherence tomography imaging (retinal nerve 
fibre layer (RNFL) thickness and optic nerve head volume measurements)  
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CONFIDENTIAL 
• 
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 
Safety Objectives 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Macular ganglion cell layer/complex thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes (PROs) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation 
Endpoints 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. 
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CONFIDENTIAL 
Secondary Endpoints 
• 
Perimetric Mean Deviation 
• 
Retinal nerve fibre layer 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 and 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.* 
*criteria defined in rescue therapy section 10.1.1 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs) 
• 
Resting 12-lead ECG 
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
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Exploratory Endpoints 
• 
Macular ganglion cell layer/complex thickness 
• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes: 
• 
Visual Function Questionnaire-25 and 10-item supplement (VFQ-25-10 item 
supp) 
• 
Headache Impact Test -6 (HIT-6) 
• 
36-item short from survey (SF-36) 
• 
EuroQol -5 dimension -5 level (EQ-5D-5L) survey  
• 
Patient Global Impression of Change (PGIC) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation  
Trial Design 
 
This is a randomised, placebo-controlled, double-blind, multi-centre trial requiring 
240 adult randomised patients with IIH to determine the efficacy and safety of Presendin. 
Consenting patients with a diagnosis of IIH will enter a 1-week screening period, in 
which there will be no investigational treatment, to gather baseline measurements and to 
check eligibility. Although a headache diary is typically over 28 days, it was felt 
unethical to have patients off treatment for this more prolonged period due to the real risk 
of visual loss. Headache diaries designed to measure headache frequency have 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [Wall, 2014, Markey, 2017 and Mollan, 2021]. Hence the baseline 
headache frequency will be calculated over 1 week as has been done in other trials. 
At the screening visit, patients will be provided with training on the self-administration of 
the trial medication and provided with a leaflet to take home. Patients will be asked to 
self-administer one (1) dose of placebo during the screening visit to ensure they are 
comfortable with self-injection. Patients who are not comfortable with self-administration 
will be deemed a screen failure and will not be randomised into the trial. Eligible patients 
will then be randomised to receive either Presendin or matching placebo for 24 weeks in 
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a 1:1 ratio. After completion of the randomisation period 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 also be performed.  
The duration of the double-blind treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy over a 3-month time 
horizon. Additionally, an alternative off label drug used in IIH (acetazolamide) evaluated 
efficacy over a 6-month period. Hence efficacy is relevant over this time frame. A longer 
period of randomisation would not be ethical if patients were expected to remain on 
placebo for 12 months as this could place their overall health at risk. The duration of the 
trial for each patient will be up to 30 weeks, which includes a 1-week screening period, a 
24-week randomised double-blind treatment period, and a treatment follow-up period of 
5 weeks. 
Trial Population 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.1, Appendix 1), 
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 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  
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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 – see Section 16.7, Appendix 7 for 
further details) 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 
Patients must not be enrolled if they meet any of the following 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 
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Vision related exclusion criteria: 
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] 
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 apnoea­hypopnea 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 [eGFR] <55 mL/min/1.73 m2, calculated at investigator site)  
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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: Hemoglobin <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 DSM-5 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 – see section 10.1.2
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Trial Assessments 
Table 1: Time and Events 
 
 
SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Informed consent  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X  
(review) 
 
 
 
 
 
 
 
 
 
 
Demography (sex, age, 
ethnicity) 
X 
 
 
 
 
 
 
 
 
Medical & Ophthalmic 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Headache history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Headache preventative 
medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Train and dispense 
headache diary 
X 
 
 
 
 
 
 
 
 
 
 
 
Review headache diary1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
 
SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Body weight and BMI 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examination 
(T = targeted) 
X  
(Full) 
X (T) 
 
 
 
X (T) 
 
X (T) 
X(T) 
X (T) 
 
(X) 
Pregnancy Test3 
X 
(Serum) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
OCT Imaging  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
Papilloedema Frisén 
grade4   
X 
X 
 
 
 
 
 
 
 
 
 
 
Perimetry  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visual Acuity Testing 
(LogMAR score) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
 
Patient Reported 
Outcomes 
(HIT-6, SF-36, EQ-5D-5L, 
VFQ-25 & 10-item supp) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Health Utilisation Form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC assessment 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments5  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
29 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
204 
Pharmacokinetic (PK) 
sampling6 
 
X7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-Drug Antibodies 
(ADA) sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Lumbar Puncture8 
 
 
 
 
 
 
 
 
 
X9 
 
 
Trial medication training10 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
Trial medication 
Dispensing  
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Trial medication 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
1 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Patients who do not meet the eligibility criteria based on diary review at 
randomisation/baseline (e.g., too few headache days or unacceptable concomitant medication use) will be considered screen failures; however, if the patient wishes and 
the Investigator is in agreement, he/she can be re-screened as a new patient. If the screening period exceeds 7 days, then eligibility will be based on the last 7 days of the 
screening period, i.e., the 7 days prior to randomisation visit. Trial site research team should review diaries remotely on a weekly basis to ensure compliance and follow 
up any patients with missing data 
2 
Vital signs to include: blood pressure and heart rate 
3 
Women of child-bearing potential. Serum pregnancy test to be conducted at screening, thereafter, highly sensitive urine pregnancy tests will be conducted. Visit 11 urine 
pregnancy test may be conducted at home 
4 
Frisén grade will be evaluated locally and the presence of papilloedema verified by the OCT Reading Centre at screening to confirm eligibility. Indeterminate cases 
should be referred to the IAC (and supplemented with fundus photography and ultrasound scan of the optic nerve) to confirm papilloedema prior to randomisation visit 
5 
Haematology, coagulation, biochemistry and urinalysis 
6 
All actual sampling times and dosing times will be recorded 
7 
Baseline Post-dose PK blood sample 
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8 
The diagnostic LP will be the baseline LP and must be performed in lateral decubitus position. Patients with ICP <25 cm  CSF at diagnosis will be excluded  
9 
Lumbar puncture to be performed after visual assessment. CSF sample from visit 10 LP will be retained for future potential analysis 
10 
Patients will be provided with training on the self-administration of the trial medication. The patient will be asked to self-administer placebo at visit 1 to demonstrate 
ability to self-inject. Patients who are not comfortable to self-inject will be excluded 
11 
If patients discontinue in the randomised double-blind treatment period they will be encouraged to return for all trial visits up to visit 11. If a patient does not want to 
return for all visits then they will be asked to return at a minimum for visit 11 procedures for safety follow up 
12 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial medication and must have self-administered their final dose within 7 days of 
visit 10. Patients will be reminded by the trial site to self-administer trial medication weekly, to continue this until the completion of visit 10 and to bring their trial 
medication with them at visit 10 for return. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial medication has been missed in the previous 4 weeks. Visit 10 should be delayed no 
more than 14 days 
13 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients in whom there is concern about visual decline or who perform inadequately or where 
there is technical failure (more than 15% false positive responses or inadequate performance indicated by the Visual Field Reading Centre for HVF; or OCT imaging not 
of satisfactory quality as determined by the  OCT Reading Centre) 
14 
In the event of any abnormal safety assessments identified at end of treatment, e.g., abnormal ECG, abnormal routine laboratory results or ongoing adverse events, this 
visit may be performed at the clinic to repeat or follow up safety assessments 
15 
Reporting of AEs/SAEs will continue up to the final follow up visit 11 
 
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background and Rational 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends [Mollan, 2019a]. There is a high rate of repeat hospital admission in 
IIH (increased by 446% in last decade), reflected in escalating healthcare costs (in 
England £462 million/year predicted by 2030 [Mollan, 2019a] and more than $444 
million in the USA [Friesner, 2011]). 
The cause of IIH is not fully understood. Recent research suggests that IIH is a disease of 
systemic metabolic dysregulation characterised by central adiposity [Hornby, 2017], 
double the risk of cardiovascular disease in excess to that mediated by obesity [Adderley, 
2019] and dysfunctional adipocyte metabolism primed for weight gain [Westgate, 2021]. 
Patients are also insulin resistant and have a unique hormone signature of androgen 
excess both systemically and in the cerebrospinal fluid.[O’Reilly, 2019] 
Morbidity in IIH is due to the elevated intracranial pressure which can cause severe 
papilloedema (swelling of the optic nerve) which can ultimately lead to blindness. The 
risk of permanent visual loss is a major concern in IIH. Visual loss occurs in greater than 
90% of those with IIH [Wall 1991] and can be severe and permanent in between 5-25%. 
Headache is an additional major disabler and affects the majority of IIH patients (over 
90%) [Yri, 2014; Markey, 2016; Mulla 2015] in the long term. Headaches significantly 
reducing quality of life [Mulla, 2015; Digre, 2015] are driven by raised intracranial 
pressure and often have a migraine- like phenotype (> 90%) [Mollan 2021a].  
Existing pharmacotherapies are limited. The most frequently used drug therapy, 
acetazolamide, is used off label and has been shown to have efficacy but due to side 
effects and treatment failures new drugs are needed. [Piper, 2015; Mollan, 2018; 
Hoffmann, 2018]. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but there is a high failure rate and frequent complications. The 
lack of licenced or targeted treatments in IIH perpetuates poor outcomes for patients. A 
priority setting exercise was run by patients with IIH (James Lind methodology) [Mollan, 
2019c] establishing effective therapy was the top priority from the patient group. 
This trial will investigate an alternative therapeutic option for lowering ICP and thereby 
reducing papilloedema and consequently reducing the risk of visual loss. By reducing 
ICP it would also aim to improve headache, improving overall patient quality of life in 
IIH [Mollan 2021a]. 
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Gut neuropeptides are increasingly being recognised for their role in the central nervous 
system (CNS). A principal gut neuropeptide is glucagon like peptide-1 (GLP-1), which is 
known to stimulate insulin release, proliferation of pancreatic beta cells and control of 
glucose regulation in diabetes [Campbell, 2013]. Exenatide is a GLP-1 receptor agonist. 
It has also been shown to have some actions in the CNS; GLP­1 is involved in regulating 
satiety and weight through signalling at the hypothalamus [Astrup, 2009]. There is also 
evidence that GLP-1 may have a role in fluid secretion. In the renal proximal tubule 
GLP-1 acts to reduce sodium resorption to promote diuresis [Gutzwiller, 2004; 
Websky, 2014]. The choroid plexus is the fluid secreting structure within the brain 
producing the majority of CSF. The structure of the choroid plexus epithelial cells is 
analogous to an inverted renal proximal tubule with a similar mechanism of secretion and 
hence GLP-1 receptor agonists may also reduce CSF secretion in the brain, leading to a 
decrease in ICP in patients with IIH. 
Exenatide as well as other GLP-1 receptor agonists can lead to weight loss. In diabetic 
patients, weight loss of 2.8 - 4.4 kg has been reported over 6 months [Di Dalmazi 2020; 
Pujante 2012]. Whilst in non-diabetic overweight and obese patients exenatide caused 
sufficient weight loss between 2.0 – 5.1 kg [Moreno 2012]. In overweight and obese 
patients with polycystic ovarian syndrome exenatide led to 2kg more weight loss 
compared to placebo in over 12 weeks [Liu 2017]. Weight loss with exenatide therapy is 
increased in the setting of calorie restriction [Rosenstock 2010]. Weight loss is a 
desirable effect of exenatide as weight loss is therapeutic in IIH. Changes in body weight 
will be monitored during the trial and the impact on outcomes measures evaluated. 
Exenatide is the active ingredient in Byetta, an immediate-release (IR) formulation and 
Bydureon, an extended-release (ER) formulation. These have been licenced for use in 
adults with type-2 diabetes since 2005 and 2014, respectively. Therefore, there is a 
wealth of available safety data from both clinical trials and real-world experience. 
Exenatide has been identified as a potential candidate for the treatment of neurological 
conditions involving raised ICP and a polylactic-co-glycolic acid (PLGA) ER exenatide 
formulation under the name Presendin, has been developed by Invex Therapeutics for the 
treatment of IIH.  
Byetta has a known issue of rapid elimination of the product when given to humans, and 
because of this it needs to be administered twice daily to achieve its pharmacological 
effects. The data on file from the IIH Pressure trial has shown that in patients with IIH, 
exenatide administered twice daily was well tolerated and produced a positive effect on 
reducing CSF pressure. However, it is considered that the immediate release formulation 
of exenatide is not ideal for treating patients with IIH on a long-term basis. Presendin has 
been developed as an extended release formulation to allow for a reduction in dosing 
frequency to once weekly and more consistent therapeutic plasma levels. 
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This trial is designed to investigate the efficacy and safety of a modified release 
formulation of exenatide (Presendin) in patients with IIH.  
Intracranial pressure 
IIH is a debilitating condition characterised by raised ICP, which is clinically measured 
by LP [Mollan, 2018]. The units for measurement of LP are cm CSF and cm H2O and 
these should be thought of as interchangeable and reflect the measurement of the height 
of the CSF column at LP. The measurement must be taken in the lateral decubitus 
position. Lumbar puncture is conducted to make a diagnosis of IIH. Lumbar puncture 
may be conducted in a clinical setting during the disease course to both monitor and treat 
the condition. Frequent therapeutic LPs are no longer recommended by the International 
IIH guidelines [Mollan, 2018]. This is because LP can be traumatic for patients and can 
occasionally cause significant complications (meningitis, spinal haematoma, pain) 
[Wright, 2012]. Hence, unnecessary LP’s should be avoided. In some patients LP can 
alter other outcome measures, including measurements of papilloedema and headache 
[Yiangou, 2019]. Hence ideally, LP should be performed after these measures and 
symptoms have been assessed. Lumbar puncture can cause post-dural puncture 
headaches. The risk is 9-36% using a traumatic needle and 3-19% using an atraumatic 
needle [Wright, 2012]. Post-dural puncture headaches typically last less than a week but 
in some patients this can be longer [Yiangou, 2019]. Lumbar puncture pressure 
assessment of ICP reflects disease activity and is a useful and recognised outcome 
measure that has been utilised in other IIH trials [Markey 2020; Mollan 2021b]. 
Due to the invasive nature of LP, non-invasive measures of ICP are valuable. The 
majority of techniques historically evaluated as non-invasive surrogate measures of ICP 
lack sufficient quantification to be used clinically or in clinical trials.  Optical coherence 
tomography (OCT) measures of the optic nerve have been shown to provide a useful 
surrogate measure to quantify changes in ICP [Vijay, 2020]. For example, at 12 months, 
Vijay et al showed that a change in optic nerve head height of 50 µ predicted a 5 cm CSF 
change in ICP [Vijay, 2020]. 
Visual Function 
Perimetry is used to measure visual function in IIH clinical practice. This is assessed 
using a Humphrey Field Analyzer (program 24-2 SITA standard using a size III white 
stimulus) test. Patients are often unaware of their visual field loss until this becomes more 
severe and compromises daily activities. In patients with severe papilloedema optic 
atrophy can develop (measured objectively as loss of the macular ganglion cell layer on 
OCT imaging) and the loss of visual field becomes permanent. Patients at risk of rapidly 
progressive visual loss (also termed fulminant IIH) should receive emergency surgical 
intervention (most commonly a CSF shunt operation) [Mollan, 2018]. Patients requiring 
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emergency surgery will not be recruited into this trial. Medical therapy is used to treat 
those IIH patients not requiring emergency surgical intervention and will be included in 
this trial. But it is expected that approximately 5-10% will go on to need more aggressive 
intervention. 
Measuring visual function with perimetry has a number of challenges in IIH which need 
to be carefully considered. The visual field test is dependent on technician and patient 
performance and can be prone to variability and inaccuracy [Cello, 2016; Wall, 2016]. 
Patients can perform poorly on automated perimetry [Cello, 2016], and there is a learning 
effect [Kutzko, 2000; Wall, 2016]. There are further confounding factors when 
considering interpretation of automated visual field testing in IIH. The high prevalence of 
functional vision loss, presenting as non-organic visual fields results in this disease, may 
bias trial outcomes [Kutzko, 2000; Ney, 2009]. Additionally, impaired executive function 
and attention deficits have been noted in IIH [Sørensen, 1986], and have been shown to 
impair performance of visual field testing in IIH [Grech, 2021]. 
The protocol has been designed with these challenges in mind and visual field testing 
performance will be assessed at trial entry and throughout with opportunity for repeated 
assessment if there is performance failure (a performance failure is defined as a 
substantial worsening of the perimetric mean deviation due to human factors rather than 
visual damage) [Cello, 2016].. The visual fields will be assessed by the Visual Field 
Reading Centre. 
Papilloedema by change in optic nerve head size measured by OCT imaging. 
Papilloedema is a reliable sign of raised ICP [Dunn, 2002]. Change in papilloedema has 
been used by all the randomised control trials in IIH to date to determine clinical 
improvement [Ball, 2011; Wall, 2014; Mollan 2021b]. Change in papilloedema has been 
graded by experts using the Frisén classification, although it is more reliably measured by 
OCT imaging [Ball, 2011; Wall, 2014]. Professional bodies and the literature endorse the 
use of OCT imaging for monitoring papilloedema in IIH [Mollan, 2018]. 
 OCT imaging measures various aspects of the optic nerve. The retinal nerve fibre layer 
(RNFL) and optic nerve head volume  are measurements that both reflect swelling of the 
optic nerve and hence the extent of papilloedema. Measures of macular volume can 
quantify the ganglion cell layer (GCL) thickness which reflects axonal loss. Optic nerve 
head measures on OCT correlate with visual field sensitivity loss [Salgarello, 2001]. 
Analysis has shown that OCT measures of the RNFL significantly reflect changes in 
visual field perimetric mean deviation (MD) (for every 10µm increase in RNFL there was 
associated with a 0.6dB decrease in MD) [Rebolleda, 2009]. Optical coherence 
tomography measures of the macula volume have been shown to predict axonal loss of 
the optic nerve [Albrecht, 2017]. Most importantly, ganglion cell volume has been shown 
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to significantly correlate with the Humphrey visual field MD [Vijay, 2020]. This 
indicates that the GCL can be measured to reflect visual function. In other neurological 
diseases OCT has also been found to measure neuronal loss and correlated with visual 
loss [Petzold, 2010]. In summary, OCT assessment of the optic nerve and GCL represent 
objective measures of papilloedema and optic nerve axons which reflects visual function. 
The scan quality can be compromised if the automated software segmentation of the OCT 
is not accurate. This occurs particularly in those optic nerves with more pronounced 
papilloedema [Aojula, 2018]. Hence the quality and segmentation of all OCT scans will 
be assured by the OCT Reading Centre and scans will be repeated if of insufficient 
quality. 
Headache 
Headache is the predominant presenting feature in IIH [Mollan, 2019a]. Patient morbidity 
is high because of disabling headaches and they have been found to be the key driver for 
poor quality of life [Mulla, 2015; Digre, 2015]. Research into headache treatments were 
endorsed as clinically relevant by a priority setting partnership which included the 
opinions of the patients’ carers and physicians [Mollan, 2019c].  
It has been well documented that headache characteristics in IIH are typically migraine-
like (up to 90%) [Mollan, 2019b; Mollan 2021a]. The headache location can be halo-
cranial, frontal, temporal or parietal with features including nausea, throbbing pain, 
photophobia and phonophobia [Yri, 2015]. A Danish trial of 44 IIH patients noted that 
82% of patients had migraine-like attacks [Yri, 2014]. A prospective trial in 52 IIH 
patients in the UK characterised 80% of headaches as migraine-like [Yiangou, 2019]. As 
reported by the Idiopathic Intracranial Hypertension Treatment Trial, US, the headache 
phenotype was recorded as migraine or probable migraine in 68% of 144 patients with 
active IIH [Friedman, 2017]. A retrospective trial in Iran in 68 IIH patients characterised 
migraine-like headaches in 63% [Sina, 2017]. Other headache characteristics are typically 
tension-type or unclassified [Mollan, 2019b]. 
Hence whilst IIH headaches are not diagnostically the same as migraine according to the 
International Classification of Headache Disorders, 3rd edition Beta, they are very similar 
in character [Olesen, 2018]. The International Headache Society core outcomes for 
migraine are therefore applicable to IIH headaches [Tassorelli, 2018]. 
Headache in active IIH is driven by ICP. This is evidenced by the fact that removal of 
CSF fluid results in improved headache severity. In a prospective cohort study, headache 
severity improved in 71% following a standardised LP [Yiangou, 2019]. Ninety-five 
percent of IIH patients had improvement in headache symptoms at 1 month following 
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shunt placement [Daou, 2020]. Weight loss leading to reduction in ICP also significantly 
reduced headache [Sinclair, 2010].  
Medications that reduce ICP have been shown to modulate headache. In an open label 
trial using topiramate and acetazolamide, both of which are known to modulate ICP 
[Scotton, 2019], relief of headache was reported after a mean treatment period of 3.75 
months in the topiramate group and 3.3 months in the acetazolamide group [Çelebisoy, 
2007]. 
Importantly, headache measures (severity and monthly headache days) in IIH 
significantly correlate with changes in ICP [Mollan 2021a]. The IIH weight trial [Mollan, 
2021b], a randomised controlled parallel group multicentre trial in the United Kingdom, 
investigates weight management methods in IIH. Participants with active IIH (evidenced 
by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. The primary 
outcome was ICP as measured by LP opening pressure at 12 months, with secondary 
outcomes of ICP at 24 months and headache outcomes at 12 and 24 months. Headache 
severity was correlated with ICP at baseline; change in headache severity and monthly 
headache days correlated with change in ICP at 12 months. Importantly those with the 
greatest reduction in ICP over 12 months had the greatest reduction in headache 
frequency and severity. This implies that treatment of ICP should improve headache in 
IIH. 
The following headache outcomes are clinically relevant and are recommended by the 
American Headache Society [American Headache Society] and International Headache 
Society to identify patients who are benefiting from treatments. Headache outcomes are 
derived from a 28-day diagnostic headache diary. This is used in clinical trials to 
prospectively collect daily information on headache occurrence, severity, associated 
symptoms, and use of acute analgesic medications.  
Although a headache diary is typically over 28 days, for IIH headache it was felt 
unethical to have patients off treatment for this more prolonged period during screening 
due to the real risk of visual loss. Headache diaries designed to measure headache 
frequency have successfully utilised over shorter time periods in previous IIH trials and 
noted to be representative [Mollan 2021b]. Hence the baseline headache frequency will 
be calculated over 1 week as has been done in other trials. 
Monthly headache days  
Monthly headache days (MHD) will include all headache days, defined as those with an 
onset, continuation or recurrence, any severity or phenotype of headache and lasting at 
least 30 minutes or which require acute headache analgesia. This is the most relevant and 
objective measure of headache. 
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Moderate to severe monthly 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. This 
outcome captures the more disabling headaches. 
Moderate to severe MHD was recently reported as the primary endpoint in a prospective 
open label study providing evaluation of the effectiveness of erenumab, a calcitonin 
gene-related peptide (CGRP) monoclonal antibody, to treat headaches in IIH patients 
[Yiangou, 2021]. It is also used to measure headache in other secondary headache 
conditions such as persistent post traumatic headache [Aojula 2018; Ashina, 2020]. 
Headache responder rate (≥50% reduction in MHD) 
Headache responder rate (≥50% reduction in MHD) is the proportion of patients 
achieving at least 50% reduction in the mean number of MHD, of any intensity, from 
baseline to the defined trial end point. This criterion is clinically relevant as it is used as 
an empirical review for continuing or discontinuing headache therapy [Diener, 2020]. 
Responder rates can be used in meta-analyses of placebo controlled randomised 
controlled trials. 
Headache responder rate (≥50% reduction in moderate to severe MHD) 
Headache responder rate (≥50% reduction in moderate to severe MHD) is the proportion 
of patients achieving at least 50% reduction in the moderate to severe MHD from 
baseline to the defined trial end point. It is well recognized that 50% responder rates may 
not fully capture the benefits of treatment [Matharu, 2017]. For example, a patient may 
improve from a disabling 20 severe headache days per month to 11 moderate headache 
days per month. Despite this considerable clinical benefit, such a patient would not be 
considered a responder because headache days were not reduced by ≥50%, and as a result 
might lose access to beneficial treatment. Hence, responder rates of ≥30% are also 
important [Vernieri, 2019]. In IIH, a disorder of chronic severe headaches, a clinically 
meaningful treatment responder rate has not been definitively established, although the 
International Headache Society Clinical Trials Subcommittee has suggested the use of a 
≥30% reduction from baseline for chronic migraine.  
Headache severity 
Headache severity is an important measure and impacts quality of life. It is vital to 
consider some treatments which benefit headache may not reduce the MHD but if the 
severity is markedly improved this will lead to great overall functional benefit to the 
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patient and is clinically relevant [Silberstein, 2008]. Recording the decrease in intensity is 
an indicator of reduced disability, which is clinically meaningful. 
Monthly use of acute headache rescue medications 
Use of acute headache analgesics reflects a judgement of the inefficacy of the test 
treatment; hence it is a helpful secondary outcome. In Sinclair et al. reduction in 
analgesic days was significant and associated with clinical remission of IIH [Sinclair, 
2010]. Additionally, a high portion of IIH, up to 48% [Yiangou, 2021] have medication 
overuse and medication overuse headache, and reduction in analgesic days mitigates 
these. Reduction in monthly use of acute headache analgesic is an additional endpoint 
that contributes to clinically meaningful results. 
Quality of life in IIH 
IIH has a detrimental effect on all aspects of the patient’s quality of life; the majority of 
which is driven by headache [Kleinschmidt, 2000, Mulla, 2015; Daniels, 2007; Digre 
2015]. IIH also impacts visual function with PMD correlating with quality of life 
[Bruce 2016]. Patient reported outcomes in clinical trials are essential not only to permit 
health technology assessments and cost effectiveness analysis, but also as key outcomes 
for a therapy’s effectiveness [Deiner, 2019]. There is currently no IIH disease specific 
quality of life outcome measure. 
Whilst there are differences in the choice of the tools used in the trials, they all 
commonly used the short-form 36 health survey (SF-36) [Mollan, 2021, Wall, 2014, 
Digre, 2015; Bruce, 2016; Ball, 2011]. The physical component score of the SF-36 has 
been shown to correlate significantly with changes in ICP [Grech 2021]. The EuroQol –5 
dimension (EQ-5D-5L) [Euroqol, 1990] is typically employed for health technology 
assessments and cost effectiveness [Ottridge, 2017; Ball, 2011]. Using the EQ-5D-5L in 
isolation may lack sensitivity as compared to the SF-36 for IIH. The National Eye 
Institute Visual Function Questionnaire-25 and 10-item supplement [Mangione, 2001] 
has also been utilised to assess visual related quality of life in IIH and is associated with 
improvement in visual field [Bruce 2016; Mangione 1998; Raphael 2006]. The 10-Item 
neuro-ophthalmic supplement was found to be significantly discriminating in a previous 
IIH drug trial [Wall 2014].  
1.1.1. 
Name and Description of the Investigational Product 
Patients will receive active treatment, Presendin, or matching placebo.  
Presendin is a modified release formulation of exenatide. Exenatide is a GLP-1 receptor 
agonist currently used in the management of type 2 diabetes. Presendin consists of a drug 
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part (white or greyish white powder in a clear vial) and a diluent part (colourless liquid in 
a pre-filled syringe). The drug part is suspended in the diluent part solution and 
administered as a suspension. The patient or responsible person will be responsible for 
rehydrating the product for injection. Presendin is administered as a once weekly SC 
sustained-release injection containing 2.0 mg exenatide. Matching placebo will also be 
supplied as 2 parts, as visually identical vial and pre-filled 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. Placebo is administered once weekly as a SC 
injection. 
1.1.2. 
Non-clinical Studies 
Exenatide, the active ingredient of Presendin, has been previously developed and licensed 
as Byetta for the treatment of type 2 diabetes. A wealth of historical toxicological and 
pharmacological safety data is available in the public domain. Please see the 
Investigator’s brochure for data from rat and mouse studies which have investigated the 
Presendin formulation of exenatide. 
In vitro and in vivo data suggests that the choroid plexus, the CSF secreting structure in 
the brain, contains GLP-1 receptors [Ast 2020]. Preclinical studies in rodents demonstrate 
that GLP-1 agonists can regulate cerebrospinal fluid dynamics and reduce ICP [Botfield, 
2017]. 
Nonclinical pharmacology studies have shown that exenatide and GLP-1 agonists bind to 
and stimulate GLP-1 receptors equipotently. Due to the ability of exenatide to affect fluid 
homeostasis in the kidney, it was investigated for its potential to modulate CSF secretion 
and reduce ICP in rats. A single SC injection of exenatide rapidly (within 30 minutes) 
reduced ICP and maintained lower ICP for 6 days of dosing, suggesting that GLP-1 
receptor agonists could provide an alternative treatment for conditions with raised ICP 
[Botfield, 2017]. 
Exenatide was subjected to full toxicological assessments during its nonclinical 
development programme, details of which are publicly available in the Byetta® Product 
Monograph, 2019 and the FDA Pharmacology Review, June 2004 (Section 15). In 
summary, no lethality or serious toxicity was observed in mice, rats and monkeys 
following single doses up to 1500 µg/kg, 3000 µg/kg and 5000 µg/kg respectively. In 
repeat-dose toxicity studies decreased body weight gain and food consumption, a known 
pharmacological effect of exenatide, were observed in all studies. Exenatide caused no 
mortality or target organ toxicities in mice, rats and monkeys at doses up to 760μg/kg/day 
(182 days), 250 μg/kg/day (91 days), or 150 μg/kg/day (273 days) respectively. 
Reproductive toxicity data from animal studies showed that Byetta had a toxicological 
effect on foetal development at three times the human exposure levels in treatment of 
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diabetes. A summary of the findings of the exenatide toxicological assessment 
programme is presented in the Investigator Brochure for Presendin.  
1.1.3. 
Clinical Studies 
Exenatide has undergone extensive healthy volunteer studies and clinical trials for over 
15 years. It is licensed as a formulation for SC injection to be used in conjunction with 
diet and exercise to improve glycaemic control in adults with type 2 diabetes. Details of 
the trials conducted on exenatide, SC injection formulation, are presented in the Byetta 
Product Monograph (Section 15). Data from these studies are notable as the dose of 
exenatide to be used in the indication of IIH is intended to produce exposure levels not 
exceeding those experienced by patients receiving Byetta. It is anticipated that the 
proposed therapeutic dose of exenatide, in the modified release formulation Presendin, 
for treatment of IIH will be within the approved dose range of Byetta, achieving a level 
of total systemic exposure comparable with the immediate release Byetta formulation. 
Therefore, safety data available from the Byetta clinical development program are 
considered relevant and supportive of exenatide development in IIH.  
The efficacy of exenatide (Byetta) was evaluated in a Phase 2 randomised, placebo 
controlled, double-blind trial of exenatide in patients with active IIH (IIH:Pressure Trial). 
Sixteen patients with a diagnosis of active IIH (LP opening pressure >25 cm CSF and 
papilloedema) were identified and recruited to the trial. Participants had a telemetric ICP 
monitor implanted and were randomised to either exenatide (first dose was 2. 0 mcg 
followed by 10 mcg BD sub-cutaneous) or a matched placebo; allocation was 1:1. The 
treatment duration was 12 weeks. The trial was powered to seek significance to at least 
alpha < 0.1 and power at least 80% using equal group sizes. Data was analysed by 
hierarchical regression analysis. 16 participants were recruited, 15 were randomised and 
completed the study. At baseline the mean age was 28 ± 9 years, BMI 38.1 ± 6.2 kg/m2, 
ICP 23.5 ± 3.9 (equivalent to 32.0 ± 5.3 cm CSF). The primary outcome, change in 
intracranial pressure between arms, was significant: at 2.5 hours -4.2 ± 2.1 mmHg 
(equivalent to 5.7 ± 2.9 cm CSF), p=0.04, at 24 hours -4.7 ± 2.1 mmHg (equivalent to 6.4 
± 2.9 cm CSF), p=0.03, and at 12 weeks -4.1 ± 2.2 mmHg (equivalent to 5.6 ± 3.0 cm 
CSF), p=0.05. A significant reduction in monthly headache days was also observed 
amongst those on exenatide (-7.7 ± 9.2, p-0.069). LogMar visual acuity also significantly 
improved in the exenatide treated arm (-0.1 ± 0.05, p=0.036). No significant weight loss 
was observed in either arm and hence weight change is unlikely to have contributed to 
the reduction kin ICP observed. Exenatide was safe and well tolerated: no treatment 
related SAE’s were reported, 8 adverse events were reported in those taking exenatide. 
The most frequent adverse event, amongst those taking exenatide, was nausea (7 reports), 
the majority of these were mild and all reports were self-limiting. There were no patient 
withdrawals due to adverse events.  
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1.1.4. 
Trial Conduct 
This trial will be conducted in accordance with the requirements of this document (the 
Clinical Trial Protocol), the Trial Reference Manual and also in accordance with the 
following as per country specific requirements:  
• 
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013) 
• 
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016) 
• 
The United Kingdom Statutory Instrument 2004 No. 1031 and UKSI 2006 No.1928 
• 
European Union Directives 2001/20/EC and 2005/28/EC 
• 
United States Code of Federal Regulations Title 21 
• 
The Australian Therapeutic Goods Act, 1989, amended December 2020 and 
Therapeutic Goods Regulations, 1990, amended January 2021 
• 
Other country specific laws and regulations 
• 
Any amendments to these regulations  
1.2. 
Risk/Benefit Assessment 
Current treatments for IIH have limited efficacy and can cause disabling side effects. 
Acetazolamide, the most commonly used drug (off licence) has a high side effect profile 
(48% discontinued in a clinical trial due to intolerable side effects) [Ball, 2011]. 
Although IIH is a rare condition, incidence is rising with rising obesity trends. Improving 
IIH morbidity with new therapeutics is clearly an unmet need.  
Safety data for Presendin (exenatide) is based on the IB (Peptron Inc.). Warnings include 
pancreatitis, hypoglycaemia when used in combination with a sulfonylurea, renal 
impairment, severe gastrointestinal disease and hypersensitivity.  
Invex Therapeutics has considered these warnings and has defined eligibility criteria to 
ensure patient safety is paramount. As such patients with known contraindications to 
GLP-1 agonists, such as pancreatitis, ketoacidosis, severe gastrointestinal disease and 
renal impairment, will not be included. Additionally, diabetic patients receiving glucose 
lowering medication will be excluded. 
An Independent Adjudication Committee (IAC), as described in Section 14.5, will assist 
the Investigators (when required) with the eligibility criteria of the patients to be enrolled, 
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and also to determine treatment failures to ensure patient safety and the efficacy of the 
trial. 
The most common adverse reactions experienced with exenatide are nausea, 
hypoglycaemia (only when used with other glucose lowering drugs, but these patients are 
excluded from the trial), vomiting, diarrhoea, feeling jittery, dizziness, headache and 
dyspepsia. 
Patients receiving the active treatment during the randomised period may benefit by 
experiencing an improvement in their IIH symptoms, although this cannot be guaranteed. 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
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. 
2.2. 
Secondary Objectives 
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 
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2.3. 
Safety Objective 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
2.4. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Macular ganglion cell layer/complex thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes 
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
The baseline LP is the diagnostic LP. 
 
3.2. 
Secondary Endpoints 
• 
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. 
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• 
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.* 
*criteria defined in rescue therapy section 10.1.1 
3.3. 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), , serious adverse 
events (SAEs) 
• 
Resting 12-lead electrocardiogram  
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
3.4. 
Exploratory Endpoints 
• 
Macular ganglion cell layer/complex thickness 
• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes (PRO): 
• 
Visual Function Questionnaire-25 and 10-item supplement 
• 
Headache Impact Test-6 
• 
36-item short form survey  
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• 
EuroQol -5 dimension -5 level survey  
• 
Patient Global Impression of Change  
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
4. 
TRIAL DESIGN 
4.1. 
Summary of Trial Design 
4.1.1. 
Trial Design 
This will be a randomised, placebo-controlled, double-blind, multi-centre clinical trial in 
approximately 240 randomised patients with IIH.  
The trial will begin with a 1-week screening period. Although a headache diary is 
typically over 28 days, it was felt unethical to have patients off treatment for this more 
prolonged period. Headache diaries designed to measure headache frequency have been 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [NORDIC, 2018; Mollan, 2021b]. Hence the baseline headache frequency 
will be calculated over 1 week. Patients will be provided with training on the self-
administration of the trial medication from the site trial coordinator and provided with a 
leaflet to take home at the screening visit. Patients will be asked to self-administer 
placebo during the screening visit to ensure they are comfortable with self-injection. 
Patients who are not comfortable with self-administration will be deemed screen failures, 
and not be randomised into the trial. The purpose of the screening period will be to 
establish baseline measurements and assess trial eligibility.  
The 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 SC dose of either Presendin 
(containing 2mg 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 that treatment visit, an end of trial 
safety follow-up telephone visit will be performed. In the event of any abnormal safety 
assessments or ongoing adverse event(s) identified at end of treatment; for example, an 
abnormal ECG or abnormal routine laboratory results, this visit may be performed at the 
clinic and a safety follow-up performed as appropriate.  
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The duration of the randomised treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy by 3 months. 
Additionally, an alternative off label drug used in IIH (acetazolamide) was evaluated over 
a 6-month period. Hence efficacy is relevant over this time frame. A longer period of 
randomisation would not be ethical if patients were expected to remain on placebo for 12 
months as this could place their overall health at risk. 
Assessments will be performed as outlined in Table 1. 
A schematic diagram of the trial can be seen in Figure 1. 
 
 
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Figure 1: Schematic Diagram 
 
 
4.1.2. 
Randomisation and Blinding 
At the end of the Screening period, eligible patients will be randomised to receive either 
Presendin or matching placebo in a 1:1 ratio using a computer system to generate 
randomisation codes. 
Investigators and other site personnel, patients, contract research organisation and 
Sponsor personnel will be blinded regarding the treatment during the randomised period. 
Only designated unblinded staff, not involved in the operational conduct of the trial, will 
be aware of the randomisation codes. 
The placebo will have the same appearance and reveal no differences, during 
administration, to either the Investigator or the patient. 
4.1.3. 
Duration of Patient Participation 
The duration of the trial for each patient will be up to 30 weeks, which includes a 1-week 
screening period, a 24-week randomised treatment period and a treatment follow-up 
period of 5 weeks.  
4.2. 
Stopping Rules 
4.2.1. 
Trial Stopping Rules 
There are no trial-specific stopping rules. The Sponsor maintains the right to stop the trial 
at any point. If this is done, then the Sponsor will provide the Investigators with the 
rationale for such early termination. 
1 week 
screening period 
I 
Treatment 
___ 
__) ~ 
Placebo 
,,__ 
24 weeks random· d-
d 
ts,e 
ouble-blind treatment 
J 
period 
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Eadof 
Treatm•t mit 
----+-
______ __; 5,1/eeks 
Safety follow 
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4.2.2. 
Individual Stopping Rules 
Patients will be withdrawn from the trial medication if they are unable to tolerate the trial 
medication and will continue to attend trial visits as per protocol. See Section 11 for 
further details. A Data Safety Monitoring Committee (DSMC) will be involved in 
decisions for patient safety (Section 14.6). 
4.3. 
End of Trial 
The end of trial is defined as last patient last visit. 
5. 
TRIAL POPULATION 
5.1. 
Number of Patients 
It is anticipated that approximately 350 patients will be required to enter the screening 
phase for 240 patients to be randomised into the treatment phase. 
5.2. 
Eligibility Criteria 
5.2.1. 
Inclusion Criteria 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of new IIH by consensus criteria (see Section 16.1, Appendix 1), 
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’ 
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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 – see Section 16.7, Appendix 7 for 
further details) 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 
5.2.2. 
Exclusion Criteria 
Patients will not be enrolled if they meet any of the following 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), 
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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 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] 
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 apnoea­hypopnea 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  
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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 [eGFR] <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: Hemoglobin <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 DSM-5 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 – see section 10.1.2
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6. 
TRIAL ASSESSMENTS AND PROCEDURES 
6.1. 
Procedures at Each Visit 
Trial procedures and timings are presented in the Time and Events Table, Table 1. 
No procedures should be performed prior to obtaining informed consent. All visits (except 
telephone call visits) should be performed at the clinic. Should a clinic visit not be possible, 
due to a patient self-isolating, the visit will be conducted at the earliest opportunity and 
will not constitute a protocol deviation. 
6.1.1. 
Visit 1 Screening 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Visit 
procedures can be performed in a single visit or over a number of visits during the 
screening period. Ideally all screening procedures should be performed on the same day.  
• 
Obtain patient’s written informed consent 
• 
Eligibility criteria 
• 
Including confirmation that diagnostic LP occurred within the last 4 weeks with 
an opening pressure ≥ 25 cm CSF in lateral decubitus position  
• 
Demographics (sex, age and ethnicity) 
• 
Medical and ophthalmic history 
• 
Concomitant mediation history 
• 
Headache history (including family history of migraine (a first degree relative with 
and migraine) and headache in the 7 days prior to diagnostic LP) 
• 
Headache preventative medication review 
• 
Headache diary dispensed and diary training – to be performed on first day of 
screening. 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Height, body weight and BMI 
• 
Full physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
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• 
Visual Assessments to both eyes 
• 
Frisén grading will be initially assessed by the site and then the presence of 
papilloedema verified by the OCT Reading Centre. Where there is uncertainty, 
fundus photos and or ultrasound scan (B scan) of the optic nerve may be 
conducted for evaluation by the IAC to confirm eligibility. 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site.  
• 
Humphrey Visual Field (24-2 SITA-Standard using a size III white stimulus)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay, and where there is uncertainty about 
eligibility this should be referred to the IAC. 
• 
Visual Acuity (LogMAR score) 
• 
Laboratory assessments 
• 
Trial medication training. Patients will be asked to self-administer 1 dose of placebo 
at the screening visit to ensure they are comfortable with self-injection. Patients who 
are not comfortable will be excluded 
6.1.2. 
Visit 2 Baseline 
• 
Review eligibility criteria 
• 
Concomitant medications review 
• 
Headache preventative medication review 
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• 
Review headache diary (Patient must meet required number of headache days as per 
inclusion criteria. If the headache diary exceeds 7 days, then eligibility will be based 
on the last 7 days of the screening period, i.e., the 7 days prior to randomisation visit) 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI 
• 
Adverse events review 
• 
Targeted physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
• 
Visual Assessments to both eyes 
• 
Frisén grading will be assessed by the site 
• 
Optical coherence tomography imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary 
• 
Health Utilisation Form 
• 
Laboratory assessments 
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• 
Anti-Drug Antibodies (ADA) blood sampling  
• 
Patient randomised  
• 
Trial medication training 
• 
Trial medication dispensed and first dose self-administered at clinic. Patients will 
then be instructed to administer subsequent doses once weekly. 
• 
Pharmacokinetic sampling (post-dose) 
6.1.3. 
Visit 3 Telephone call 
All patients will receive a telephone call at visit 3 to conduct headache preventative 
medication review, check for any AEs or changes in medication, procedures outside of 
protocol, health utilisation, to remind them to complete their diary and to answer any 
questions they may have on administration or storage of the trial medication.  
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI (not visit 4) 
• 
Adverse event review 
• 
Targeted physical examination (visit 6, 8 and 9 only) 
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload processes to the OCT Reading Centre, without delay. 
The OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
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• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary (not visit 4)  
• 
Health Utilisation Form 
• 
Laboratory assessments  
• 
Pharmacokinetic blood sampling  
• 
Anti-Drug Antibodies blood sampling  
• 
Trial medication dispensing (not Visit 4) and accountability - patients should be 
reminded by the trial site to self-administer the trial medication weekly and to return 
used and unused trial medication at clinic visits 
6.1.5. 
Visit 10 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial 
medication and must have self-administered their final dose within 7 days of visit 10. 
Patients will be reminded by the trial site to self-administer trial medication weekly, to 
continue this until the completion of visit 10 and to bring their trial medication with them 
at visit 10 for return.  
Where more than one dose has been missed during the 4 weeks preceding visit 10, visit 
10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial 
medication has been missed in the previous 4 weeks. Visit 10 should be delayed no more 
than 14 days. 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
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• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI  
• 
Adverse event review 
• 
Targeted physical examination  
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Sites should initially check the scan quality. The OCT scan should then go 
through the upload process to the OCT Reading Centre, without delay. The 
OCT scan will then be reviewed by the OCT Reading Centre for a full 
quality assessment. The report from the OCT Reading Centre will be sent to 
the site. Where the OCT is of insufficient quality it should be repeated as 
soon as possible at an unscheduled visit. Where the OCT processing is of 
insufficient quality it should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. The report 
from the Visual Field Reading Centre will be received by the site. Where 
the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
• 
Lumbar puncture (within 7 days of last dose of trial medication) 
• 
Lumbar puncture to be performed ideally after visual assessments 
• 
Performed in the lateral decubitus position according to LP SOP 
• 
In some cases the lumbar puncture might be conducted using imaging guidance 
according to the preference of the individual and site. This could be using x-
rays, computer tomography or ultrasound guidance. 
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• 
If the procedure is not successfully performed it should be re-booked and 
repeated as soon as possible and the patient should remain on trial medication 
with the last dose within 7 days of the LP. 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary  
• 
Health Utilisation Form 
• 
Patient global impression of change question 
• 
Laboratory assessments 
• 
Pharmacokinetic blood sampling 
• 
Anti-drug antibodies blood sampling  
• 
Trial medication accountability 
Where it is not feasible to conduct all of visit 10 procedures on the same day, these could 
be split provided visual assessments are performed before the LP and the patient remains 
on trial medication with the last dose within 7 days of the LP. 
6.1.6. 
Visit 11 Follow-Up  
This visit will be performed as a telephone call to conduct headache preventative 
medication review and check for any AEs or changes in medication. In the event of any 
abnormal safety assessments identified at the end of treatment, e.g., abnormal ECG, 
abnormal routine laboratory results or ongoing adverse events, this visit may be 
performed at the clinic to repeat or follow up safety assessments. 
A urine pregnancy test (for women of childbearing potential) will be performed, this can 
be conducted at home if the visit is performed by telephone call. 
 
6.1.7. 
Unscheduled visit for repeat visual assessments 
Optional unscheduled visit for visual testing (HVF, OCT, LogMAR) for patients where 
there is concern about their visual decline or who perform inadequately or where there is 
technical failure (more than 15% false positive responses or inadequate performance 
indicated by the Visual Field Reading Centre for HVF; or OCT imaging not of 
satisfactory quality as determined by the OCT Reading Centre). Imaging only in the 
study eye(s). 
• 
Optical coherence tomography Imaging  
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 
Sites should initially check the scan quality. The OCT scan should go 
through the upload process to the OCT Reading Centre. The OCT scan will 
then be reviewed by the OCT Reading Centre for a full quality assessment. 
The report from the OCT Reading Centre will be sent to the site. Where the 
OCT is of insufficient quality it should be repeated as soon as possible at an 
unscheduled visit. Where the OCT processing is of insufficient quality it 
should be reprocessed as soon as possible by the site. 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
Sites should initially check the performance quality of the HVF (to ensure 
no more than 15% false positives). The HVF should then be uploaded to the 
Visual Field Reading Centre without delay (an initial quality assessment 
takes place during the upload procedure). The HVF will then be reviewed 
by the Visual Field Reading Centre for a full quality assessment. Quality 
reports from the Visual Field Reading Centre will be received by the site. 
Where the visual field is of insufficient quality it should be repeated at an 
unscheduled visit without delay. 
• 
Visual Acuity (LogMAR score) 
 
6.2. 
Trial Procedures 
6.2.1. 
Screening Procedures 
6.2.1.1. 
Demographics 
The Investigator, or designee, should record the patient’s sex, ethnicity, age, height, body 
weight and BMI at screening. 
Ethnicity data will be collected in order to monitor any response differences in IIH 
disease progression/symptoms in different ethnicities. 
6.2.1.2. 
Medical, Headache and Ophthalmic History 
The Investigator, or designee, should record any ongoing co-morbidities and significant 
medical, headache and ophthalmic history along with the year in which such 
co-morbidities began (where known).  
6.2.1.3. 
Reporting of Prior and Concomitant Medication 
Concomitant treatment is any medication or therapeutic intervention being continued by 
the patient at trial entry and any new medication received during the trial. Prior treatment 
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includes previous medications, treatments and interventions received in the past but no 
longer ongoing. 
For this trial, only relevant prior concomitant medications within the last 4 months will 
be recorded. These include: 
• 
Treatment to lower ICP (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)  
• 
Headache preventative medication (including oral or botulism toxin A or monoclonal 
antibodies against CGRP or CGRP antagonists, or greater occipital nerve block)  
• 
GLP-1 receptor agonist 
• 
Warfarin 
• 
Glucose lowering medication 
• 
Recreational or illicit drugs 
At every visit the Investigator or a qualified designee will ask the patient about relevant 
concomitant medication. 
No new medication should be started during the trial, unless medically necessary. The 
patient should be advised to consult the Investigator or designee before taking any 
prescribed or over-the-counter medications. In the case of headache preventative 
medications or ICP lowering medications please see details in the rescue therapy section. 
Acute headache analgesics are permitted and should be reported in the diary. 
6.2.2. 
Safety Procedures 
6.2.2.1. 
Physical Examination 
A full physical examination will be performed at the screening visit. At a minimum the 
following will be assessed: ear, nose and throat, cardiovascular system, pulmonary 
system, skin, abdomen and neurological system. At all other time points a targeted 
(symptom directed) examination will be performed at the Investigator’s discretion. 
6.2.2.2. 
Twelve- Lead Electrocardiogram  
Twelve lead ECGs should be performed at the times outlined in the Time and Events 
table (Table 1) in a standardized manner, i.e., after the patient has rested in the semi-
supine position for at least 10 minutes. Measurements will be made using an ECG 
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machine that automatically calculates the heart rate and measures PR, RR, QRS, and QT 
intervals.  
All ECG traces will be reviewed and signed by the Investigator or designee and any 
abnormalities will be marked as clinically significant or not clinically significant. 
6.2.2.3. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure and heart rate, will be 
measured at the time points specified in Table 1. 
Patients should rest in a supine position for 10 minutes before the vital signs are assessed. 
Three recordings will be taken and averaged.  
6.2.2.4. 
Laboratory Assessments 
Blood and urine samples will be processed at the site. Routine biochemistry and 
haematology samples will be evaluated at the trial appointed central laboratory. PK, ADA 
and CSF samples will be stored at the central laboratory and evaluated at a qualified 
international laboratory. Details of handling and shipping are described in the Laboratory 
Manual.  
6.2.2.4.1. Haematology 
Blood for the assessment of haematology parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
• 
Total blood count; consisting of: 
• 
Red blood cells  
• 
Haematocrit 
• 
Mean cell volume 
• 
Mean cell haemoglobin 
• 
Mean cell haemoglobin concentration 
• 
Glycated haemoglobin (HbA1C) 
• 
Blood glucose (non-fasting) 
• 
Platelets 
• 
White blood cells 
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• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Coagulation (prothrombin time, international normalised ratio, activated partial 
thromboplastin time, thrombin time, fibrinogen) 
• 
Basophils 
6.2.2.4.2. Clinical Chemistry 
Blood for the assessment of clinical chemistry parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be assessed 
during the trial: 
• 
Sodium  
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Total bilirubin 
• 
Total protein 
• 
Albumin 
• 
Alanine transaminase 
• 
Aspartate aminotransferase 
• 
Alkaline phosphatase 
6.2.2.4.3. Urinalysis 
Urine samples will be collected at the times outlined in the Time and Events table (Table 1). 
The following parameters will be assessed at each time point: 
• 
Glucose 
• 
Ketones 
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•
Specific gravity
•
Blood
•
pH
•
Protein
•
Urobilinogen
6.2.2.4.4. CSF
CSF sample from visit 10 LP will be retained for future potential analysis of disease and 
drug related biomarkers. 
6.2.2.4.5. Pregnancy 
At screening blood will be collected to enable a serum pregnancy test to be performed. At 
visits thereafter, urine will be collected from female patients of childbearing potential at 
the times outlined in the Time and Events table (Table 1) to enable highly sensitive urine-
based pregnancy tests to be performed. Female patients who are identified as being 
pregnant during the trial will be withdrawn from further treatment but will continue to 
attend safety follow-up visits.  
The Investigator or designee should report any pregnancies in female patients to the 
Sponsor or designee, using the Pregnancy Report Form, within 24 hours. The contact 
details for reporting are: 
 
Female patients or partners of patients who become pregnant should be followed until 
delivery, stillbirth or termination. The outcome of the pregnancy and, if applicable, the 
health of the baby, should be reported to the Sponsor using the Pregnancy Report Form. 
6.2.2.4.6. Pharmacokinetic sampling 
Pharmacokinetic sampling is to characterize the pharmacokinetics of exenatide after once 
weekly subcutaneous administration of Presendin at the times outlined in the Time and 
Events table (Table 1). 
The primary purpose of the pharmacokinetic sampling is to characterize the steady state 
concentrations of exenatide. All actual sampling times and dosing times will be recorded. 
Sampling and processing will be performed as described in the Laboratory Manual. 
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6.2.2.4.7. Anti-drug Antibodies sampling 
Anti-drug antibodies sampling will be performed in all subjects at the times outlined in 
the Time and Events table (Table 1). 
Sampling and processing will be performed as described in the Laboratory Manual. 
6.2.2.5. 
Adverse Events 
Patients will be asked non-leading questions to assess how they are feeling at each clinic 
visit. Adverse events will be assessed and reported as outlined in Section 12. 
6.3. 
Efficacy Procedures 
6.3.1. 
Intracranial Pressure 
Assessment of ICP will be measured by LP in the lateral decubitus position. The 
diagnostic LP is performed by the clinical team prior to recruitment and the measurement 
must be made from the lateral decubitus position. The research LP will be performed 
according to LP standard operating procedure (SOP). Lumbar puncture will ideally be 
performed after visual assessments as outlined in the Time and Events table (Table 1).  
In some cases the lumbar puncture might be conducted using imaging guidance according 
to the preference of the individual and site. This could be using x-rays, computer 
tomography or ultrasound guidance. 
Any additional LP procedures, outside of the protocol would constitute a protocol 
deviation and ideally should be discussed with the Investigator before the procedure is 
performed.  
Non-protocol LPs should be recorded in the Case Report Form. 
6.3.2. 
Visual Assessments 
Visual assessments should be performed on both eyes. All visual assessments should be 
uploaded without delay on the day of the visit to the OCT and Visual Field Reading 
Centres. In all cases the site is responsible for initial checks of the clinical data in the 
wider context of the patient’s disease, as well as a data quality check. 
6.3.2.1. 
Frisén grade  
At Screening (visit 1) Frisén grading (0 – 5) should initially be performed at the site 
through a dilated pupil. The presence of papilloedema  will be verified  by the OCT 
Reading Centre at screening (visit 1) and a report sent to the site.  During screening, 
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where there is uncertainty regarding the presence of papilloedema and / or Frisén grade a 
fundus photo and or ultrasound scan (B scan) of the optic nerve may be conducted (or 
may be requested by the OCT Reading Centre) and if uncertainty persists evaluated by 
the IAC. 
At Baseline (visit 2) sites will reconfirm the Frisén grade 
6.3.2.2. 
Optical Coherence Tomography 
Imaging may be acquired using Heidelberg Engineering or Cirrus platforms according to 
the OCT SOP. Key measures are RNFL, optic nerve head size, and macular ganglion cell 
layer/complex thickness.. 
• 
Sites should initially check the clinical interpretation of the OCT scan and scan 
quality. The OCT should then go through the upload processes to the OCT Reading 
Centre. The OCT will then be reviewed by the OCT Reading Centre for a full quality 
assessment. The report from the OCT Reading Centre will then be sent to the site. 
Where the OCT is of insufficient quality, it should be repeated as soon as possible. 
Where the OCT has not been processed correctly at the site the processing should be 
re-performed as soon as possible thereafter. Repeated or reprocessed images would 
then be again transmitted to the OCT Reading Centre for a full assessment. 
• 
If the site is concerned with the OCT findings, suggesting that the patient is a 
potential treatment failure and may require rescue therapy, the OCT Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
6.3.2.3. 
Humphrey Visual Field 
The visual field will be measured by Humphrey Visual Field analysis (24-2 SITA-
Standard) including standardised refraction as indicated, according to the Visual Field 
Centre SOP (Manual of Procedures).  
• 
At screening HVF will be reviewed by the Visual Field Reading Centre to confirm 
eligibility. 
• 
Inability to perform a reliable visual field examination as deemed by the Visual Field 
Reading Centre in study eyes (including >15% false positives), is an exclusion 
criterion. HVF can be repeated to obtain as assessment with reliable performance. 
• 
If the site is concerned with the HVF findings, suggesting that the patient is a 
treatment failure and may require rescue therapy, the Visual Field Reading Centre 
review will be prioritised and when indicated expedited to the IAC.  
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6.3.2.4. 
Visual Acuity  
Assessment of visual acuity will be recorded using a LogMAR chart (unaided, best 
corrected, and with pin hole). 
6.3.3. 
Headache Assessments 
Patients will be provided with an electronic/paper diary at screening to complete during 
the trial. Information collected will be used to assess the following headache parameters: 
• 
Monthly headache days 
• 
Monthly moderate to severe headache days 
• 
Responder rate 
• 
Monthly acute analgesic use 
• 
Headache severity (11-point NRS) 
 
6.3.3.1. 
Headache Preventative Medication Review 
A review of any headache preventative medications taken by the patient will be 
undertaken at each clinic visit. If the Investigator alters the headache preventative 
medication, this will be considered rescue medication (Section 10.1.1) and the IAC 
consulted. Use of headache preventative medication will be recorded at trial visits as 
outlined in the Time and Events table (Table 1). 
Patients will record their acute headache analgesic use in their trial diary. 
6.3.4. 
Patient Reported Outcomes 
6.3.4.1. 
Visual related 
Assessment of visual related quality of life will be derived from self-reported responses 
to the VFQ-25-10 item supp (see Section 16.5 Appendix 5). 
6.3.4.2. 
Health-related 
Assessment of health-related quality of life will be derived from self-reported responses 
using the following questionnaires: 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
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A Healthcare Utilisation Form will be completed by the trial site staff at clinic visits. 
All questionnaires can be found in Section 16, Appendix 2 for SF-36 and Appendix 3 for 
the EuroQoL- 5D-5L survey. 
6.3.4.3. 
Headache related Quality of Life 
Assessment of headache-related quality of life will be derived from self-reported 
responses to the Headache Impact Test-6 questionnaire and performed at time points as 
outlined in the Time and Events table (Table 1). A copy of this questionnaire can be 
found in Section 16.4, Appendix 4. 
6.3.4.4. 
Patient Global Impression of Change  
The Patient Global Impression of Change will be conducted at visit 10, as outlined in the 
Time and Events table (Table 1).  
It is a single item questionnaire using a seven-point verbal response scale to assess 
overall change in the patient’s status since taking trial medication. A copy of this 
questionnaire can be found in Section 16.6, Appendix 6 
6.3.5. 
Body Weight and Body Mass Index 
The patient’s body weight and BMI will be measured at the time points as outlined in the 
Time and Events table (Table 1).  
The patient’s height will be measured at Screening (shoes off).  
 
 
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7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS 
The COVID-19 global pandemic presents numerous challenges to the conduct of ongoing 
clinical trials. In line with the FDA and European Medicines Agency's Guidance on the 
Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic 
(EMA, 2021), the following protocol considerations are provided to ensure patients 
safety is maintained and adequate benefit/risk analyses are applied relative to the 
completion of study procedures and maintaining the investigational product supply chain.  
Other unforeseen global crises may occur during the conduct of the study, similar to the 
COVID-19 global pandemic, in which case the following protocol considerations may 
also be applied. 
Recognizing the flexibility required to manage the impact of the pandemic (or other 
global crisis) on this clinical study, additional details will be added to respective study 
manuals, project plan documents, and communicated to the investigative sites as needed.  
For any additional questions, the investigator should confer with the sponsor. 
Number of Trial Patients 
The evolving situation of the pandemic (or other global crisis) may result in a substantial 
number of patients’ early withdrawal from the study, which could affect the data integrity 
of the study.  Because of this risk, the sponsor may decide to recruit additional patients in 
the study, beyond the expected number, to mitigate such risk. 
Study Visits 
There are a number of on-site visits that would be required to ensure study validity.  If 
there are local travel restrictions, isolation requirements, or the investigator determines it 
to be unsafe for patients to attend their scheduled study visits, the site staff may conduct 
certain visits via telemedicine (phone or video calls) to minimize patient risk as follows. 
Screening Period 
The following visit must be performed in person: 
• Screening/Visit 1 
Note:  To minimize direct, in-person contact between site personnel and patients, 
certain screening procedures may be performed remotely via telemedicine.  All 
other procedures should be done in-person while the subject is on-site.  
Specifically, the following procedures may be done remotely: 
o Informed consent (where applicable, per approved IRB/IEC process) 
o Demography 
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o Medical and ophthalmic history 
o Concomitant medication history 
o Headache history 
o Headache preventative medication review 
o Train and dispense headache diary 
o Trial medication training 
Randomised period 
• Baseline (Visit 2) 
There are essential aspects to the baseline visit which must be performed in 
person. 
If the baseline visit is delayed the headache diary should utilise the preceding 7 
days data. Where the visit is delayed by more than 10 days due to a global crisis 
the patient will be considered to have failed screening.  Patients who screen failed 
due to the pandemic (or other global crisis) may be rescreened at a later time, if 
feasible. 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 4, 5, 6, 7, and 8 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
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o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 10 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
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o Lumbar puncture* 
 
* Lumbar puncture to be ideally performed after visual assessments. In the 4 weeks prior 
to visit 10, patients must not have missed more than one dose of trial medication and 
must have self-administered their final dose within 7 days of visit 10. Patients will be 
reminded by the trial site to self-administer trial medication weekly, to continue this until 
the completion of visit 10 and to bring their trial medication with them at visit 10 for 
return.  
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days, if 
possible, but this can be extended according to local government policy if a patient is 
unable to attend (for example if a patient is self-isolating) as long as medication use is 
maintained as above. 
 
• Follow up/ Visit 11 
This should be performed as a telephone visit unless clinical contact is necessary, as 
per protocol. Where face to face contact is required, this should be conducted at the 
earliest available opportunity.  
 
Study Drug Dispensation and Distribution 
If a patient is not able to attend a clinic visit, to ensure the continuity of providing 
patients’ study drug within the constraints imposed by the pandemic (or other global 
crisis), the site staff may decide to supply study drug to patient as follows: 
o Adequate supplies of study drug can be shipped to the patient by the study staff 
using a third-party service with approval from the patient.  The third-party vendor 
will be agreed upon with the sponsor. 
o The patient may request, with prior arrangement/agreement with the site, an 
authorized individual (a relative or delegate) to retrieve the study drug from the 
study site if the patient is unable to personally to do so. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed; however, the site monitor will continue to 
employ off-site monitoring practices such as routine communication methods (e.g., phone 
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calls, emails, video visits) with the sites to get information on study progress, patient 
status, and information on issue resolution as detailed in the Data Monitoring Guidelines, 
Remote source data verification. 
If the trial site monitor cannot be on-site to carry out the final drug accountability for 
reconciliation purposes, and the operation cannot be postponed, it may be carried out by a 
pharmacist from the site pharmacy or by the study coordinator/data manager with suitable 
training. The study drug can be returned to the sponsor by the site pharmacy directly, or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 
Direct Contracts with Third Parties/Specialized Service Companies 
If necessary, direct contracts can be established with third-party local physicians to 
conduct activities related to the clinical management of patient for whom the investigator 
is responsible and maintains oversight.  In such situations, the investigator is required to 
provide the local physician with a delegation letter listing all delegated activities.  The 
sponsor, through the study investigator or institution, will reimburse the local physician 
for the test/procedures conducted outside of the standard of care. 
Clinic visits should take place to the extent possible and usual protocol requirements 
adopted for all subjects as soon as the crisis-related limitations permit. 
All safety data that are possible to obtain locally should be collected at a remote visit. 
These measurements may include the use of local practitioners and resources. 
Exceptional measures taken in response to a crisis (e.g., COVID-19) and their impact on 
study results, such as tests done in a local laboratory, will be explained, assessed and 
reported in the clinical study report following ICH E3 guidance. 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS 
Patients will receive lifestyle advice as per routine care from their treating physician. 
9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Dosage and Administration 
9.1.1. 
Randomised Period 
During the 24-week randomised treatment period (Figure 1) patients will be randomised 
in a 1:1 ratio to receive active treatment or placebo. 
Either 
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Presendin (2.0mg exenatide) as a SC injection, self-administered once weekly. 
Presendin is supplied as 2 parts, one vial consisting of a drug part (white or grayish 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 as a 
suspension.  
or 
Placebo as a SC injection, self-administered once weekly. 
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 as a suspension. 
 
9.2. 
Dose Rationale 
The proposed 2mg weekly dose was based on the pharmacokinetic performance of the 
Peptron formulation (PT320). Pharmacokinetic profiles obtained after repeated once 
weekly dosing of 2mg of PT320 s.c. (as specified in the Presendin IB phase 2 clinical 
study in patients with type 2 diabetes) were comparable to those predicted by the 
population PK model developed for weekly s.c. administration of the recommended dose 
of the 2mg Bydureon extended-release formulation [Cirincione 2017],with time to reach 
the steady state slightly shorter for PT320 than for Bydureon (7-8 weeks vs 8-10 weeks) 
and with steady state plasma concentrations remaining within a comparable range for 
both products. Based on the same molecule and dose, comparable plasma concentrations 
for PT320 and Bydureon and the established safety profile of Bydureon a similarly 
acceptable safety and tolerability profile for PT320 is expected. 
9.3. 
Maintaining the Blind 
This is a double-blind trial.  
A computer/website system will be used to maintain the blind for this trial. The site will 
be provided with website login details for the system. If the Investigator needs to unblind 
a patient’s treatment, due to a medical emergency, the website should be accessed to 
unblind for that patient. . 
The responsibility to break the treatment code in emergency situations resides solely with 
the investigator. 
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9.4. 
Treatment Assignment 
Patients will be randomised in a ratio of 1:1 to receive active treatment (Presendin) or 
placebo. A computer/website system will be used to randomly assign each patient to a 
treatment arm.  
9.5. 
Packaging and Labelling 
Individual supplies of trial medication will be provided to the sites in a double-blind 
format. The labels will contain all information required to meet the applicable local 
regulatory requirements. 
Further information on packaging, labelling and dispensing are included in the Pharmacy 
Manual. 
9.6. 
Preparation 
Each dose of trial medication is provided as two parts, a single use vial and a pre-filled 
syringe of diluent. Patients will receive training and be provided with an instruction sheet 
with details, on how to store, prepare, self-administer and discard/keep used trial 
medication.  
9.7. 
Handling and Storage 
Presendin, the active trial medication, contains the active ingredient, exenatide, which is 
hygroscopic and light sensitive and must be protected from light during storage. Prior to 
use, all trial medication should be stored refrigerated at 2-8ºC.  
9.8. 
Product Accountability and Assessment of Compliance 
In accordance with International Council of Harmonisation – Good Clinical Practice 
(ICH-GCP), each trial centre will account for all supplies of trial medication. Details of 
receipt, storage, assembly, and return will be recorded. The unit of accountability will be 
one single active or placebo vial. Needles will be disposed of in a sharps box. 
All unused supplies will either be destroyed or returned to the trial Sponsor at the end of 
the trial in accordance with instruction by the Sponsor. 
All trial medication will be self-administered by the patients. If a dose is not administered 
as planned, patients will record the missed dose in their electronic/paper diaries and it 
will be documented in the electronic case report form (eCRF). 
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9.9. 
Treatment of Investigational Product Overdose 
Definition of Overdose: More than 1 (one) dose in 24 hours. 
In the event a patient overdoses on trial medication the Investigator should be notified as 
soon as possible. If symptoms appear, the Investigator will treat the patient according to 
their clinical judgement depending on the type of clinical signs and symptoms exhibited 
by the patient. The Sponsor should be notified in writing within 24 hours of the 
Investigator becoming aware. 
Effects of overdose that may be seen include severe nausea, severe vomiting and rapidly 
declining blood glucose concentrations. 
9.10. 
Occupational Safety 
There are no known occupational safety risks to staff. The Material Safety Data Sheet 
will be made available where required by local regulations. 
10. 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
10.1. 
Recording Prior and Concomitant Medication 
All relevant medication taken within 4 months of screening should be recorded in the 
eCRF along with all relevant medication taken from the start of the screening period until 
the final follow-up visit (Section 6.2.1.3). 
At a minimum the following information will be collected: 
• 
Generic name 
• 
Dose 
• 
Frequency 
• 
Date started 
• 
If ongoing (or if not, then the date stopped will be recorded) 
• 
Reason for taking the medication  
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10.1.1. 
Treatment Failure 
Rescue therapy can be initiated when there is a treatment failure. Since perimetric 
variability increases with increasing visual field damage, a two-tiered approach is used 
[Wall, 2013].  
10.1.1.1. 
Possible treatment failure  
Possible treatment failure is defined as those with baseline PMD between -2 and -3.5dB 
who experience a decline of > or equal to 2dB. In those with a baseline PMD between -
3.5 and -7 dB, those who experience a decline of  > or equal to 3 dB.  
When a possible treatment failure is identified, perimetry, and if needed, other visual 
tests, should be repeated at an unscheduled visit. 
 
10.1.1.2. 
Definite treatment failure  
A definite treatment failure occurs when a patient with baseline PMD between -2 and -
3.5dB experiences a decline of  > or equal to 2dB which remains after repeat perimetry. 
Or in those with a baseline PMD between -3.5 and -7 dB who experience a decline of > 
or equal to 3 dB which remains after repeat perimetry.  
These cases should be reviewed without delayby the IAC (who will review all visual and 
clinical data) to confirm or refute a definite treatment failure. 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive Visual Loss 
When a treatment failure occurs, rescue therapy can be initiated, in addition to study 
treatment, based on the medical judgement of the Investigator. Decisions should always 
be discussed with the IAC without delay and if possible before any action is taken, unless 
in the opinion of the Investigator there is no time to do so as it is judged to be a medical 
emergency. In all cases the final decision lies with the Investigator. 
Patients showing progressive visual loss will be considered for rescue therapy with 
acetazolamide or an alternative diuretic. In cases where the visual loss is severe and 
“rapid”, and believed by the Investigator to necessitate surgical intervention, the 
intervention will be conducted in accordance with local emergency practice. 
10.1.2.1. Rescue Therapy for Headache 
If the Investigator wishes to alter the headache preventative medication (any drug can be 
considered), this decision should always be discussed with the IAC before any action is 
taken, unless in the opinion of the Investigator there is no time to do so as it is judged to 
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be a medical emergency. Use of headache preventative medication will be recorded at 
trial visits. 
Use of acute headache analgesics is not considered as rescue medication and is permitted 
but must be documented in the headache diary (monthly analgesic use). 
10.2. 
Prohibited Medications 
10.2.1. 
Prior to screening and randomisation  
• 
Treatment to lower ICP within 1 week prior to screening (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).  
• 
Exposure to fluoroquinolones, lithium, vitamin A, or tetracyclines within 2 months 
of diagnostic LP 
• 
Glucagon like peptide-1 receptor agonist within last 4 weeks prior to screening 
• 
Warfarin 
• 
Glucose-lowering medicationCOVID-19 vaccine within 2 weeks prior to screening  
• 
Recreational or illicit drugs during screening period 
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 – see section 10.1.2.
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10.2.2. 
During the trial 
• 
Treatment to lower ICP (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). These will all be considered rescue medication (Section 10.1.2) and the 
IAC consulted. Use will be considered a protocol deviation. 
• 
If the Investigator alters the headache preventative medication (including oral or 
botulism toxin A or monoclonal antibodies against CGRP or CGRP antagonists, or 
greater occipital nerve block) this will be considered headache rescue medication 
(Section 10.1.2) and the IAC consulted.  
• 
Glucagon like peptide-1 receptor agonists 
• 
Recreational or illicit drugs  
• 
Warfarin 
• 
Glucose-lowering medication 
• 
Regarding COVID-19 vaccination, the risks of receiving or not receiving the 
vaccination have been considered in relation to the IMP and no additional risks are 
envisaged. Hence patients may choose to have or not have COVID-19 vaccination or 
booster during this trial. 
The investigator should follow the cautions and guidance on the management of other 
concomitant medication or DDIs as detailed in section 9.2.5.2 (Drug-Drug Interactions) 
of the IB. 
 
11. 
PATIENT COMPLETION AND WITHDRAWAL 
11.1. 
Patient Completion 
Patients will be classed as having completed the trial once they have completed all 
required trial visits. See Section 11.2.1 for early discontinuations. 
11.2. 
Patient Withdrawal 
11.2.1. 
Patient Withdrawal from Trial Treatment 
A patient will be withdrawn from treatment for any of the following reasons: 
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• 
Withdrawal of consent to continue in the trial. The reason for this will be 
documented if provided 
• 
The Investigator or Sponsor, for any reason, decides the patient should be withdrawn 
from the treatment 
• 
Lack of compliance with the trial medication is classified as <75% or >125% of 
scheduled doses over the course of the trial, excluding supply issues 
• 
Adverse events, which cannot be tolerated by the patient 
• 
Pregnancy during the treatment period 
Patients will be encouraged to continue in the trial to the end of the randomised treatment 
period even if they stop trial medication so that data can be collected for the Intention-
To-Treat (ITT) population.  
If a patient is withdrawn from treatment during the randomised treatment period, they 
will be encouraged to return for all trial visits up to visit 10. If a patient does not want to 
return then at a minimum they should be encouraged to attend for visit 11 procedures as a 
safety follow-up visit.  
11.3. 
Treatment after the End of the Trial 
Patients will not be provided with trial medication following the end of the trial. 
11.4. 
Screen and Baseline Failures 
Information will be collected on all patients who sign the Informed Consent Form (ICF). 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
12.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
12.1.1. 
Causal Relationship 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs. To promote consistency, the following guidelines should be taken into consideration 
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along with good clinical and scientific judgment when determining the relationship of drug 
treatments to an AE: 
• 
Probable relationship: event occurs in a plausible time relationship to the medication 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals; the response to the withdrawal of the drug should be clinically plausible 
• 
Possible relationship: event occurs with a reasonable time sequence to the medication 
administration, but could also be explained by concurrent disease or other drugs or 
chemicals; information on the drug withdrawal may be lacking or unclear 
• 
Unlikely relationship: event occurs with little temporal relationship to the medication 
administration and other factors such as drugs, chemicals or underlying disease 
provide plausible explanations 
• 
Not related: event has no temporal relationship to the medication administration or 
there is a definite alternative aetiology 
12.1.2. 
Severity Criteria 
An assessment of severity grade will be made using the following categorical descriptors: 
• 
Grade 1 means a relatively minor side effect 
• 
Grade 2 means a moderate side-effect  
• 
Grade 3 means a severe or medically significant but not immediately life-threatening 
side-effect  
• 
Grade 4 means life-threatening consequences 
• 
Grade 5 death related to AE 
The exact definition of each number in the scale depends on the particular side effect 
according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
[CTCAE].  
The Investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the patient (e.g., laboratory abnormalities). 
Adverse events occurring as a result of LP should be specifically recorded. Occurrence of 
post lumbar headache will be specifically reported. 
12.1.3. 
Reporting Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated informed consent form is obtained until completion of 
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the patient's final safety follow-up visit. The Sponsor will evaluate any safety information 
that is spontaneously reported by an Investigator beyond the time frame specified in the 
protocol. Adverse events reported after dosing will be classed as treatment emergent AEs. 
All AEs, regardless of seriousness, severity, or presumed relationship to trial therapy, must 
be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common 
aetiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the source 
documents and the eCRF their opinion concerning the relationship of the AE to trial 
therapy. All measures required for AE management must be recorded in the source 
document and reported according to Sponsor instructions. 
The patient must be provided, on the first day of trial medication (Day 1), with a "patient 
card" indicating the following: 
• Patient number 
• Name of the investigational product 
• Investigator's name and 24-hour contact information 
• Statement that the patient is participating in a clinical trial 
12.2. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
Medical and scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not reach the 
above definition but may jeopardise the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive or malignant 
cancers, intensive treatment in an accident and emergency department or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse. 
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Deterioration of IIH necessitating CSF shunting or optic nerve sheath fenestration or 
dural venous sinus stenting will be recorded as an SAE and reported. 
Deterioration of IIH necessitating hospital admission will be recorded as an SAE and 
reported. 
Pre-defined exclusions: 
•
Hospitalisation for unrelated elective procedures
•
Post LP headache
12.2.1. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to be 
related to the trial medication and are both unexpected (i.e., the nature or severity is not 
expected from the information provided in the Investigator Brochure) and serious. 
12.2.2. 
Expected Adverse Events 
Perceived deterioration of IIH necessitating attendance or admission to hospital will not 
be reported as an SAE, but these events will be reported and recorded at follow-up. Non-
protocol LPs will be reported at follow-up. 
12.2.3. 
Reporting Serious Adverse Events 
All SAEs occurring during clinical studies must be reported to the appropriate Sponsor 
designee (contract research organisation) within 24 hours of their knowledge of the event. 
SAEs will be reported from the time a signed and dated informed consent form is obtained 
until completion of the patient's final safety follow-up visit.  
Information regarding SAEs will be transmitted to the Sponsor’s safety contact using the 
SAE Form, which must be completed and signed by the Investigator, and transmitted to 
the Sponsor’s safety contact within 24 hours.  
The contact details are: 
 
The Sponsor assumes responsibility for appropriate reporting of SAEs or SUSARs to the 
regulatory authorities. The Investigator (or Sponsor where required) must report these 
events to the appropriate Independent Ethics Committee (IEC) that approved the protocol 
unless otherwise required and documented by the IEC. 
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An annual safety report will be submitted to the Institutional Review Board once a year via 
the Investigator. 
12.3. 
Reporting and Handling of Pregnancies 
Pregnant patients will be withdrawn from the trial. 
Female patients will be instructed to notify the Investigator immediately if they become 
pregnant during the trial and up to 12 weeks after discontinuation/completion of trial 
medication. Pregnant patients will be withdrawn from further trial treatment. The patients 
will also be instructed to report pregnancies discovered after the last visit, if they believe 
that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the trial medication 
has interfered with the efficiency of any contraceptive measures. The Investigator should 
report all pregnancies to the Sponsor contact or designee within 24 hours of being 
informed of them. The pregnancy report form should be used instead of the SAE form. 
The pregnant patients will be followed until the end of the pregnancy. Any complication 
during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, 
stillbirth, birth defect/congenital anomaly, death, or other serious infant condition must be 
reported and followed up as an SAE. 
Patients will give consent on enrolment that the Investigator will report any pregnancy to 
the Sponsor and that further information will be collected until delivery. 
 
 
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13. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will be finalised prior to database lock providing 
detailed methods for the analyses outlined below. 
13.1. 
Hypotheses 
This trial compares outcomes in IIH patients under Presendin and matched placebo. The 
primary hypothesis that will be tested is: 
• 
The ICP measurement in the Presendin group is equal to the ICP measurement in the 
placebo group at Week 24; against the alternative that the outcomes differ 
13.2. 
Trial Design Considerations 
13.2.1. 
Sample Size Assumptions 
The target sample size for the trial is 240 randomised patients, i.e., 120 patients per arm. 
We justify this figure in the following sections. The two outcomes for which we sought to 
power the study are ICP and PMD.  
13.2.1.1. Intracranial Pressure Power 
The most difficult parameters to specify for a sample size calculation pertain to the 
variability of outcomes. We present a brief summary of the literature. Baseline standard 
deviations (SD) of ICP in previous trials were: 5.4 (n=10) and 6.3 (n=17) in the Drug 
Trial [Markey, 2017]; 5.0 (n=16) (data on file); and 5.7 (n=32) and 5.3 (n=30) in the 
Weight Trial [Ottridge, 2017]. Post-baseline standard deviations were slightly lower (and 
less than 6.0) in three of these five arms; and increased slightly in one (but remained less 
than 6.0). The post-baseline standard deviation however increased to over 8.0 in the 
surgery arm of the Weight Trial because the surgical intervention dramatically impacted 
ICP in some patients.  In the NORDIC trial [Wall, 2014] however, the standard deviation 
of baseline ICP was much higher, at 9.4 in the treatment arm (n=86). Seeking to avoid 
underpowering the study, we elected to proceed with the SD estimate for the NORDIC 
trial as this is the most similar trial population to the planned IIH EVOLVE trial (both 
recruiting acute IIH). We assume that control arm baseline and 24-week ICP SD equals 
9.4, Presendin baseline ICP SD equals 9.4, and Presendin 24-week ICP SD equals 10.4. 
These values assume the variability of ICP measures in untreated patients is as high as 
has been seen in the NORDIC trial and assumes that the variability in treated patients is 
slightly higher still. We anticipate that the standard deviation will be slightly higher in the 
experimental arm as treatment effects will potentially manifest changes in ICP. However, 
we do not expect such variability to be as inflated in this trial relative to control as it was 
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in the Weight Trial because of the likely difference in treatment effect between surgical 
and drug interventions.  
Under this parameterisation, when testing for a difference between arms at 24-weeks of 5 
CSF (justified below) using a total sample size of 240, assuming that up to 50% of 
observations are missing (i.e. 60 final LPs are completed in each arm), using a 5% 
significance level by Analysis of Covariance (ANCOVA) adjusted for baseline ICP, the 
two stratification variables, and treatment arm, we expect to have approximately 85% 
power. If 40% of observations are missing (i.e. 72 final LPs are completed in each arm), 
we expect power to be 91%. These figures have been inferred by computer simulation. Of 
the 165 patients in IIHTT [Wall, 2014] it was reported that “only 85 participants (47 
[55%] in the [treated] group and 38 [48%] in the placebo group) agreed to a lumbar 
puncture at month 6.” 
We expect a high rate of missing data because lumbar puncture is an invasive procedure 
that patients can find painful and traumatising [Scotton, 2018]. If patients have an 
unpleasant experience at the diagnostic LP they are also more likely to decline the LP at 
trial outcome. If patients do decline the final LP, logically it will be because of the 
baseline experience rather than their prevailing ICP. If data for the LP at 24 weeks is 
missing, the reason will be recorded. 
Outcomes from previous trials show that baseline and post-baseline distributions of ICP 
show central tendency with approximate symmetry, so we conclude that normality is a 
reasonable assumption and therefore ANCOVA is a defensible analysis method. 
13.2.1.1. Perimetric Mean Deviation Power 
We summarise here the estimated power for detecting differences between arms in the 
PMD outcome measure. In the NORDIC trial [Wall, 2014], the authors observed that the 
improvement from baseline to 6-months in PMD was 0.71dB greater in the experimental 
arm than the control arm. Cross-sectional SD of PMD was 1.1-1.2 at baseline. Table 2 in 
their publication shows that the standard error of mean PMD is higher at 6m than at 
baseline, likely reflecting a combined effect of missing data at 6-months and greater 
variability of post-baseline measures. We plan to take repeated measures of PMD at 
baseline, 2 weeks, 1-month (m), 2m, 3 m, 4m, 5m and 6m. Assuming that the overall SD 
of PMD scores is 1.8, thus introducing some reasonable inflation on Wall et al.’s baseline 
variability parameter for the reasons identified, using the formula given on p.31 of 
Diggle, Liang & Zeger (1994) we would expect to require 142 patients in total to detect a 
difference of 0.71dB (justified below) with 90% power at a 5% significance level, if the 
serial correlation between repeated measures is 0.4 (and we expect a value in this region) 
[Diggle, 1994]. If the serial correlation parameter is as low as 0.3, the required sample 
size increases to 166.  
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Note that the method used above assumes full follow-up and data collection. Although 
every effort will be made to collect all outcomes, naturally some missing data is 
expected. If we inflate the maximum sample size identified above by up to 30% to 
account for some data loss, we require up to 166 / 0.7 = 237 patients. The assumed 30% 
missing data rate was adjudged to be realistic by the Sponsor based on previous trials in 
IIH. Thus, we expect to be able to cover the impact of missing data using the extra 
patients necessitated by the sample size calculation for ICP. 
The above assumes only one eye is measured per patient. In actuality, some patients may 
provide outcomes for both eyes because any eye that satisfies the eligibility criteria (see 
Section 5.2) will be enlisted in the study. Put another way, all patients will provide 
outcomes in at least one eye, and some will provide outcomes in two. Second eyes will 
naturally be highly correlated with first eyes. From a sample size perspective, this means 
the additional information in second eyes will be of modest value. Nevertheless, 
outcomes on second eyes will contain some additional information and should be 
included in the analysis in the interest of efficiency. When estimating sample size, for the 
sake of simplicity and because of uncertainty in the rate of eligibility in second eyes, we 
have assumed that each patient yields outcomes from only one eye. Eligible second eyes 
will be included in the analysis with appropriate model terms to handle the within-patient 
correlation (further details are included in the SAP). As such we expect outcomes from 
second eyes to provide a modest uplift in power to the scenarios presented here. 
This section assumes a longitudinal analysis method such as hierarchical regression. 
 
13.2.2. 
Stratification 
At the outset, it is expected that markers of disease severity will be prognostic of 
potential efficacy. For this reason, it is proposed to stratify randomisation by, baseline 
ICP (<35cm or ≥35 cm), baseline body mass index (< 30 kg/m2 or ≥30 kg/m2) and 
baseline PMD (worse than or equal to -3.5dB or better than -3.5dB).   
13.2.3. 
Sample Size Sensitivity 
13.2.3.1. Clinically Meaningful Effect Sizes 
Minimally relevant effect sizes have not been fully determined in IIH given it is a rare 
disease with relatively few previous trials.  
The ICP diagnostic threshold in IIH is 25 cm CSF [Mollan, 2018]. However, it is not 
necessary to reduce ICP <25 cm CSF to achieve remission from signs and symptoms of 
IIH in all patients [Sinclair, 2010]. The clinical importance of a particular change in ICP 
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will vary depending on the starting ICP and the impact this pressure has on vision and 
headache. Changes in ICP of 5 cm CSF are generally considered meaningful when 
treating IIH patients. For example, in a clinical study evaluating the benefits of weight 
loss in IIH patients, a 16.5% (6.2 cm CSF) reduction in ICP resulted in a statistically 
significant improvement in headache and vision measures as well as quality of life 
[Sinclair, 2010]. In the IIH Treatment trail (n=165), a study evaluating the drug treatment 
acetazolamide against placebo, a reduction of -5.9 cm CSF was seen in association with 
significant improvement in PMD, OCT measures of papilloedema and quality of life 
measures [Wall, 2014]. 
The minimally clinically important change in the perimetric mean deviation adopted into 
clinical practice was stablished by the Neuro-Ophthalmology Research Disease 
Investigator Consortium (NORDIC) group and the IIH Treatment Trial (IIHTT). The 
investigators found a 0.71dB difference in the PMD between the two trial arms 
(comparing acetazolamide with placebo) that was clinically meaningful. The change of 
0.71dB was interpreted as clinically meaningful as this was accompanied by significant 
changes in LP opening pressure, papilloedema (measured by OCT), general quality of life 
and visual related quality of life [Wall, 2014, Bruce, 2016].  
The clinically meaningful effect size for MHD reflects that for a phenotypically similar 
headache, chronic migraine. Recent randomised trials in patients with chronic migraine 
[Tepper, 2017; Silberstein, 2017], episodic migraine [Goadsby, 2017], or both 
[Camporeale, 2018] have shown in post-baseline months 1–3, odds of migraine relative 
to baseline of 0.5–0.8 with placebo and 0.5–0.3 with experimental drugs. Decreases in 
MHD relative to baseline grew in time, and placebo responses were stronger in chronic 
migraine than episodic migraine. In the three placebo-controlled, blinded trials, these 
equated to odds-ratios of migraine compared with placebo of 0.8–0.6, or absolute 
differences of 1.5–2.5 MHD [Sinclair, 2010; Tepper 2017; Silberstein, 2017; 
Goadsby, 2017].  
 
13.2.4. 
Trial Stopping Criteria 
There are no trial-specific stopping rules.  
13.3. 
Data Analysis Considerations 
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13.3.1. 
Estimands 
We have specified intercurrent events that are material to the measurement of our 
primary and secondary outcomes, and unbiased estimation of treatment effects 
attributable to Presendin. 
ICP-lowering medication include:  acetazolamide, topiramate, diuretics, glucocorticoids 
(oral dexamethasone and oral prednisolone). Headache-preventative medications include: 
amitriptyline, topiramate, nortriptyline, beta blockers, candesartan, sodium valproate, 
pizotifen, botox, CGRP-therapy. 
13.3.1.1. Outcome: Intracranial pressure (ICP) 
13.3.1.1.1. Intercurrent event: ICP-lowering medications 
All patients are expected to have elevated ICP because it is a defining characteristic of 
the disease. ICP is a physiological variable that is unlikely to show spontaneous 
improvement without treatment. For these reasons, we expect ICP-lowering medication 
use to be greater in the placebo arm. If a patient takes medication that is intended to 
reduce their ICP, it is logical to expect that their ICP will be reduced. Outcomes from 
patients that take ICP-lowering medications will confound the estimation of the causal 
treatment effect of Presendin. We have no data to estimate the length of effects of ICP-
lowering medications. For these reasons, we propose to remove 24-week ICP outcomes 
from all patients that have used ICP-lowering medications and replace these observations 
with arm-specific imputations. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. Patients will consent at enrolment to forgo 
the use of ICP-lowering medications and be informed that taking ICP-lowering 
medications during the trial would constitute rescue therapy and a treatment failure and 
be a protocol deviation. 
13.3.1.1.2. Intercurrent event: Off-protocol lumbar punctures 
Lumbar punctures are commonly conducted to reduce intracranial pressure [Weisberg, 
1977; Johnston, 1981; De Simone, 2005]. In some centres, they are given routinely 
although this has now been advised against in the International IIH Guidelines (Soler, 
1998; Mollan, 2018). As such, they remain a material therapeutic option. LP is expected 
to reduce ICP mean opening pressure 32 (28-37) cm CSF to 19 (17-21) cm CSF post LP 
[Yiangou, 2019]. Beneficial effects dissipate with time and whilst there has been no 
longitudinal assessment to quantify change in ICP after an LP, it is expected that effects 
in the majority of change would have dissipated completely within two months [Yiangou, 
2019]. Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove 24-week ICP outcomes from all patients that have had an off-protocol LP within 
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two months of the protocol-scheduled 24-week LP and replace these observations with 
arm-specific imputations. Where patients require off-protocol LP this would be a protocol 
deviation. 
13.3.1.1.3. Inter-current event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in ICP [Sinclair, 2010]., Sudden dramatic weight loss, 
e.g. arising from a surgical procedure will likely yield material changes to IIH symptoms. 
This will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove 24-week ICP outcomes from all patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure and 
replace with arm-specific imputations. Patients will be ineligible for the trial if they have 
had a surgical weight-loss procedure within 3 months of randomisation or fail to confirm 
that they do not intend to undertake such a procedure during the trial. They will also be 
informed at enrolment that undergoing a surgical weight-loss procedure would be a 
protocol deviation. 
13.3.1.2. Outcome: Perimetric Mean Deviation (PMD) 
13.3.1.2.1. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication (rescue medication due to treatment failure ), it is 
logical to expect that their ICP will decrease and that papilloedema will reduce as a 
result, allowing visual fields to improve. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the PMD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
13.3.1.2.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema, allowing visual fields to improve. Patients that have LPs are expected to 
experience less pressure on the optic nerve, less papilloedema, and have better chances of 
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their visual fields improving. Beneficial effects dissipate with time and whilst there has 
been no longitudinal assessment to quantify papilloedema after an LP the consensus of 
clinicians would predict that effects of the LP on papilloedema and therefore visual fields 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
PMD outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove PMD outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.2.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including improvements in visual fields [Sinclair, 2010]. Sudden dramatic 
weight loss, e.g. arising from a surgical procedure will likely yield material changes to 
IIH symptoms. This will confound the estimation of the causal treatment effect of 
Presendin. For these reasons, we propose to remove PMD outcomes of patients that 
experience weight loss exceeding 10% of baseline weight after a surgical weight-loss 
procedure from the date of procedure. These outcomes will be replaced with patient-
within-arm imputations generated by a method suitable for longitudinal data imputation. 
13.3.1.3. Outcome: Papilloedema measured by OCT (optic nerve head size, 
retinal nerve fibre layer) 
13.3.1.3.1. Intercurrent event: ICP-lowering medications 
All patients will suffer from papilloedema at enrolment as it is the hallmark feature of the 
disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient takes ICP-lowering 
medication, it is logical to expect that their ICP will decrease and that the papilloedema 
will reduce in turn. As stated, we expect ICP-lowering medication use to be greater in the 
placebo arm. Outcomes from patients that take these medications will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove the OCT outcomes following the administration of ICP-lowering medications and 
replace these observations with imputations generated by a method suitable for 
longitudinal data imputation. Outcomes recorded at the unscheduled visit when the 
treatment failure is confirmed (and just prior to starting ICP lowering medication) will be 
defined as the last analysed visit. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. 
13.3.1.3.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
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associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilloedema. Patients that have LPs are expected to experience less pressure on the optic 
nerve and therefore relatively less papilloedema. Beneficial effects dissipate with time 
and whilst there has been no longitudinal assessment to quantify papilloedema after an 
LP the consensus of clinicians would predict that effects of the LP on papilloedema 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
OCT outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove OCT outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.3.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in papilloedema [Sinclair, 2010]. Sudden dramatic weight 
loss, e.g. arising from a surgical procedure will likely yield material changes to IIH 
symptoms. This will confound the estimation of the causal treatment effect of Presendin. 
For these reasons, we propose to remove OCT outcomes of patients that experience 
weight loss exceeding 10% of baseline weight after a surgical weight-loss procedure from 
the date of procedure. These outcomes will be replaced with patient-within-arm 
imputations generated by a method suitable for longitudinal data imputation. 
13.3.1.4. Outcome: Monthly headache days (MHD)  
13.3.1.4.1. Intercurrent event: Headache-preventative medications 
The great majority of patients are expected to suffer from headache because it is a 
common symptom of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient 
takes medication that is intended to prevent headache, it is logical to expect that their 
headache burden will be decreased. Despite the widely-observed short-term placebo-
effect observed in headache outcomes, we expect headache-preventative medication use 
to be greater in the placebo arm. Outcomes from patients that take headache-preventative 
medications will confound the estimation of the causal treatment effect of Presendin 
(more so with botulinum toxin A and CGRP therapies). For these reasons, we propose to 
remove the headache outcomes following the administration of headache-preventative 
medications and replace these observations with imputations generated by a method 
suitable for longitudinal data imputation. This will allow estimation of the treatment 
effect that is purely and causally attributable to Presendin. Patients who require a change 
to their headache preventative medications will do this through consultation with the IAC 
and such a change would be regarded as headache rescue therapy. 
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13.3.1.4.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing the frequency and intensity of 
headache. Beneficial effects dissipate with time. Prospective data documents alterations 
in headache for at least 7 days and whilst there is no prospective longitudinal data over a 
longer time period consensus amongst clinicians would widely acknowledge that 
headache in some individuals can be influenced for up to a month [Yiangou, 2019]. 
Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. MHD outcomes will be recorded 
daily via diaries. For the reasons stated, we propose to remove MHD outcomes recorded 
in the 4-weeks following each off-protocol LP and replace these observations with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4.3. Intercurrent event: Dramatic weight-loss  
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in headache frequency and severity [Sinclair, 2010]. 
Sudden dramatic weight loss, e.g. arising from a surgical procedure will likely yield 
material changes to IIH symptoms. This will confound the estimation of the causal 
treatment effect of Presendin. For these reasons, we propose to remove MHD outcomes 
of patients that experience weight loss exceeding 10% of baseline weight after a surgical 
weight-loss procedure from the date of procedure. These outcomes will be replaced with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4.4. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication, it is logical to expect that their ICP will decrease 
and that headache will reduce as a result. As stated, we expect ICP-lowering medication 
use to be greater in the placebo arm. Outcomes from patients that take these medications 
will confound the estimation of the causal treatment effect of Presendin. For these 
reasons, we propose to remove the MHD outcomes following the administration of ICP-
lowering medications and replace these observations with imputations generated by a 
method suitable for longitudinal data imputation. Outcomes recorded at the unscheduled 
visit when the treatment failure is confirmed (and just prior to starting ICP lowering 
medication) will be defined as the last analysed visit. This will allow estimation of the 
treatment effect that is purely and causally attributable to Presendin. 
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13.3.1.5. Primary Estimand (Hypothetical assuming no concurrent procedures, 
irrespective of adherence to treatment) 
The primary estimand is defined as the following for the primary endpoint: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect ICP. 
The primary estimand for the initial secondary endpoint will be handled similarly to the 
primary endpoint using the “Hypothetical” approach. The initial secondary endpoint is 
defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect PMD. 
 
13.3.1.6. Secondary Estimand (Hypothetical) 
The secondary estimand for the primary endpoint is defined as follows: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, if all patients adhered to 
treatment, where patients did not have medications or procedures likely to materially 
affect ICP. 
The secondary estimand for the initial secondary endpoint will be defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, if all patients adhered to treatment, 
where patients did not have medications or procedures likely to materially affect 
PMD. 
All details will be defined in the SAP. 
 
13.3.2. 
Analysis Populations 
The following analysis populations are planned for this trial:  
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• 
Safety Population: The Safety population includes all patients randomised to 
treatment who receive at least one dose of trial medication. This will be the 
population used for all safety analyses unless otherwise specified. 
• 
Intent-To-Treat Population (ITT): The ITT population includes all patients 
randomised to treatment. This will be the main population for all efficacy analyses 
unless otherwise specified. 
• 
Per Protocol (PP): The PP population includes all patients randomised to treatment 
without important non-evaluable protocol deviations. Only protocol deviations with 
the potential to affect the trial results significantly, or to invalidate the interpretation 
of the data obtained, will lead to exclusion of patients from the PP population. 
Protocol deviations to be considered will include (but will not be limited to): 
• 
Failure to meet inclusion/exclusion criteria 
• 
Wrong treatment or incorrect volume of drug administration 
• 
Prohibited concomitant medications 
• 
Compliance of less than 75% or>125% with trial drug administration 
• 
Use of rescue procedures, including, off-protocol LPs, LP shunts or bariatric 
surgery 
Assignment of patients to populations will be confirmed at a blinded data review meeting 
to be held before the trial database is locked. 
If a patient is randomised incorrectly or is administered the incorrect trial medication, 
analyses of the ITT will be based on the assigned treatment, whereas all other analyses 
will be based on the actual treatment received. 
13.3.3. 
Treatment Comparisons 
Treatment comparisons will be undertaken between active and control groups. The 
primary outcome will be analysed as described in Section 13.2.1.  
13.3.4. 
Safety Analyses 
Safety will be evaluated from reported AEs, changes in clinical laboratory values, 
changes in vital signs, and ECG results. 
All safety analyses will be performed on the Safety population. 
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13.3.4.1. Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (the most recent 
version before starting the trial will be used).  
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of trial medication. 
The number and percentage of patients reporting TEAEs, grouped by MedDRA system 
organ class and preferred term will be tabulated by treatment group. Summaries will be 
presented for all TEAEs, TEAEs by severity and TEAEs by relationship to trial 
medication. 
In the AE data listings, all AEs will be displayed. Adverse events that are not treatment-
emergent will be flagged. The observation period in which an AE started will also be 
provided. 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm. Treatment failures will be displayed by trial arm. 
13.3.4.2. Clinical Laboratory Evaluations  
Laboratory test results for each biochemistry and haematology parameter will be 
summarized descriptively by treatment group and time point as both observed values and 
change from baseline values. 
The number of patients with clinical laboratory (biochemistry, haematology, and 
urinalysis) values categorized as below, within, or above the normal ranges (or as either 
normal or abnormal for urinalysis variables that do not have quantitative ranges), will be 
tabulated in relation to baseline (shift tables), for each clinical laboratory analyte by 
treatment group and time point. 
Laboratory values will be displayed in the data listings and those that are outside the 
reference ranges will be flagged, along with corresponding normal ranges. Any patients 
with any markedly abnormal laboratory results will also be provided in a listing. 
Pregnancy test results including reason, if not performed, will be listed. 
13.3.4.3. Vital Signs and Body Mass Index Evaluations 
Descriptive summaries of observed values and changes from baseline will be calculated 
for systolic blood pressure, diastolic blood pressure and heart rate by treatment group and 
time point.  
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Body mass index will be derived at Screening, Baseline and Weeks 4, 8, 16, 24, 32 and 
48 using height captured at Screening and weight at the respective assessment. Body 
mass index and weight will be summarized descriptively by treatment group and time 
point as both observed values and change from baseline values for Safety and ITT 
populations. 
13.3.4.4. Electrocardiogram 
Descriptive statistics of observed values and change from baseline will be presented for 
ECG measures of PR interval, QRS interval, QT interval, QT interval corrected 
according to Fridericia’s formula (QTcF). These summaries will be presented by 
treatment and time point for the Safety population.  
The number and percentage of patients with values beyond clinically important limits 
will be summarised including those with an increase in QTcF >30 msec increase from 
baseline and >60 msec increase from baseline or those with an absolute QTcF value of 
>450 msec (male patients) or >470 msec (female patients). 
13.3.4.1. Other Safety Evaluations 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed by trial arm.  
13.3.5. 
Patient Reported Outcomes Analyses 
All patient reported outcome endpoints (VFQ-25, HIT-6, SF-36, EQ-5D-5L) will be 
analysed as observed and presented with change from baseline in a descriptive summary 
of treatment and visit  
The number and percentages of PGIC responses will be tabulated by treatment and visit. 
13.3.6. 
Missing Data 
Although every effort will be made to collect responses from all patients at all scheduled 
time points, there undoubtedly will be some missing data.  The SAP describes in detail 
steps for dealing with missing data using relevant imputation strategies for specific 
endpoints that adjust for treatment arm, centre, baseline value, and stratification 
variables. 
13.3.7. 
Reporting Deviations from the Statistical Plan 
Any deviations from the planned analyses will be described and justified in the final 
clinical trial report. 
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14. 
TRIAL ADMINISTRATION 
14.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Before initiation of a trial site, the Sponsor will obtain approval from the appropriate 
regulatory agency to conduct the trial in accordance with ICH-GCP and applicable 
country-specific regulatory requirements. 
The trial will be conducted in accordance with all applicable regulatory requirements. 
The trial will be conducted in accordance with the EU Clinical Trial Regulation 
536/2014, ICH-GCP, all applicable patient privacy requirements and the ethical 
principles that are outlined in the Declaration of Helsinki 2013, including, but not limited 
to: 
• 
An IEC/Institutional Review Board review and approval of trial protocol and any 
subsequent amendments and all ICFs or other information given to the patient 
• 
Patient informed consent 
• 
Investigator reporting requirements 
The Sponsor will provide full details of the above procedures, either verbally, in writing, 
or both. 
Written informed consent must be obtained from each patient before participation in the 
trial. Written informed consent will be collected following a review of the patient’s 
information leaflet by the potential patient and a discussion between the patient and the 
Investigator or suitably qualified designee. 
The Investigator will cooperate with all regulatory inspections and will notify the 
Sponsor as soon as they are aware of an inspection which may involve this trial. With the 
exception of statutory regulatory authority inspections, the Sponsor will be consulted in 
the event of inspection of the clinical site(s) by an outside authority before the Inspectors 
are permitted access to any of the trial records or the trial areas. 
14.2. 
Trial Monitoring 
In accordance with applicable regulations, ICH-GCP, the monitoring plan and the 
Sponsor’s and/or delegate procedures, monitors will contact the site before the start of the 
trial to review with the site staff the protocol, trial requirements, and their responsibilities 
to satisfy regulatory, ethical, and the Sponsor’s requirements. When reviewing data 
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collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. 
The Sponsor and or delegated monitors will perform risk-based monitoring during the 
conduct of the trial to ensure that: 
• 
The data are authentic, accurate and complete 
• 
The patient’s safety and rights are being protected 
• 
The trial is conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH-GCP and all applicable regulatory requirements 
14.2.1. 
Access to Source Data 
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor, Sponsor-appointed auditors and regulatory inspectors direct access to 
all relevant documents. 
14.2.2. 
Data Handling and Record Keeping 
Following closure of the trial, the Investigator or head of the medical institution (where 
applicable) must maintain all site trial records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
Investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The Investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
The Sponsor will inform the Investigator of the time period for retaining the site records 
in order to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, the Sponsor SOPs and/or institutional requirements. 
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
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ownership of the records in the event that the Investigator is no longer associated with the 
site. 
14.3. 
Provision of Trial Results and Information to Investigators 
and Publications 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical trial report. The Investigator will be provided 
reasonable access to statistical tables, figures and relevant reports and will have the 
opportunity to review the complete trial results at a mutually agreeable location. 
The Sponsor will also provide the Investigator with the full summary of the trial results. 
The Investigator is encouraged to share the summary results with the trial patients, as 
appropriate. 
If the Sponsor decides to publish the results, then they will provide the Investigator with 
an opportunity to review the manuscript. If the Investigator wishes to publish anything 
related to the trial, then they must provide the Sponsor with the draft publication and 
allow them no less than 14 days to review the document. The Investigator cannot publish 
without written authorisation from the Sponsor. 
14.4. 
Data Management 
For this trial, patient data will be collected using an eCRF and combined with data 
provided from other sources in a validated data system. Patient’s identifiable data (e.g., 
name, initials, address etc.) will not be collected in the eCRF or transferred to Invex 
Therapeutics. Clinical data management will be performed with the objective of 
removing errors and inconsistencies in the data which would otherwise impact on the 
statistical analysis or the credibility of the Clinical Study Report. Original CRFs will be 
retained by Invex Therapeutics; the Investigator will also retain a copy. 
Management of clinical data will be performed in accordance with the applicable Sponsor 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using the Medical Dictionary for Regulatory Affairs and World Health 
Organisation Drug dictionary.  
When using electronic trial data handling and/or remote electronic trial data systems, the 
Sponsor or designee will:  
a. 
Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation) 
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b. Maintain SOPs for using these systems 
c. 
Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail) 
d. Maintain a security system that prevents unauthorised access to the data 
e. 
Maintain a list of the individuals who are authorised to make data changes 
f. 
Maintain adequate backup of the data 
g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing) 
Training on the use of the electronic data collection system will be provided to all 
relevant trial site staff. 
14.5. 
Independent Adjudication Committee 
The IAC will consist of  international medical experts in neurology or ophthalmology 
who are independent of the Sponsor team. 
The role of the IAC will be: 
• 
To support the Investigators with opinions on the eligibility of potential patients 
• 
To provide opinions regarding treatment failure and need for rescue medications 
required during the trial 
Further details on the composition, activities and responsibilities of the IAC can be found 
in the IAC charter. 
14.6. 
Data Safety Monitoring Committee 
Details on the composition, activities and responsibilities of the DSMC can be found in 
the DSMC charter. 
14.7. 
Insurance, Indemnity and Finance 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
The Sponsor will indemnify all Investigators participating in this trial against future 
claims by trial patients; the terms of this will be detailed within a separate letter of 
indemnification. The indemnity will only apply where all trial procedures have been 
carried out according to this protocol. 
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The financial aspects of the trial are addressed in a separate agreement. 
 
 
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Jun;89(6):3055–61.  
Henson DB, Emuh T. Monitoring vigilance during perimetry by using pupillography. 
Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3540-3.  
Hoffmann J, Mollan SP, Paemeleire K, Lampl C, Jenson RH, Sinclair AJ. European 
headache federation guideline on idiopathic intracranial hypertension. J. Headache Pain. 
2018 Oct 8;19(1):93. 
Hornby C, Botfield H, O’Reilly MW et al. Evaluating the Fat Distribution in Idiopathic 
Intracranial Hypertension Using Dual-Energy X-ray Absorptiometry Scanning. 
Neuroophthalmology, 2017 Jun. 42(2): p. 99-104. 
Johnston I, Paterson A, Besser M. The treatment of benign intracranial hypertension: a 
review of 134 cases. Surg Neurol 1981 Sep;16:218–24. 
Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. 
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CONFIDENTIAL 
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Piper RJ, Kalyvas AV, Young AMH, Hughes MA, Jamjoom AAB, Fouyas IP. 
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item neuro-ophthalmic supplement to the NEI-VFQ-25 Am J Ophthtalmol 2006 
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intracranial hypertension treatment trial JAMA 2014 Apr 23-30;311(16):1641-51  
Wall M, Johnson CA, Cello KE et al. Visual Field Outcomes for the Idiopathic 
Intracranial Hypertension Treatment Trial (IIHTT). Invest Ophthalmol Vis Sci. 2016 
Mar;57(3):805-812. 
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and metabolic dysregulation in idiopathic intracranial hypertension. JCI insight 
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review. J Neurol. 2012 Aug;259(8):1530-45.  
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hypertension: A prospective open-label evaluation. Headache. 2021 Jan;61(1):157-169. 
Yiangou A, Mitchell J, Markey KA et al. Therapeutic lumbar puncture for headache in 
idiopathic intracranial hypertension: Minimal gain, is it worth the pain? Cephalalgia. 
2019 Feb;39(2):245-253.  
Yri HM, Rönnbäck C, Wegener M, Hamann S, Jensen RH. The course of headache in 
idiopathic intracranial hypertension: A 12-month prospective follow-up study. Eur. J. 
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testing of the ICHD diagnostic criteria. A case-control study. Cephalalgia. 2015 
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16. 
APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-
301 
16.1. 
Appendix 1: IIH Diagnostic criteria [Mollan, 2018] 
A. Papilloedema 
B. Normal neurological examination (except sixth cranial nerve palsy) 
C. Neuroimaging: normal brain parenchyma (no hydrocephalus, mass, structural 
lesion or meningeal enhancement). Venous thrombosis excluded in all. 
D. Normal CSF constituents (less than or equal to 7 white cells per mm3 with normal 
protein and glucose  
E. Elevated lumbar puncture pressure ≥ 25cm  CSF  
 
 
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16.2. 
Appendix 2: 36-item short from survey  
 
HEALTH 
• • 
RAND > RAND Health > Surveys > RAND Medical Outcomes Study > 36-ltem Short Form Survey (SF-36) > 
vex 
THERAPEUTlCS 
-m 
36-ltem Short Form Survey Instrument 
(SF-36) 
RAND 36-ltem Health Survey 1.0 Questionnaire Items 
Choose one option for each questionnaire item_ 
L In general, would you say your health is: 
,,...... 1- Excellent 
,....,_ 2 - Very good 
0 3- Good 
0 4-Fair 
"
5-Poor 
2. Compared to one year ago, how would you rate your health in general now? 
0 
1- Much better now than one year ago 
0 2 - Somewhat better now than one year ago 
0 3 -About the same 
" 
4 - Somewhat worse now than one year ago 
n s - Much worse now than one year ago 


 
 
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The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so, how much? 
Yes, 
Yes, 
No.not 
limited a 
limited a 
limited at 
lot 
little 
all 
3. Vigorous activities, such as running, lifting heavy objects, 
n
1 
n
2 
n
3 
participating in strenuous sports 
4. Moderate activities, such as moving a table, pushing a 
r"\ 1 
0
2 
C) 3 
vacuum cleaner, bowling, or playing golf 
s. Lifting or carrying groceries 
'1 1 
( h 
n
3 
6. Climbing several flights of stairs 
0 l 
0
2 
0
3 
1. Climbing one flight of stairs 
(' l 
n
2 
n
3 
8. Bending, kneeling, or stooping 
IJ l 
() 2 
0
3 
9. Walking more than a mile 
'] l 
n
2 
n 
3 
10. Walking several blocks 
0
1 
0
2 
0
3 
11. Walking one block 
""") l 
n
2 
n
3 
12. Bathing or dressing yourself 
C' l 
0
2 
0
3 


 
 
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During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
13. Cut down the amount of time you spent on work or other activities 
14. Accomplished less than you would like 
1s. Were limited in the kind of work or other activities 
16. Had difficulty performing the work or other activities (for example, it took extra 
effort) 
Yes 
n 
I'""'\ 
n 
n 
No 
n 
2 
0 
2 
0 
2 
n 
2 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
Yes 
No 
17- Cut down the amount of time you spent on work or other activities O 1 
Q 2 
18. Accomplished less than you would like 
,) 1 n 2 
19. Didn't do work or other activities as carefully as usual 
O 1 
0 2 
20. During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors, or 
groups? 
":: 1 - Nat at all 
n 2-Slightly 
,,....._ 3 - Moderately 
n 
4 - Quite a bit 
,,....._ 5 - Extremely 


 
 
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21. How much bodily pain have you had during the past 4 weeks? 
0 1- None 
".:) 2-Verymild 
r'l 3-Mild 
0 4 - Moderate 
C:, 5-Severe 
C 6 -Very severe 
22. During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
0 1-Notatall 
l'J 2-Alittlebit 
r:: 3 - Moderately 
n 4 - Quite a bit 
{') s - Extremely 
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THERAPEUTlCS 
These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question, please give the one answer that comes closest to the way 
you have been feeling. 
How much of the time during the past 4 weeks ... 
All of 
Most 
A good 
Some 
A little 
None 
the 
of the 
bit of the 
of the 
ofthe 
ofthe 
time 
time 
time 
time 
time 
time 
23. Did you feel full of pep? 
C' l 
0
2 
0
3 
0
4 
C' 5 
O s 
24. Have you been a very nervous 
0
1 
n
2 
'J 3 
(") 4 
I, 5 
n
s 
person? 
25. Have you felt so down in the 
(' l 
0
2 
Q 3 
0
4 
O
s 
O s 
dumps that nothing could cheer you 
up? 
26. Have you felt calm and peaceful? 
n
1 
n
2 
n 3 
(") 4 
I, 5 
n
s 
27- Did you have a lot of energy? 
0
1 
0
2 
r, 3 
n
4 
I, 5 
n
s 
28. Have you felt downhearted and 
n
1 
n 2 
0
3 
0 4 
n
s 
n s 
blue? 
29. Did you feel worn out? 
0
1 
n 2 
n 3 
(") 4 
n
s 
n
s 
30. Have you been a happy person? 
C' l 
0
2 
0
3 
0
4 
') 5 
O s 
31. Did you feel tired? 
r' 1 
n z 
0
3 
n 4 
'J 5 
n s 
32. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
n 1 -All of the time 
r'\ 2 - Most of the time 
r, 3 - Some of the time 
r, 4 - A little of the time 
r'\ s-Noneofthetime 


 
 
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THERAPEUTlCS 
How TRUE or FALSE is each of the following statements for you. 
Definitely 
Mostly 
Don't 
Mostly 
Definitely 
true 
true 
know 
false 
false 
33. I seem to get sick a little easier than 
0 1 
O z 
0
3 
') 4 
O s 
other people 
34- I am as healthy as anybody I know 
0 1 
') 2 
0
3 
') 4 
n s 
35. I expect my health to get worse 
'l 1 
'J 2 
n 3 
r, 4 
n s 
36. My health is excellent 
n 1 
() 2 
() 3 
'] 4 
n s 
ABOUT 
The RAND Corporation is a research organization that develops solutions to public policy challenges to help make 
communities throughout the world safer and more secure. healthier and more prosperous. RAND is nonprofit. nonpartisan. 
and committed to the public interest. 
II 
1776 Main Street 
Santo Monico, California 90401-3208 
RAND• is a registered trademark. Copyright© 1994-2016 RAND Corporation. 


 
 
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16.3. 
Appendix 3: EuroQol -5 dimension-5 level survey  
 
vex 
THERAPEUTlCS 
UK (English} © 2009 EuroQof Group EQ-5O'" is a trade mark of/he EuroQol Group 


 
 
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Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, hou 
leisure activities) 
I have no problems doing my usual 
I have slight problems doing my usu 
I have severe problems d 
lh 
s or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
UK /English) © 2009 EuroQol Group EQ-5O'" is a trade mark of the EuroQol Group 
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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TOD 
• 
Now, please write the number you marked on the scale in the 
below. 
UK (English) © 2009 EuroQo/ Group EQ-5D™ is a trade mark of the EuroQo/ Group 
vex 
THERAPEUTlCS 
The best health 
you can imagine 
100 
The worst health 
you can imagine 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 


 
 
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16.4. 
Appendix 4: Headache Impact Test-6 
 
vex 
THERAPEUTlCS 
HIT-6™ 
(VERS ION 1.1) 
~HE 
This questionnaire was designed to help you describe and communicate 
the way you feel and what you cannot do because of headaches. \ 'J'MT TESTN 
To complete, please circle one answer for each question. 
When you have headaches, how often is the pain severe? 
Never 
Rarely 
Sometimes 
How often do headaches limit your ability to do usual daily activities in 
work, work, school, or social activities? 
Never 
Rarely 
V When you have a headache, how often do yo 
Never 
Rarely 
In the past 4 weeks, how often have yo 
of your headaches? 
Never 
+ 
COLUMN 1 
COLUMN 2 
(6 poin ts each) 
(8 poin ts each) 
Sometimes 
COLUMN 3 
(10 points each) 
To score, add points for answers in each column. 
Please share your HIT-6 results with your doctor. 
llll-6"US(foglish)V,rs011.1 
"2000,2001 OualityMctrit,lnc.andGlaxoSm~hKlint:Gro;p<XCompani,s 
+ 
Always 
do work or daily activities because 
Very Often 
Very Often 
Very Often 
COLUMN 4 
(1 1 poin ts each) 
+ 
Always 
Always 
Always 
COLUMN 5 
(13 points each) 
Total Score ._I ___ 
__. 
Higher scores indicate 
greater impact on your life. 
Score range is 36-78. 


 
 
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vex 
THERAPEUTlCS 
HEADACHE 
IMPACT TEST™ 
What Does Your Score Mean? 
T 
If You Scored 60 or More 
Your headaches are having a very severe impact on your life. You may be experiencing disabli1 
are more severe than those of other headache sufferers. Don't let your headaches stop you fr 
your life, like family, work, school or social activities. 
Make an appointment today to discuss your HJT-6 results and your headaches with your d 
T 
If You Scored 56 - 59 
Your headaches are having a substantial impact on your life. As a result y 
symptoms, causing you to miss some time from family, work, school, or so 
Make an appointment today to discuss your HIT-6 results and y 
T 
If You Scored 50 - 55 
Your headaches seem to be having some impact on your 
work, school, or social activities. 
Make sure you discuss your HJT-6 results and ym 
T 
If You Scored 49 or 
Your headaches seem to be havin 
T 
T 
ur 
ecause research shows that when doctors understand exactly how badly 
tients, they are much more likely to provide a successful treatment program, which may 
et at www.headachetest.com. 
ou to print out a personal report of your results as well as a special detailed version for your doctor. 
gain or try the Internet version to continue to monitor your progress. 
The Headache Impact Test (HIT) is a tool used to measure the impact headaches have on your ability to function on the job, at 
school, at home and in social situations. Your score shows you the effect that headaches have on normal daily life and your 
ability to function. HIT was developed by an international team of headache experts from neurology and primary care medicine 
in collaboration with the psychometricians who developed the SF-36®* health assessment tool. 
HIT is not intended to offer medical advice regarding medical diagnosis or treatment. You should talk to your healthcare 
provider for advice specific to your situation. 
SF-36® is a registered trademark of Medical Outcomes Trust and John E. Ware, Jr. 
HIT-6 Scoring lnterprelalion English Version I.I 
©2001 QualityMetric, Inc. and GlaxoSmithKline Group of Companies. All rights reserved. 


 
 
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16.5. 
Appendix 5: Visual Function Questionnaire-25 & 10-item 
Supplement 
 
 
National Eye institute 
Visual FunctioninrJ Questionnaire - 25 
{VFQ-25) 
version 2000 
PB/SA 
"•ti s 
0'ftt1l5 r-Jf l v:,· 
S - July 1996 accept!; fu!I resp::>n!;ibi!lt~•. and Jgree!: to hold RAr-m harmlt£!;, tor 1hca 
·rac.y of any trar.slat:01 
".' t:,e NEJ VFQ-ZC. k st Version - July 1396 into ar,ott,cr :,mguc.gc ~nd for ,lily errors, 
liSSiC>rl~:;~~-ttiQ •~::-<./ COli!'oP.(IUeltCltS lhHE:-(if. 
·~tnts,.L
00 -Q.i°f . July 1995 lt.:Ce-pts !U!I re~ponst!Jility, J!ld a;irn-~s ~o t!O!d RANU Mrml::!SS, fer .:my 
J~~Ces resulti 
om lhe..ise ufthe NEI 'JFQ-26. 
4. The IJ~('.'r of ttlt: • 
• HJ-:li - .July ·\~iiJ •vl!I pro>nd~ cl. crectic line w!lE'r! printing tJ.nd cHstr!l,!IUng: th!s Oor::ument 
.::,r in pu~W,esultt or 1rna11s-es Mse-d en this tnetrum2-nt ac!<new\Mging tt!Jt it WJ$ dc•1etop~d .lt RAND 
unocr u,~·~Sh:p of tt.c Notkmc.l Eve Institute. 
1:w:sc 
@ HAND 1996 
vex 
THERAPEUTlCS 


 
 
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Compound No.: Presendin™ 
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Version: 3.0 
 
 
CONFIDENTIAL 
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vex 
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- 1 -
version 2000 
The following is a survey with statements about problems which involve your 
vision or feelings that you have about your vision condition. After each question 
please choose the response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
Please take as much time as you need to answer each question. 
answers are confidential. In order for this survey to improve our 
about vision problems and how they affect your quality of life, 
be as accurate as possible. Remember, if you wear glasses 
please answer all of the following questions as though you were_,,.,,r1ar< 
INSTRUCTIONS 
1. 
In general we would like to have people try to 
their own. If you find that you need a 
project staff and they will assist yo 
2. 
Please answer every question 
3. 
4. 
5. 
6. 
because they don't apply t 
u). 
ionn 
efore leaving the center and give it to 
Do not take it home . 
.ni.ll"!s~~.olease feel free to ask a member of the project 
I be glad to help you. 
would permit identification of any person who completed this 
e regarded as strictly confidential. Such information will be 
---."" purposes of this study and will not be disclosed or released for 
poses without prior consent, except as required by law. 
©RAND 1996 


 
 
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Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEAL TH AND VISION 
1. 
2. 
One) 
1 
2 
3 
4 
........................................ 5 
ou say your eyesight using both eyes (with 
ou wear them) is excellent. good, fair, 
u completely blind? 
(Circle One) 
Excellent ............................... 1 
Good ...................................... 2 
Fair ......................................... 3 
Poor ........................................ 4 
Very Poor .............................. 5 
Completely Blind ................ 6 
©RAND 1996 


 
 
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3. 
How much of the time do you worry about your eyesight? 
(Circle One) 
None of the time............................. 1 
A little of the time........................... 2 
Some of the time................. 
.. .... . 
Most of the time ............ 
. ........... . 
4. 
How much pain or discomfort have you h 
(for example, burning, itching, or achin 
2 
3 
4 
5 
The next questions are a 
certain activi • 
for that activ 
. 
ffloli"III~ difficulty, if any, you have doing 
or contact lenses if you use them 
5 . 
have reading ordinary print in 
...,_._..'Wl,,,,..,""-~._,.ould you say you have: 
(Circle One) 
ifficulty at all ................... ...................................... 1 
tie difficulty............................................................. 2 
3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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6. 
How much difficulty do you have doing work or hobbies tha.t require 
you to see well up close, such as cooking, sewing, fixing things 
around the house, or using hand tools? Would you say: 
(Circle One) 
No difficulty at all ................... ...................................... 1 
.A little difficulty .... ,. ..................... ., ......... ,. ... ,. ........ ., ..... .. 
Moderate difficulty ....... ,. ............................................. . 
Extreme dlfficuity .................................................. .. 
Stopped doing this because of your eyesigh 
Stopped doing this for other reasons or not 
interested in doing this ......................................... .. 
7. 
Because ot your eyesight, how much 
someihing on a crowded shelf? 
8. 
No difficulty at all ............. ..,_·.,...,,.,-...,.. 
A little difficulty.... .. .. ...... .. 
2 
3 
" .... ........ 4 
eyes,ght ..... 5 
have ,·eading stteet signs or ihv names oi 
(Circle Ona) 
. Hy at ;,II .................................... ................ 1 
difficulty............................................................. 2 
ate difficulty....................................................... 3 
4 
Stc ppec! doing this because of ycur eyasight..... 5 
Stopped doing this for other reasons c, not 
internsted in doing this ........................................... 6 
9. 
Be,~ausc, of your eyesight, how much dlfficu!ty de you have goinq 
down st-eps, stairs er curbs in dim Hght c-r 1lt night? 
© RAND 1996 


 
 
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Version: 3.0 
 
 
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(Circle One) 
No difficulty at all ................... ...................................... 1 
A !ittl~ difficulty ...................................................................... 2 
Moderate difficult:,,....................................................... 3 
Ex ire me difficuity ................... ...................................... 4 
Stopped doing this because of your eyesight ... .. 
Stopped doing this for other reasons or not 
interested in doing this ....................................
........ 6 
10. Because of your eyesight, how much diffi 
'i1. 
objects off to the side while you are .w,.,,_.a,.,,lk"'i,_,n'!:l!lli::.-::= 
No difficulty at all ............. . 
A little difficulty ............. . 
Extreme difficulty . 
Stoppe ··• 
• • • 
Stopp 
int 
3 
4 
5 
w much ciifficuity do you have seeing 
say?' 
(Circ!e One) 
cuHy at all ......................................................... 1 
··tficulty............................................................. 2 
difficulty....................................................... 3 
me difficulty ..... .............. ..... ... ... .... ... . . ..... ....... 4 
,,,.,......,..,,...,.~,pped doing '.chi<; because of ycur eyesight..... 5 
• Stopped doing this for other reasons or not 
interestaci in doing U1is ........................................... 6 
© RAND 1996 


 
 
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12. Because of your eyesight, how much difficulty do you have u_icJ5J11.q.21u 
and match!no your own clothes? 
(Circle One) 
No difficulty at all ................... ...................................... 1 
A little difficulty., ....................... ........ , .......... ,, ........ , ..... , ........ 2 
Moderate difficulty ............... .......... ......... ..... .... ...... . 
Exireme di'fficuity ............................................. ........... . 
Stopped doing this because of your eyesight .· 
Stopped doing this for other reasons or not 
interested in doing this ........................................ . 
13. Because ot your eyesight, how much 
with eo le in their homes at arti 
No difficulty at all ............. ..,_·,,,-,.,-...,.. 
A little difficulty.... .. . . ...... .. 
2 
3 
" .... ........ 4 
eyes,ght ..... 5 
w much difficulty do you have going out 
, 
rts ·,wcenls? 
(Circ!e One) 
ifficulty :at all .... .... .... ... ... ... .... .... .... ... 
1 
,,,..,_...,..,...tr ittie difficulty ............................................................. 2 
f\/loderate difficulty....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your eyesight. ... 5 
Stopped doing this for other reasons c.,, not 
lnten:sfod in doing tili!:: .......................... ,. ................ 6 
15.. 
,~re you currcnt.!y driving . .at least. once in a •Nh!le? 
© RAND 1996 


 
 
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(Circle One) 
Yes........................ 1 Skip To Q 15c 
1·Jo ......................... 2 
15a. 
IF NO: Have you never driven a car or have you 
15b. 
griying? 
eyesight, mainly_for 
fill~S!ghia.nd_gt!J.eL ............. _... 
(Circle One) 
Never drove........ "i 
e of_your 
e of bot1Lvoyr 
·j 
Skip To Part 3, Q 17 
£. Skip To A:,rt 3, Q 17 
cc 
Skip Tu Pc:,rt 3, 0 17 
TL Y DR!\/lf\lG: Hovv much difficulty do you have 
___ ... !.rio,g_!rut,..gr!YtilmlirLffilililll!!'..~~§? \I\Jould you sav 
••• • a,~ 
(Circle One.l 
No difficulty at all................................. 1 
A little difficulty ........... . ,. ... ,.................. 2 
Mochm ,te di'!ficulty ............................... 3 
Extreme difficulty................................. 4 
© RAND 1996 


 
 
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Version: 3.0 
 
 
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16. How much difficulty do you have driving_ainia.ht? Would you say vou 
have: 
(Circle One) 
No difficulty at all....................................... 1 
A little difficulty .... ,. ...................... ,................ 2 
Moc:lern,te difficuHy ...................................... 3 
Extreme dift'iculty .......................... .. ....... 4 
Have you stopped doing this 
ause 
of your eyesight............. _ .............. .. 
Have you stopped doing t 
reasons or are you not int 
doing this .................................. . 
16A. How much difficulty do you have ,._d,_,ri_.,vl-'i lll:l/"',¼-"'-'-'~ll,lc'~"-'-'~,1111.l/14-'s"'u"'-c"'-'h 
as in bad weather durin rush hou 
traffic? 
Would you say you have: 
2 
..................................... 3 
4 
u sklpped doing this because 
r eye:,,;ight .................................... 5 
ave you stopped doing this 1'or otiIer 
reasons or are you not interested in 
cloing ,his................................................ 6 
© RAND 1996 


 
 
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Version: 3.0 
 
 
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PART 3· R.ESPONSES TO VISION PROBLEMS 
The next questions are about how things you do may be affected by your 
vision. For each one, please circle the number to indicate whether for you 
the statement is true for you all, most, some, a little, or none of the time. 
READ CATEGORIES: 
17. Do you accomplish less 
than you would tike 
because of your vk,ion? 
18. P,re you !!mlted in how 
long you czn \,vork or do 
other activitie~-because of 
your vision? ....... ,, ... ......... . 
19.. 
Ho1N much does pain or 
discomfort i!lOLM.Q!!J'_g 
your eves, for 
burning, itchin 
aching, keep y 
doing w 
be doi 
(Circle One On Each Line) 
Ali of 
Most of 
Some 
A 
None of 
the 
the 
the 
time 
time 
2 
3 
5 
.2 
3 
4 
s 
©RAND 1996 


 
 
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Version: 3.0 
 
 
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For each of the fo!lm'lling statements, please circle the number to indicate 
whether for you the statement is definitely true, mostlv true, mostlv false, 
or @fiDi~ly_f<!l.s~ for you or you are n..oLsYf~. 
(Circle One On Each Line) 
Definitely 
Mostly 
i\lot 
True 
Ttue 
Sui"e 
20.. ! stay horn,) most of the· time 
because of my eyesight. .... 
1 
21 
! feel frustrated a lot of the 
time because of my 
eyesight .................................... 
1 
22.. 
I have much less contrcit 
over what I do, because of 
my eyesight. ......................... . 
23. Because ot my eyesight, I 
have to rely too much on 
what other people teii me ... 
25. 
© RAND 1996 
2 
3 
3 
2 
3 
2 
3 
4 
4 
4 
Definitely 
False 
5 
5 
5 
5 


 
 
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Appendix of Optional Additional Questions 
SUBSCALE: GENERAL HEALTH 
A1. How would you rate your overall health, on a sca:e where 
bad as death and ·10 is beat poasible heaHh? 
0 
Worst 
2 
SUBSCALE GENERAL VISION 
(Circle One) 
4 
5 
6 
? 
A2. How would you rate your eyesi. 
on, if you wear them), on a sc 
worst possibie eyesight, as •• ad 
means the 
, and 10 
means the best possible 
• •• ht'? 
0 
1/\Jorst 
8 
9 
rn 
Best 
SUBSCALE: 
A3. 
ow 
h difficulty do you have r~,c:li_rig_th~,J!_ITlaH 
ne boo!s._ on a medicine bottle....9r on l~al forms? 
(Circle One) 
ifficuliy at all ................... ...................................... 1 
_,__,..__.~ little difficulty............................................................. 2 
Moderate difficulty.............................................................. 3 
Exi:remci diffkuity ..... ,. ................................. ······-····-··--··· 4 
Stopped doing this because of your eyes,ght ..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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Version: 3.0 
 
 
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.A4. Because of your eyesight, how much difficulty do you have fi_g_y_ri.ng 
out whether bills_you receive are accurate? 
(Circle One) 
No difficulty at all ................... .......................... ............ 1 
.A l.ittle difficulty ........ .... .... .... ... .... ............ .... ...... . 
Moderate difficulty ......... ,, ......... .................... , ......... , ........ . 
Extreme dl"l'ficuity .................................................. .. 
Stopped doing this because of your eyes1gh 
Stopped doing this for other reasons or not 
interested in doing this ......................................... .. 
A5. Because ot you 
• •• 
things I ike §S:!lh!i:!aY..V!..!'.llWm'J!ill!9...]cQ!dlL!:~IO~!!l?l~!9J!ICI~illil~',1 
No diffic 
A little di 
2 
3 
..... ........ 4 
eyes,ght ..... 5 
r eyesight, how much difficuity do you have 
le ou know from across a room? 
ing 
(Circle One) 
il'ficuity at all ................... ...................................... 1 
little difficulty............................................................. 2 
Moderate difficulty ... ,. .......................... ., ........ .,............ 3 
Extreme d!fficu!ty ............. ,............................. ............ 4 
Stepped doing this bacause of ycur eyesight..... 5 
Stopped doing this tor other reasons or not 
interested in doing ti'lis ........................................... 6 
© RAND 1996 


 
 
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Compound No.: Presendin™ 
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Version: 3.0 
 
 
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A7. Because of your eyesight, how much difficulty do you have mking _ 
_t)~!'1 
i11 active sports or other outdoor activities that you eniQY (like golf, 
bowling. jogging, or walking)? 
(Circle One) 
i\Jo difficulty at all ................... ...................................... 1 
A little difficulty ................................................ ........... . 
Moderate difficulty ................. ..... ...... ........................ . 
Extreme di-ffi-cuity ................................................. . 
Stopped doing this because of your eyesight ..... 
Stopped doing this for other reasons or not 
interested in doing this.............. . 
.. .................... 6 
AS. Because ot your eyesight, how much 
enjoying programs on TV? 
No difficulty at all ............. ..,_·.,...,,.,-...,.. 
A little difficulty.... .. . . ....... . 
2 
3 
..... ........ 4 
eyes,ght ..... 5 
;-- eyesight, how much dlfficuity do you have 
''lds ,md f.!,mil in our he-me? 
(Circle Ore) 
ifficu!ty at .:,ill ................................................. 
1 
,,,..,_......,...., ltUe difficulty ............................................................. 2 
Moderate difficulty....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your ei,esight ..... 5 
Stopped d,oing this for -other reas;;.ms er not 
lnten:sfod in doing tili!:: .................................. ., ......... 6 
© RAND 1996 
and 


 
 
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Version: 3.0 
 
 
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SUBSCALE DRIVING 
A10. [This item, " driving in difficult conditions" , has been included as part 
of the base set of 25 items as item 16a.I 
SUBSCALE ROLE LIMITATIONS 
A1 I. The next questions are about things you may do be,:; 
·. islon. For each Hem, please cird e the number to ind,· 
you this is true for you all, most, "'ome, a lit'iie, m nom, 0 1 
a. 
J;)Q_,VQ! !J Jave more ~IQ 
from others because of 
your vision? ... .... ......... ... . 
b. Are~u .limited i 
kinds of things yo'"""""'·.-:-...-.... 
because of your vis1 
3 
3 
© RAND 1996 
4 
4 
Hone of 
the 
time 
5 
5 


 
 
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SUBSCALES WELL-BEING/DISTRESS (#A1 2) and DEPENDENCY (#A13) 
The next questions are about how you deal with your vision. For each 
statement, please circle the number to indicate whether for you it is 
definiteiy true, mostly true, mostly false, or definitely false for you or you 
don't know. 
Defi niialy 
Mcstiy 
f~ot 
True 
True 
Sur-:e 
A 12. I am often irritable because 
of my eyesight....................... 
1 
2 
A 13.1 don't go out of my home 
alone, because of my 
eyesight. ............................... .. 
© RAND 1996 
5 


 
 
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10-ITEM NEURO-OPHTHALMIC SUPPLEMENT TO THE NEI-VFQ-25 
The following are additional questions and statements about problems that involve your vision or 
feelings you may have about your vision condition. After each question, there will be a list of possible answers. 
Please choose the response that best describes your situation. 
Please answer all questions as if you were wearing your glasses or contact lenses (if any). Please take as much 
time as you need to answer each question. 
1. How much difficulty do you have performing tasks when your eyes are tired? 
/Circle One) 
None 
Mild 
2 
Moderate 
3 
Severe, or 
4 
Very severe? 
5 
2. Because of your visio11, how much difficulty do you have identl~ 
sunlight? 
{Circle One) 
None 
Mild 
Moderate 
Severe, or 
Very severe? 
3. Because of your visior1, how much difficult 
have 
• g a car? 
/Circle One) 
Na difficulty at all 
A little difficulty 
2 
Moderate difficulty 
3 
Extreme difficulty 
4 
Stopped doing this because of our ey • 
5 
Stopped dmng th 
"-· _..._..,..... 
r n 
rested 1n doing this 
6 
4. Because of y 
··:,;_,.-.;-.,.:: 
you have using a computer? 
/Circl 
N 
4 
5 
6 
I wing statements, please indicate if it is definitely true, mostly true, mostly false, or 
definitely false for you or if you are not sure. 
5. I have a feeling that my two eyes see differently, even with correction {glasses or contact lenses). 
{Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
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6. I have a feeling that my eye or eyelid appearance i, unusual. 
(Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
For each of the following, please indicate if it is true fo r you all, most, some, a little, or none of the time. 
7. My vision is blurry, not clear, or "fuzzy." 
(Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
8. I have trouble focusing on or following moving objects. 
(Circle One) 
All of the time 
Most of the time 
Some of th e time 
A little of the time 
None of the time 
9. I have double vision wittl both eyes open t 
t pres 
ther eye is covered. 
(Circle One) 
All of the time 
Mostofthe t1me 
Some of the time 
A little of the time 
None of the time 
4 
5 
1 
2 
3 
4 
5 
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16.6. 
Appendix 6: Patient Global Impression of Change  
 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
Since the start of the study, my overall status is 
one box only: 
[1] 
Very much Improved 
[2] 
Much Improved 
[3] D Minimally Improved 
[4] 
No change 
[5] 
Minimally Worse 
[6] D Much Worse 
[7] D Very much Worse 
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16.7. 
Appendix 7: Contraception 
Birth control methods which may be considered as highly effective (that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are 
considered as highly effective birth control methods).  
Patients should be instructed not to take their oral contraceptive within 1 hour prior to 
administration of trial medication. 
Such methods include: 
• combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system ( IUS)  
• bilateral tubal occlusion  
• vasectomised partner 1 
• sexual abstinence 2 
 
1. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the trial participant.  
2. In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
 
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Compound No.: Presendin 
Protocol 
Version: 1.0 
 
Page 1 of 135 
 
CONFIDENTIAL 
 
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 
Effective Date: 
02-DEC-2021 
 
Short Title: A Phase III trial to determine the efficacy and safety of Presendin in 
IIH – IIH EVOLVE 
Abstract: 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 release 
formulation of exenatide (Presendin) in the reduction of intracranial pressure (ICP) in 
patients with IIH. The primary outcome will be determined by change in ICP, as 
measured by lumbar puncture (LP).  
Eligible, consenting patients will be randomised in a ratio of 1:1 to receive Presendin or 
placebo as a weekly dose for 24 weeks. 
 
Author  
Department 
Company 
Emma de Launay 
Clinical Operations 
Invex Therapeutics Ltd. 
 
 
 
 
The information contained in this document is the property of Invex Therapeutics and 
may not be produced, published or disclosed to others without written authorisation from 
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CONFIDENTIAL 
Invex Therapeutics 
 
 
 
 
 
 
 
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Study Number: INVEX-CLIN-IIH-301 
Protocol 
SPONSOR SIGNATURE PAGE 
Sponsor Signatory: 
~h.,d&c r---
Doctor A7xancfra Sinclair 
MBChB, PhD, FRCP 
Chief Scientific Officer 
lnvex Therapeutics Ltd. 
 
 
 
 
CONFIDENTIAL 
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Com ound No.: Presendin 
Version: 1.0 
0 2, 12. '20 21 
Date 
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Study Number: INVEX-CLIN-IIH-301 
Compound No.: Presendin 
Protocol 
Version: 1.0 
 
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CONFIDENTIAL 
SPONSOR INFORMATION PAGE 
Role 
Name and 
Title 
Email Address 
Address 
Non-
Executive 
Chairman 
Dr Jason 
Loveridge 
 
Invex Therapeutics 
Ltd 
 
 
 
 
Medical 
Monitor 
(CRO) 
Premier 
Research 
Medical 
Monitor 
Premier Research 
3800 Paramount 
Parkway 
Suite 400 
Morrisville 
NC 27560 
USA 
Head of 
Clinical 
Operations 
Carol 
Parish 
 
Invex Therapeutics 
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Senior 
Clinical 
Trials 
Manager 
Emma de 
Launay 
 
Invex Therapeutics 
Ltd 
 
 
 
 
 
Sponsor Contact Information:   
Invex Therapeutics Ltd 
 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, have read and understood the protocol and am aware of my 
responsibilities as an Investigator. I agree to conduct the study in accordance with this 
protocol, the Trial Reference Manual and any subsequent amendments, the Declaration of 
Helsinki, ICH GCP guidelines, and the laws and regulations of the country in which the 
study is being conducted. 
 
Investigator Name and Qualifications: _____________________________________ 
 
 
 
Investigator Signature 
 
Date 
[Investigator Affiliation] 
 
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INVESTIGATOR INFORMATION PAGE 
Details will be provided in the Investigator Site File  
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS .......................................................................................................12 
PROTOCOL SUMMARY ............................................................................................14 
1. 
INTRODUCTION .................................................................................................26 
1.1. 
Background and Rational .............................................................................. 26 
1.1.1. 
Name and Description of the Investigational Product ................... 33 
1.1.2. 
Non-clinical Studies........................................................................ 34 
1.1.3. 
Clinical Studies ............................................................................... 34 
1.1.4. 
Trial Conduct .................................................................................. 35 
1.2. 
Risk/Benefit Assessment ............................................................................... 36 
2. 
OBJECTIVES.......................................................................................................36 
2.1. 
Primary Objective .......................................................................................... 37 
2.2. 
Secondary Objectives .................................................................................... 37 
2.3. 
Safety Objective ............................................................................................. 37 
2.4. 
Exploratory Objectives ................................................................................... 37 
3. 
ENDPOINTS ........................................................................................................38 
3.1. 
Primary Endpoint ........................................................................................... 38 
3.2. 
Secondary Endpoints .................................................................................... 38 
3.3. 
Safety Endpoints ............................................................................................ 39 
3.4. 
Exploratory Endpoints ................................................................................... 39 
4. 
TRIAL DESIGN ....................................................................................................39 
4.1. 
Summary of Trial Design ............................................................................... 39 
4.1.1. 
Trial Design .................................................................................... 39 
4.1.2. 
Randomisation and Blinding .......................................................... 41 
4.1.3. 
Duration of Patient Participation .................................................... 41 
4.2. 
Stopping Rules .............................................................................................. 41 
4.2.1. 
Trial Stopping Rules ....................................................................... 41 
4.2.2. 
Individual Stopping Rules .............................................................. 42 
4.3. 
End of Trial ..................................................................................................... 42 
5. 
TRIAL POPULATION ..........................................................................................42 
5.1. 
Number of Patients ........................................................................................ 42 
5.2. 
Eligibility Criteria ............................................................................................ 42 
5.2.1. 
Inclusion Criteria ............................................................................ 42 
5.2.2. 
Exclusion Criteria ........................................................................... 43 
6. 
TRIAL ASSESSMENTS AND PROCEDURES ...................................................45 
6.1. 
Procedures at Each Visit ............................................................................... 45 
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6.1.1. 
Visit 1 Screening ............................................................................ 46 
6.1.2. 
Visit 2 Baseline ............................................................................... 47 
6.1.3. 
Visit 3 Telephone call ..................................................................... 48 
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits .............................................. 48 
6.1.5. 
Visit 10 ............................................................................................ 49 
6.1.6. 
Visit 11 Follow-Up .......................................................................... 51 
6.1.7. 
Unscheduled visit for repeat visual assessments ......................... 51 
6.2. 
Trial Procedures ............................................................................................ 51 
6.2.1. 
Screening Procedures ................................................................... 51 
6.2.1.1. 
Demographics .............................................................. 51 
6.2.1.2. 
Medical, Headache and Ophthalmic History ............... 51 
6.2.1.3. 
Reporting of Prior and Concomitant Medication ......... 51 
6.2.2. 
Safety Procedures .......................................................................... 52 
6.2.2.1. 
Physical Examination ................................................... 52 
6.2.2.2. 
Twelve- Lead Electrocardiogram ................................. 52 
6.2.2.3. 
Vital Signs .................................................................... 53 
6.2.2.4. 
Laboratory Assessments ............................................. 53 
6.2.2.4.1. 
Haematology ........................................... 53 
6.2.2.4.2. 
Clinical Chemistry .................................... 54 
6.2.2.4.3. 
Urinalysis ................................................. 54 
6.2.2.4.4. 
CSF .......................................................... 55 
6.2.2.4.5. 
Pregnancy................................................ 55 
6.2.2.4.6. 
Pharmacokinetic sampling ...................... 55 
6.2.2.4.7. 
Anti-drug Antibodies sampling ................ 55 
6.2.2.5. 
Adverse Events ............................................................ 56 
6.3. 
Efficacy Procedures ....................................................................................... 56 
6.3.1. 
Intracranial Pressure ...................................................................... 56 
6.3.2. 
Visual Assessments ....................................................................... 56 
6.3.2.1. 
Optical Coherence Tomography .................................. 56 
6.3.2.2. 
Humphrey Visual Field ................................................. 57 
6.3.2.3. 
Visual Acuity ................................................................. 57 
6.3.3. 
Headache Assessments ................................................................ 57 
6.3.3.1. 
Headache Preventative Medication Review ................ 58 
6.3.4. 
Patient Reported Outcomes .......................................................... 58 
6.3.4.1. 
Visual related................................................................ 58 
6.3.4.2. 
Health-related ............................................................... 58 
6.3.4.3. 
Headache related Quality of Life ................................. 58 
6.3.4.4. 
Patient Global Impression of Change .......................... 58 
6.3.5. 
Body Weight and Body Mass Index ............................................... 59 
7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS ..........................................60 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS .............................................64 
9. 
INVESTIGATIONAL PRODUCT .........................................................................64 
9.1. 
Dosage and Administration ........................................................................... 64 
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9.1.1. 
Randomised Period........................................................................ 64 
9.2. 
Dose Rationale .............................................................................................. 65 
9.3. 
Maintaining the Blind ..................................................................................... 65 
9.4. 
Treatment Assignment .................................................................................. 65 
9.5. 
Packaging and Labelling ............................................................................... 66 
9.6. 
Preparation .................................................................................................... 66 
9.7. 
Handling and Storage .................................................................................... 66 
9.8. 
Product Accountability and Assessment of Compliance .............................. 66 
9.9. 
Treatment of Investigational Product Overdose............................................ 66 
9.10. 
Occupational Safety....................................................................................... 67 
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ....................67 
10.1. 
Recording Prior and Concomitant Medication .............................................. 67 
10.1.1. 
Treatment Failure ........................................................................... 67 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive 
Visual Loss ..................................................................................... 68 
10.1.2.1. Rescue Therapy for Headache .................................... 68 
10.2. 
Prohibited Medications .................................................................................. 68 
10.2.1. 
Prior to enrolment ........................................................................... 68 
10.2.2. 
Prior to randomisation (visit 2) ....................................................... 69 
10.2.3. 
During the trial ................................................................................ 69 
11. PATIENT COMPLETION AND WITHDRAWAL ..................................................69 
11.1. 
Patient Completion ........................................................................................ 69 
11.2. 
Patient Withdrawal ......................................................................................... 70 
11.2.1. 
Patient Withdrawal from Trial Treatment ....................................... 70 
11.3. 
Treatment after the End of the Trial .............................................................. 70 
11.4. 
Screen and Baseline Failures ....................................................................... 70 
12. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................70 
12.1. 
Adverse Events .............................................................................................. 70 
12.1.1. 
Causal Relationship ....................................................................... 71 
12.1.2. 
Severity Criteria .............................................................................. 71 
12.1.3. 
Reporting Adverse Events ............................................................. 72 
12.2. 
Serious Adverse Events ................................................................................ 72 
12.2.1. 
Suspected Unexpected Serious Adverse Reactions..................... 73 
12.2.2. 
Expected Adverse Events .............................................................. 73 
12.2.3. 
Reporting Serious Adverse Events ................................................ 73 
12.3. 
Reporting and Handling of Pregnancies ....................................................... 74 
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ..............................75 
13.1. 
Hypotheses .................................................................................................... 75 
13.2. 
Trial Design Considerations .......................................................................... 75 
13.2.1. 
Sample Size Assumptions ............................................................. 75 
13.2.1.1. Intracranial Pressure Power ........................................ 77 
13.2.1.1. Perimetric Mean Deviation Power ............................... 78 
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13.2.2. 
Stratification.................................................................................... 79 
13.2.3. 
Sample Size Sensitivity .................................................................. 79 
13.2.3.1. Clinically Meaningful Effect Sizes ................................ 79 
13.2.4. 
Sample Size Re-estimation............................................................ 80 
13.2.5. 
Trial Stopping Criteria .................................................................... 80 
13.3. 
Data Analysis Considerations ....................................................................... 80 
13.3.1. 
Estimands ....................................................................................... 80 
13.3.1.1. Outcome: Intracranial pressure (ICP) .......................... 80 
13.3.1.1.1. Intercurrent event: ICP-lowering 
medications.............................................. 80 
13.3.1.1.2. Intercurrent event: Off-protocol 
lumbar punctures ..................................... 81 
13.3.1.1.3. Inter-current event: Dramatic 
weight-loss following surgery .................. 81 
13.3.1.2. Outcome: Perimetric Mean Deviation (PMD) .............. 81 
13.3.1.2.1. Intercurrent event: ICP-lowering 
medications.............................................. 81 
13.3.1.2.2. Intercurrent event: Off-protocol 
lumbar punctures ..................................... 82 
13.3.1.2.3. Intercurrent event: Dramatic 
weight-loss following surgery .................. 82 
13.3.1.3. Outcome: Papilledema measured by OCT 
(including central thickness, CT, retinal nerve 
fibre layer, RNFL) ......................................................... 83 
13.3.1.3.1. Intercurrent event: ICP-lowering 
medications.............................................. 83 
13.3.1.3.2. Intercurrent event: Off-protocol 
lumbar punctures ..................................... 83 
13.3.1.3.3. Intercurrent event: Dramatic 
weight-loss following surgery .................. 83 
13.3.1.4. Outcome: Monthly headache days (MHD) .................. 84 
13.3.1.4.1. Intercurrent event: Headache-
preventative medications......................... 84 
13.3.1.4.2. Intercurrent event: Off-protocol 
lumbar punctures ..................................... 84 
13.3.1.4.3. Intercurrent event: Dramatic 
weight-loss following surgery .................. 84 
13.3.1.4.4. Intercurrent event: ICP-lowering 
medications.............................................. 85 
13.3.1.4.5. Intercurrent event: Off-protocol 
lumbar punctures ..................................... 85 
13.3.1.4.6. Intercurrent event: Dramatic 
weight-loss following surgery .................. 85 
13.3.1.5. Primary Estimand (Hypothetical assuming no 
concurrent procedures, irrespective of 
adherence to treatment) ............................................... 86 
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13.3.1.6. Secondary Estimand (Hypothetical) ............................ 86 
13.3.2. 
Analysis Populations ...................................................................... 87 
13.3.3. 
Treatment Comparisons ................................................................ 87 
13.3.4. 
Safety Analyses ............................................................................. 87 
13.3.4.1. Adverse Events ............................................................ 88 
13.3.4.2. Clinical Laboratory Evaluations ................................... 89 
13.3.4.3. Vital Signs and Body Mass Index Evaluations ............ 89 
13.3.4.4. Electrocardiogram ........................................................ 89 
13.3.5. 
Patient Reported Outcomes Analyses ........................................... 90 
13.3.6. 
Missing Data................................................................................... 90 
13.3.7. 
Reporting Deviations from the Statistical Plan .............................. 90 
14. TRIAL ADMINISTRATION...................................................................................90 
14.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................... 90 
14.2. 
Trial Monitoring .............................................................................................. 91 
14.2.1. 
Access to Source Data .................................................................. 91 
14.2.2. 
Data Handling and Record Keeping .............................................. 92 
14.3. 
Provision of Trial Results and Information to Investigators and 
Publications.................................................................................................... 92 
14.4. 
Data Management ......................................................................................... 93 
14.5. 
Independent Adjudication Committee ........................................................... 94 
14.6. 
Data Safety Monitoring Committee ............................................................... 94 
14.7. 
Insurance, Indemnity and Finance ................................................................ 94 
15. REFERENCES ....................................................................................................95 
16. APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-301........................ 104 
16.1. 
Appendix 1: IIH Diagnostic criteria [Mollan, 2018] ...................................... 104 
16.2. 
Appendix 2: 36-item short from survey ....................................................... 105 
16.3. 
Appendix 3: EuroQol -5 dimension-5 level survey ...................................... 111 
16.4. 
Appendix 4: Headache Impact Test-6 ......................................................... 114 
16.5. 
Appendix 5: Visual Function Questionnaire-25 & 10-item 
Supplement .................................................................................................. 116 
16.6. 
Appendix 6: Patient Global Impression of Change ..................................... 134 
16.7. 
Appendix 7: Contraception .......................................................................... 135 
 
 
 
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ABBREVIATIONS 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCRF 
Electronic Case Report Form 
BMI 
Body Mass Index 
CGRP 
Calcitonin Gene-Related Peptide 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DGM 
Data-Generating Models 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
GCL 
Ganglion Cell Layer 
GLP-1 
Glucagon Like Peptide-1 
HVF 
Humphrey Visual Field 
ICF 
Informed Consent Form 
ICP 
Intracranial Pressure 
IAC 
Independent Adjudication Committee 
ICH-GCP 
International Council of Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IIH 
Idiopathic Intracranial Hypertension 
ITT 
Intention-to-Treat 
LP 
Lumbar Puncture 
MAR 
Missing At Random 
MD 
Mean Deviation 
MHD 
Monthly Headache Days 
NRS 
Numeric Rating Scale 
OCT 
Optical Coherence Tomography 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QTcF 
QT Interval corrected according to Fridericia’s formula 
RNFL 
Retinal Nerve Fibre Layer 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SF-36 
36-item short form survey 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
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VFQ-25-10 item  
Visual Function Questionnaire-25 and 10-item supplement 
 
 
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PROTOCOL SUMMARY 
Rationale 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends.  
IIH has significant associated morbidity and reduced quality of life. Elevated ICP causes 
papilloedema universally at disease onset and can lead to permanent visual loss. Visual 
loss occurs in greater than 90% of those with IIH [Wall 1991] and can be severe and 
permanent in between 5-25%. Besides risk of visual loss, the most disabling aspect for 
patients is severe chronic headaches driven by elevated ICP. Existing pharmacotherapies 
are limited. The most frequently used drug therapy, acetazolamide, is used off label and 
has been shown to have efficacy but due to side effects and treatment failures new drugs 
are needed. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but the high failure rates are high and frequent complications 
and side effects occur. 
A modified release formulation of exenatide (Presendin) has been developed and this trial 
has been designed to evaluate the efficacy and safety of Presendin in IIH. The modified 
release formulation has been chosen to enable a once weekly dosing.  
Objectives 
Primary Objective 
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 lumbar 
puncture (LP) at baseline and at 24 weeks. 
Secondary Objectives 
To determine the effect of Presendin on change in: 
• 
Perimetric Mean Deviation (PMD) as measured by Humphrey Visual Field analysis 
(24-2 SITA-Standard) 
• 
Papilloedema by change in optical coherence tomography (optic nerve head volume 
and retinal nerve fibre layer (RNFL) thickness)  
• 
Monthly headache days (MHD) 
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• 
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 
Safety Objectives 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Ganglion cell layer thickness 
• 
Retinal nerve fibre layer thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes (PROs) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation 
Endpoints 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
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Secondary Endpoints 
• 
Perimetric Mean Deviation 
• 
Optic nerve head size 
• 
Retinal nerve fibre layer thickness 
• 
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 and 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 
• 
Treatment failure, defined as initiation of either medical therapy or a surgical 
intervention to lower ICP.* 
*criteria defined in rescue therapy section 10.1.1 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), adverse events of 
special interest (AESIs), serious adverse events (SAEs) 
• 
Resting 12-lead ECG 
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
Exploratory Endpoints 
• 
Ganglion cell layer thickness 
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• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes: 
• 
Visual Function Questionnaire-25 and 10-item supplement (VFQ-25-10 item 
supp) 
• 
Headache Impact Test -6 (HIT-6) 
• 
36-item short from survey (SF-36) 
• 
EuroQol -5 dimension -5 level (EQ-5D-5L) survey  
• 
Patient Global Impression of Change (PGIC) 
• 
Body Mass Index (BMI) 
• 
Body Weight 
• 
Health Utilisation  
Trial Design 
 
This is a randomised, placebo-controlled, double-blind, multi-centre trial requiring 
240 adult randomised patients with IIH to determine the efficacy and safety of Presendin. 
Consenting patients with a diagnosis of IIH will enter a 1-week screening period, in 
which there will be no investigational treatment, in order to gather baseline 
measurements and to check eligibility. Although a headache diary is typically over 28 
days, it was felt unethical to have patients off treatment for this more prolonged period 
due to the real risk of visual loss. Headache diaries designed to measure headache 
frequency have successfully utilised over shorter time periods in previous IIH trials and 
noted to be representative [Mollan, 2021]. Hence the baseline headache frequency will be 
calculated over 1 week as has been done in other trials. 
At the screening visit, patients will be provided with training on the self-administration of 
the trial medication and provided with a leaflet to take home. Patients will be asked to 
self-administer one (1) dose of placebo during the screening visit to ensure they are 
comfortable with self-injection. Patients who are not comfortable with self-administration 
will be deemed a screen failure and will not be randomised into the trial. Eligible patients 
will then be randomised to receive either Presendin or matching placebo for 24 weeks in 
a 1:1 ratio. After completion of the randomisation period patients will have an end of 
treatment clinic visit. Four weeks after the end of treatment visit, an end of trial safety 
follow up telephone visit will also be performed.  
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The duration of the double-blind treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy over a 3-month time 
horizon. Additionally, an alternative off label drug used in IIH (acetazolamide) evaluated 
efficacy over a 6-month period. Hence efficacy is relevant over this time frame. A longer 
period of randomisation would not be ethical if patients were expected to remain on 
placebo for 12 months as this could place their overall health at risk. The duration of the 
trial for each patient will be up to 30 weeks, which includes a 2-week screening period, a 
24-week randomised double-blind treatment period, and a treatment follow-up period of 
4 weeks. 
Trial Population 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of IIH by consensus criteria (see Section16.1, Appendix 1), 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. Lumbar puncture opening pressure ≥ 25 cm H2O cerebrospinal fluid (CSF) at 
baseline 
4. Screening commenced no more than 4 weeks after the diagnostic LP  
5. Presence of bilateral papilloedema established from (optical coherence 
tomography) OCT imaging by the reading centre (Frisén grade ≥1). Where there 
is uncertainty fundus photography and/or ultrasound scan (B scan) of the optic 
nerve should be conducted for evaluation by the reading centre 
6. Perimetric mean deviation (PMD) (with mild/moderate visual loss) -2 to -7 
decibels (dB) 
7. Reproducible visual loss present on automated perimetry including no more than 
15% false positive responses (reliability confirmed by the reading centre) 
8. Greater than 3 days headache 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 – see Section 16.7, Appendix 7 for 
further details) during the whole trial duration including the last follow-up visit 
(12 weeks after ceasing drug). Female patients who are lactating must agree to 
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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. Greater than 2 weeks prior to screening since COVID-19 vaccination (for 
patients that have received the Covid-19 vaccination)  
12. Able to provide written informed consent 
Patients must not be enrolled if they meet any of the following exclusion criteria: 
IIH related exclusions 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 nerve palsy or palsies) 
5. Treatment to lower ICP within 1 week prior to screening visit (e.g., 
acetazolamide, topiramate, diuretics, glucocorticoids (oral dexamethasone and 
oral prednisolone)) 
Vision related exclusion criteria: 
6. Patients with a past ophthalmic history or diseases causing visual loss, other than 
cataract extraction, or pre-existing optic disc or retinal diseases that may (in the 
opinion of the Independent Adjudication Committee [IAC]) affect interpretation 
of the visual outcomes (e.g., ischaemic optic neuropathy, optic neuritis, 
pronounced optic disc drusen, optic atrophy, retinal, or choroidal diseases) 
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7. Existing clinically relevant optic atrophy which, in the opinion of the IAC, may 
affect interpretation of the visual outcomes  
8. Refractive error > +/- 6.00 sphere or > +/- 3.00 cylinder in either eye. In 
addition, participants with myopia of >-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. Poor Humphrey Visual Field (HVF) test quality which, in the opinion of the 
IAC, may affect interpretation of the HVF that is not rectified through repeat 
testing 
Headache related exclusion criteria: 
10. Has received botulinum toxin or monoclonal antibodies targeting calcitonin 
gene­related peptide (CGRP) or CGRP antagonist injections within the last 4 
months for headache or has intention to initiate such injections during the trial 
11. Has undergone nerve block (occipital or other) in the head or neck within the 
last 4 weeks or has intention to undergo nerve block in the head or neck during 
the trial 
12. Does not complete ≥6 days of electronic/paper trial diary during the 7-day 
screening period 
Other exclusion criteria: 
13. Untreated documented obstructive sleep apnoea with historically recorded 
apnoea­hypopnea index greater than 15 
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, in the opinion of the investigator or the IAC, may affect the 
safety of the patient 
16. Currently taking or has received a GLP-1 receptor agonist within the last 4 
weeks 
17. Using any glucose-lowering medication 
18. Currently taking warfarin 
19. 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 
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predominantly indirect [with normal direct bilirubin level]; and ALT, AST and 
ALP ≤1x ULN) 
20. Kidney disease (as defined by serum cystatin C-based estimated glomerular 
filtration rate [eGFR] <55 mL/min/1.73 m2, calculated at investigator site)  
21. 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) 
22. Using recreational (including cannabidiol) or illicit drugs (including marijuana) 
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 
23. Is unable to self-administer the trial medication (or unable to administer trial 
medication with support) after receiving training during the Screening period 
24. 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 
25. Has participated in any other interventional trial within 1 month prior to the 
screening visit. COVID vaccination trials are not considered an exclusion 
criteria provided the COVID vaccination has occurred  > 2 weeks prior to 
screening visit. 
26. Is pregnant or breastfeeding 
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Trial Assessments 
Table 1: Time and Events 
 
 
SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
28 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
197 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X  
(review) 
 
 
 
 
 
 
 
 
 
 
Demography (sex, age, 
ethnicity) 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical & Ophthalmic 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Headache history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Headache preventative 
medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Train and dispense 
headache diary 
X 
 
 
 
 
 
 
 
 
 
 
 
Review headache diary1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
28 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
197 
Body weight and BMI 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examination 
(T = targeted) 
X  
(Full) 
X (T) 
 
 
 
X (T) 
 
X (T) 
X(T) 
X (T) 
 
(X) 
Urine Pregnancy Test 
(HCG)3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Electrocardiogram 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
OCT Imaging  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
Papilloedema Frisén 
grade4   
X 
X 
 
 
 
 
 
 
 
 
 
 
Perimetry  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visual Acuity Testing 
(LogMAR score) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
 
Patient Reported 
Outcomes 
(HIT-6, SF-36, EQ-5D-5L, 
VFQ-25 & 10-item supp) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Health Utilisation Form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC assessment 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments5  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
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SCREENING 
PERIOD1 
RANDOMISED 
PERIOD11 
 
FOLLOW UP 
Visit 
V1  
Clinic 
V2 
Clinic 
Baseline 
V3 
TC 
V4 
Clinic 
 
V5 
Clinic 
V6 
Clinic 
V7 
Clinic 
V8 
Clinic 
V9 
Clinic 
V1012 
Clinic 
Unscheduled 
repeat visual  
assessments13 
V11 
TC/Clinic14 
Visit Window (days) 
 
+3 
± 1 
± 3 
± 3 
± 5 
± 5 
± 5 
± 5 
± 14 
 
± 5 
Month  
0 
0 
 
 
1 
2 
3 
4 
5 
6 
 
 
Week 
-1 
0 
 
2 
4 
8 
12 
16 
20 
24 
 
28 
Day 
-7  
1  
3 
15 
29 
57 
85 
113 
141 
169 
 
197 
Pharmacokinetic (PK) 
sampling6 
 
X7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-Drug Antibodies 
(ADA) sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Lumbar Puncture8 
 
 
 
 
 
 
 
 
 
X9 
 
 
Trial medication training10 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
Trial medication 
Dispensing  
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Trial medication 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
1 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Patients who do not meet the eligibility criteria based on diary review at 
randomisation/baseline (e.g., too few headache days or unacceptable concomitant medication use) will be considered screen failures; however, if the patient wishes and 
the Investigator is in agreement, he/she can be re-screened as a new patient. If the screening period exceeds 7 days, then eligibility will be based on the last 7 days of the 
screening period, i.e., the 7 days prior to randomisation visit. Trial site research team should review diaries remotely on a weekly basis to ensure compliance and follow 
up any patients with missing data 
2 
Vital signs to include: blood pressure and heart rate 
3 
Women of child-bearing potential 
4 
Frisén grade will be determined by OCT at a central reading centre at screening to confirm eligibility. Indeterminate cases should be referred to the IAC to allow option 
to repeat OCT and confirm papilloedema grade prior to randomisation visit 
5 
Haematology, biochemistry and urinalysis 
6 
All actual sampling times and dosing times will be recorded 
7 
Baseline Pre-dose PK blood sample 
8 
The diagnostic LP will be the baseline LP and must be performed in lateral decubitus position. Patients with ICP <25 cm H2O CSF at baseline will be excluded  
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9 
Lumbar puncture to be performed after visual assessment. CSF sample from visit 10 LP will be retained for future potential analysis 
10 
Patients will be provided with training on the self-administration of the trial medication. The patient will be asked to self-administer placebo at visit 1 to demonstrate 
ability to self-inject. Patients who are not comfortable to self-inject will be excluded 
11 
If patients discontinue in the double-blind treatment period they will be encouraged to return for all trial visits up to visit 11. If a patient does not want to return for all 
visits then they will be asked to return at a minimum for visit 11 procedures for safety follow up 
12 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial medication and must have self-administered their final dose within 7 days of 
visit 10. Patients will be reminded by the trial site to self-administer trial medication weekly, to continue this until the completion of visit 10 and to bring their trial 
medication with them at visit 10 for return. 
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial medication has been missed in the previous 4 weeks. Visit 10 should be delayed no 
more than 14 days 
13 
Optional visit for visual testing (HVF, OCT, LogMar) for patients who perform inadequately or where there is technical failure (more than 15% false positive responses 
for HVF; or OCT imaging not amenable to segmentation (even when manually corrected) which, in the opinion of the IAC, may affect interpretation of the OCT 
imaging) 
14 
In the event of any abnormal safety assessments identified at end of treatment, e.g., abnormal ECG, abnormal routine laboratory results or ongoing adverse events, this 
visit may be performed at the clinic to repeat or follow up safety assessments 
 
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background and Rational 
Idiopathic intracranial hypertension (IIH) is a condition characterised by raised 
intracranial pressure (ICP) with unknown aetiology, occurring most frequently in obese 
women of childbearing age. IIH is a rare condition; however, incidence is increasing with 
rising obesity trends [Mollan, 2019a]. There is a high rate of repeat hospital admission in 
IIH (increased by 446% in last decade), reflected in escalating healthcare costs (in 
England £462 million/year predicted by 2030 [Mollan, 2019a] and more than $444 
million in the USA [Friesner, 2011]). 
The cause of IIH is not fully understood. Recent research has identified that IIH is a 
disease of systemic metabolic dysregulation  characterised by central adiposity 
[Hornby, 2017], doubled the risk of cardiovascular disease in excess to that mediated by 
obesity [Adderley, 2019] and adipocyte metabolism primed for weight gain 
[Westgate, 2021]. Patients are also insulin resistant and have a unique hormone signature 
of androgen excess in both systemically and in the cerebrospinal fluid.[O’Reilly, 2019] 
Morbidity in IIH is due to the elevated intracranial pressure which can cause severe 
papilloedema (swelling of the optic nerve) which can ultimately lead to blindness. The 
risk of permanent visual loss is a major concern in IIH. Visual loss occurs in greater than 
90% of those with IIH [Wall 1991] and can be severe and permanent in between 5-25%. 
Headache is an additional major disabler and affects the majority of IIH patients (over 
90%) [Yri, 2014; Markey, 2016; Mulla 2015] in the long term. Headaches significantly 
reducing quality of life [Mulla, 2015; Digre, 2015] are driven by raised intracranial 
pressure and often have a migraine- like phenotype (> 90%) [Mollan 2021a].  
Existing pharmacotherapies are limited. The most frequently used drug therapy, 
acetazolamide, is used off label and has been shown to have efficacy but due to side 
effects and treatment failures new drugs are needed. [Piper, 2015; Mollan, 2018; 
Hoffmann, 2018]. Surgical therapy to lower ICP is a last resort and used as an emergency 
procedure to save vision but there is a high failure rate and frequent complications. The 
lack of licenced or targeted treatments in IIH perpetuates poor outcomes for patients. A 
priority setting exercise was run by patients with IIH (James Lind methodology) [Mollan, 
2019c] establishing effective therapy was the top priority from the patient group. 
This trial will investigate an alternative therapeutic option for lowering ICP and thereby 
reducing papilloedema and consequently reducing the risk of visual loss. By reducing 
ICP it would also aim to improve headache, improving overall patient quality of life in 
IIH [Mollan 2021a]. 
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Gut neuropeptides are increasingly being recognised for their role in the central nervous 
system (CNS). A principal gut neuropeptide is glucagon like peptide-1 (GLP-1), which is 
known to stimulate insulin release, proliferation of pancreatic beta cells and control of 
glucose regulation in diabetes [Campbell, 2013]. Exenatide is a GLP-1 receptor agonist. 
It has also been shown to have some actions in the CNS; GLP­1 is involved in regulating 
satiety and weight through signalling at the hypothalamus [Astrup, 2009]. There is also 
evidence that GLP-1 may have a role in fluid secretion. In the renal proximal tubule 
GLP-1 acts to reduce sodium resorption to promote diuresis [Gutzwiller, 2004; 
Websky, 2014]. The choroid plexus is the fluid secreting structure within the brain 
producing the majority of CSF. The structure of the choroid plexus epithelial cells is 
analogous to an inverted renal proximal tubule with a similar mechanism of secretion and 
hence GLP-1 receptor agonists may also reduce CSF secretion in the brain, leading to a 
decrease in ICP in patients with IIH. 
Exenatide as well as other GLP-1 receptor agonists can lead to weight loss. In diabetic 
patients weight loss of 2.8 - 4.4 kg has been reported over 6 months [Di Dalmazi 2020; 
Pujante 2012]. Whilst in non-diabetic overweight and obese patients exenatide caused 
sufficient weight loss between 2.0 – 5.1 kg [Moreno 2012]. In overweight and obese 
patients with polycystic ovarian syndrome exenatide led to 2kg more weight loss 
compared to placebo in over 12 weeks [Liu 2017]. Weight loss with exenatide therapy is 
increased in the setting of calorie restriction [Rosenstock 2010]. Weight loss is a 
desirable effect of exenatide as weight loss is therapeutic in IIH. Changes in body weight 
will be monitored during the trial and the impact on outcomes measures evaluated. 
Exenatide (known as Byetta, developed by Amylin Pharmaceuticals LLC) is a currently 
approved drug for the treatment of type-2 diabetes. It has been identified as a potential 
candidate for the treatment of neurological conditions involving raised ICP and a 
modified release formulation, Presendin, has been developed for the treatment of IIH. 
Byetta has a known issue of rapid elimination of the product when given to humans, and 
because of this it needs to be administered twice daily to achieve its pharmacological 
effects. The data on file from the IIH Pressure trial has shown that in patients with IIH, 
exenatide administered twice daily was well tolerated and produced a positive effect on 
reducing CSF pressure. However, it is considered that the immediate release formulation 
of exenatide is not ideal for treating patients with IIH on a long-term basis. Presendin has 
been developed as a modified release formulation to allow for a reduction in dosing 
frequency to once weekly. 
This trial is designed to investigate the efficacy and safety of a modified release 
formulation of exenatide (Presendin) in patients with IIH.  
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Intracranial pressure 
IIH is a debilitating condition characterised by raised ICP, which is clinically measured 
by LP [Mollan, 2018]. The units for measurement of LP are cm CSF and cm H2O and 
these should be thought of as interchangeable and reflect the measurement of the height 
of the CSF column at LP. Lumbar puncture is conducted to make a diagnosis of IIH. 
Lumbar puncture may be conducted in a clinical setting during the disease course to both 
monitor and treat the condition. Frequent therapeutic LPs are no longer recommended by 
the International IIH guidelines [Mollan, 2018]. This is because LP can be traumatic for 
patients and can occasionally cause significant complications (meningitis, spinal 
haematoma, pain) [Wright, 2012]. Hence, unnecessary LP’s should be avoided. In some 
patients LP can alter other outcome measures, including measurements of papilloedema 
and headache [Yiangou, 2019]. Hence ideally, LP should be performed after these 
measures and symptoms have been assessed. Lumbar puncture can cause post-dural 
puncture headaches. The risk is 9-36% using a traumatic needle and 3-19% using an 
atraumatic needle [Wright, 2012]. Post-dural puncture headaches typically last less than a 
week but in some patients this can be longer [Yiangou, 2019]. Lumbar puncture pressure 
assessment of ICP reflects disease activity and is a useful and recognised outcome 
measure that has been utilised in other IIH trials [Markey 2020; Mollan 2021b]. 
Due to the invasive nature of LP, non-invasive measures of ICP are valuable. The 
majority of techniques historically evaluated as non-invasive surrogate measures of ICP 
lack sufficient quantification to be used clinically or in clinical trials.  Optical coherence 
tomography (OCT) measures of the optic nerve have been shown to provide a useful 
surrogate measure to quantify changes in ICP [Vijay, 2020]. For example, at 12 months, 
Vijay et al showed that a change in optic nerve head height of 50 µ predicted a 5 cm CSF 
change in ICP [Vijay, 2020]. 
Visual Function 
Perimetry is used to measure visual function in IIH clinical practice. This is assessed 
using a Humphrey Field Analyzer (program24-2 SITA standard) test. Patients are often 
unaware of their visual field loss until this becomes more severe and compromises daily 
activities. In patients with severe papilledema optic atrophy can develop (measured 
objectively as loss of the ganglion cell layer on OCT) and the loss of visual field becomes 
permanent. Patients at risk of rapidly progressive visual loss (also termed fulminant IIH) 
should receive emergency surgical intervention (most commonly a CSF shunt operation) 
[Mollan, 2018]. Patients requiring emergency surgery will not be recruited into this trial. 
Medical therapy is used to treat those IIH patients not requiring emergency surgical 
intervention and will be included in this trial. But it is expected that approximately 5-10% 
will go on to need more aggressive intervention. 
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Measuring visual function with perimetry has a number of challenges in IIH which need 
to be carefully considered. The visual field test is dependent on technician and patient 
performance and is prone to variability and inaccuracy [Cello, 2016; Wall, 2016]. 
Patients can perform poorly on automated perimetry [Cello, 2016], and there is a learning 
effect [Kutzko, 2000; Wall, 2016]. There are further confounding factors when 
considering interpretation of automated visual field testing in IIH. The high prevalence of 
functional vision loss, presenting as non-organic visual fields results in this disease, may 
bias trial outcomes [Kutzko, 2000; Ney, 2009]. Additionally, impaired executive function 
and attention deficits have been noted in IIH [Sørensen, 1986], and have been shown to 
impair performance of visual field testing in IIH [Grech, 2021]. 
The protocol has been designed with these challenges in mind and visual field testing 
performance will be assessed at trial entry with opportunity for repeated assessment in 
the setting of performance failure. The visual fields will be assessed at the visual reading 
centre. 
Papilloedema by change in optic nerve head size measured by OCT 
Papilloedema is a reliable sign of raised ICP [Dunn, 2002]. Change in papilloedema has 
been used by all the randomised control trials in IIH to date to determine clinical 
improvement [Ball, 2011; Wall, 2014]. Change in papilloedema has been graded by 
experts using the Frisén classification, although it is more reliably measured by OCT 
imaging [Ball, 2011; Wall, 2014]. Professional bodies and the literature endorse the use 
of OCT for monitoring papilloedema in IIH [Mollan, 2018]. 
Optical coherence tomography measures different aspects of the optic nerve. The optic 
nerve head size and retinal nerve fibre layer (RNFL) are measurements that both reflect 
swelling of the optic nerve and hence the extent of papilledema. Measures of macular 
volume can quantify the ganglion cell layer (GCL) which reflects axonal loss. Optic 
nerve head measures on OCT correlate with visual field sensitivity loss 
[Salgarello, 2001]. Analysis has shown that OCT measures of the RNFL significantly 
reflect changes in visual field perimetric mean deviation (MD) (for every 10µm increase 
in RNFL there was associated with a 0.6dB decrease in MD) [Rebolleda, 2009]. Optical 
coherence tomography measures of the macula volume have been shown to predict 
axonal loss of the optic nerve [Albrecht, 2017]. Most importantly, ganglion cell volume 
has been shown to significantly correlate with visual field MD [Vijay, 2020]. This 
indicates that the GCL can be measured to reflect visual function. In other neurological 
diseases OCT has also been found to measure neuronal loss and correlated with visual 
loss [Petzold, 2010]. In summary, OCT assessment of the optic nerve and GCL represent 
objective measures of papilledema and optic nerve axons which determine visual 
function. 
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The scan quality can be compromised if the automated software segmentation of the OCT 
is not accurate. This occurs particularly in those optic nerves with more pronounced 
papilloedema [Aojula, 2018]. Hence the quality and segmentation of all OCT scans will 
be assessed by the visual reading centre and repeated if of insufficient quality. 
Headache 
Headache is the predominant presenting feature in IIH [Mollan, 2019a]. Patient morbidity 
is high because of disabling headaches and they have been found to be the key driver for 
poor quality of life [Mulla, 2015; Digre, 2015]. Research into headache treatments were 
endorsed as clinically relevant by a priority setting partnership which included the 
opinions of the patients’ carers and physicians [Mollan, 2019c].  
It has been well documented that headache characteristics in IIH are typically migraine-
like (up to 90%) [Mollan, 2019b; Mollan 2021a]. The headache location can be halo-
cranial, frontal, temporal or parietal with features including nausea, throbbing pain, 
photophobia and phonophobia [Yri, 2015]. A Danish trial of 44 IIH patients noted that 
82% of patients had migraine-like attacks [Yri, 2014]. A prospective trial in 52 IIH 
patients in the UK characterised 80% of headaches as migraine-like [Yiangou, 2019]. As 
reported by the Idiopathic Intracranial Hypertension Treatment Trial, US, the headache 
phenotype was recorded as migraine or probable migraine in 68% of 144 patients with 
active IIH [Friedman, 2017]. A retrospective trial in Iran in 68 IIH patients characterised 
migraine-like headaches in 63% [Sina, 2017]. Other headache characteristics are typically 
tension-type or unclassified [Mollan, 2019b]. 
Hence whilst IIH headaches are not diagnostically the same as migraine according to the 
International Classification of Headache Disorders, 3rd edition Beta, they are very similar 
in character [Olesen, 2018]. The International Headache Society core outcomes for 
migraine are therefore applicable to IIH headaches [Tassorelli, 2018]. 
Headache in active IIH is driven by ICP. This is evidenced by the fact that removal of 
CSF fluid results in improved headache severity. In a prospective cohort study, headache 
severity improved in 71% following a standardised LP [Yiangou, 2019]. Ninety-five 
percent of IIH patients had improvement in headache symptoms at 1 month following 
shunt placement [Daou, 2020]. Weight loss leading to reduction in ICP also significantly 
reduced headache [Sinclair, 2010].  
Medications that reduce ICP have been shown to modulate headache. In an open label 
trial using topiramate and acetazolamide, both of which are known to modulate ICP 
[Scotton, 2019], relief of headache was reported after a mean treatment period of 3.75 
months in the topiramate group and 3.3 months in the acetazolamide group [Çelebisoy, 
2007]. 
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Importantly, headache measures (severity and monthly headache days) in IIH 
significantly correlate with changes in ICP [Mollan 2021a]. The IIH weight trial [Mollan, 
2021b], a randomised controlled parallel group multicentre trial in the United Kingdom, 
investigates weight management methods in IIH. Participants with active IIH (evidenced 
by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. The primary 
outcome was ICP as measured by LP opening pressure at 12 months, with secondary 
outcomes of ICP at 24 months and headache outcomes at 12 and 24 months. Headache 
severity was correlated with ICP at baseline; change in headache severity and monthly 
headache days correlated with change in ICP at 12 months. Importantly those with the 
greatest reduction in ICP over 12 months had the greatest reduction in headache 
frequency and severity. This implies that treatment of ICP should improve headache in 
IIH. 
The following headache outcomes are clinically relevant and are recommended by the 
American Headache Society [American Headache Society] and International Headache 
Society to identify patients who are benefiting from treatments. Headache outcomes are 
derived from a 28-day diagnostic headache diary. This is used in clinical trials to 
prospectively collect daily information on headache occurrence, severity, associated 
symptoms, and use of acute analgesic medications.  
Although a headache diary is typically over 28 days, for IIH headache it was felt 
unethical to have patients off treatment for this more prolonged period during screening 
due to the real risk of visual loss. Headache diaries designed to measure headache 
frequency have successfully utilised over shorter time periods in previous IIH trials and 
noted to be representative [Mollan 2021b]. Hence the baseline headache frequency will 
be calculated over 1 week as has been done in other trials. 
Monthly headache days  
Monthly headache days (MHD) will include all headache days, defined as those with an 
onset, continuation or recurrence, any severity or phenotype of headache and lasting at 
least 30 minutes or which require acute headache analgesia. This is the most relevant and 
objective measure of headache. 
Moderate to severe monthly 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. This 
outcome captures the more disabling headaches. 
Moderate to severe MHD was recently reported as the primary endpoint in a prospective 
open label study providing evaluation of the effectiveness of erenumab, a calcitonin 
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gene-related peptide (CGRP) monoclonal antibody, to treat headaches in IIH patients 
[Yiangou, 2021]. It is also used to measure headache in other secondary headache 
conditions such as persistent post traumatic headache [Aojula 2018; Ashina, 2020]. 
Headache responder rate (≥50% reduction in MHD) 
Headache responder rate (≥50% reduction in MHD) is the proportion of patients 
achieving at least 50% reduction in the mean number of MHD, of any intensity, from 
baseline to the defined trial end point. This criterion is clinically relevant as it is used as 
an empirical review for continuing or discontinuing headache therapy [Diener, 2020]. 
Responder rates can be used in meta-analyses of placebo controlled randomised 
controlled trials. 
Headache responder rate (≥50% reduction in moderate to severe MHD) 
Headache responder rate (≥50% reduction in moderate to severe MHD) is the proportion 
of patients achieving at least 50% reduction in the moderate to severe MHD from 
baseline to the defined trial end point. It is well recognized that 50% responder rates may 
not fully capture the benefits of treatment [Matharu, 2017]. For example, a patient may 
improve from a disabling 20 severe headache days per month to 11 moderate headache 
days per month. Despite this considerable clinical benefit, such a patient would not be 
considered a responder because headache days were not reduced by ≥50%, and as a result 
might lose access to beneficial treatment. Hence, responder rates of ≥30% are also 
important [Vernieri, 2019]. In IIH, a disorder of chronic severe headaches, a clinically 
meaningful treatment responder rate has not been definitively established, although the 
International Headache Society Clinical Trials Subcommittee has suggested the use of a 
≥30% reduction from baseline for chronic migraine.  
Headache severity 
Headache severity is an important measure and impacts quality of life. It is vital to 
consider some treatments which benefit headache may not reduce the MHD but if the 
severity is markedly improved this will lead to great overall functional benefit to the 
patient and is clinically relevant [Silberstein, 2008]. Recording the decrease in intensity is 
an indicator of reduced disability, which is clinically meaningful. 
Monthly use of acute headache rescue medications 
Use of acute headache analgesics reflects a judgement of the inefficacy of the test 
treatment; hence it is a helpful secondary outcome. In Sinclair et al. reduction in 
analgesic days was significant and associated with clinical remission of IIH [Sinclair, 
2010]. Additionally, a high portion of IIH, up to 48% [Yiangou, 2021] have medication 
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overuse and medication overuse headache, and reduction in analgesic days mitigates 
these. Reduction in monthly use of acute headache analgesic is an additional endpoint 
that contributes to clinically meaningful results. 
Quality of life in IIH 
IIH has a detrimental effect on all aspects of the patient’s quality of life; the majority of 
which is driven by headache [Kleinschmidt, 2000, Mulla, 2015; Daniels, 2007; Digre 
2015]. IIH also impacts visual function with PMD correlating with quality of life 
[Bruce 2016]. Patient reported outcomes in clinical trials are essential not only to permit 
health technology assessments and cost effectiveness analysis, but also as key outcomes 
for a therapy’s effectiveness [Deiner, 2019]. There is currently no IIH disease specific 
quality of life outcome measure. 
Whilst there are differences in the choice of the tools used in the trials, they all 
commonly used the short-form 36 health survey (SF-36) [Mollan, 2021, Wall, 2014, 
Digre, 2015; Bruce, 2016; Ball, 2011]. The physical component score of the SF-36 has 
been shown to correlate significantly with changes in ICP [Grech 2021]. The EuroQol –5 
dimension (EQ-5D-5L) [Euroqol, 1990] is typically employed for health technology 
assessments and cost effectiveness [Ottridge, 2017; Ball, 2011]. Using the EQ-5D-5L in 
isolation may lack sensitivity as compared to the SF-36 for IIH. The National Eye 
Institute Visual Function Questionnaire-25 and 10-item supplement [Mangione, 2001] 
has also been utilised to assess visual related quality of life in IIH and is associated with 
improvement in visual field [Bruce 2016; Mangione 1998; Raphael 2006]. The 10-Item 
neuro-ophthalmic supplement was found to be significantly discriminating in a previous 
IIH drug trial [Wall 2014].  
1.1.1. 
Name and Description of the Investigational Product 
Patients will receive active treatment, Presendin, or matching placebo.  
Presendin is a modified release formulation of exenatide. Exenatide is a GLP-1 receptor 
agonist currently used in the management of type 2 diabetes. Presendin consists of a drug 
part (white or greyish white powder in a clear vial) and a diluent part (colourless liquid in 
a pre-filled syringe). The drug part is suspended in the diluent part solution and 
administered as a suspension. The patient or responsible person will be responsible for 
rehydrating the product for injection. Presendin is administered as a once weekly SC 
sustained-release injection containing 2.0 mg exenatide. Matching placebo will also be 
supplied as 2 parts, as visually identical vial and pre-filled 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. Placebo is administered once weekly as a SC 
injection. 
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1.1.2. 
Non-clinical Studies 
Exenatide, the active ingredient of Presendin, has been previously developed and licensed 
as Byetta for the treatment of type 2 diabetes. A wealth of historical toxicological and 
pharmacological safety data is available in the public domain. Please see the 
Investigator’s brochure for data from rat and mouse studies which have investigated the 
Presendin formulation of exenatide. 
In vitro and in vivo data suggests that the choroid plexus, the CSF secreting structure in 
the brain, contains GLP-1 receptors [Ast 2020]. Preclinical studies in rodents demonstrate 
that GLP-1 agonists can regulate cerebrospinal fluid dynamics and reduce ICP [Botfield, 
2017]. 
Nonclinical pharmacology studies have shown that exenatide and GLP-1 agonists bind to 
and stimulate GLP-1 receptors equipotently. Due to the ability of exenatide to affect fluid 
homeostasis in the kidney, it was investigated for its potential to modulate CSF secretion 
and reduce ICP in rats. A single SC injection of exenatide rapidly (within 30 minutes) 
reduced ICP and maintained lower ICP for 6 days of dosing, suggesting that GLP-1 
receptor agonists could provide an alternative treatment for conditions with raised ICP 
[Botfield, 2017]. 
Exenatide was subjected to full toxicological assessments during its nonclinical 
development programme, details of which are publicly available in the Byetta® Product 
Monograph, 2019 and the FDA Pharmacology Review, June 2004 (Section 15). In 
summary, no lethality or serious toxicity was observed in mice, rats and monkeys 
following single doses up to 1500 µg/kg, 3000 µg/kg and 5000 µg/kg respectively. In 
repeat-dose toxicity studies decreased body weight gain and food consumption, a known 
pharmacological effect of exenatide, were observed in all studies. Exenatide caused no 
mortality or target organ toxicities in mice, rats and monkeys at doses up to 760μg/kg/day 
(182 days), 250 μg/kg/day (91 days), or 150 μg/kg/day (273 days) respectively. 
Reproductive toxicity data from animal studies showed that Byetta had a toxicological 
effect on foetal development at three times the human exposure levels in treatment of 
diabetes. A summary of the findings of the exenatide toxicological assessment 
programme is presented in the Investigator Brochure for Presendin.  
1.1.3. 
Clinical Studies 
Exenatide has undergone extensive healthy volunteer studies and clinical trials for over 
15 years. It is licensed as a formulation for SC injection to be used in conjunction with 
diet and exercise to improve glycaemic control in adults with type 2 diabetes. Details of 
the trials conducted on exenatide, SC injection formulation, are presented in the Byetta 
Product Monograph (Section 15). Data from these studies are notable as the dose of 
exenatide to be used in the indication of IIH is intended to produce exposure levels not 
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exceeding those experienced by patients receiving Byetta. It is anticipated that the 
proposed therapeutic dose of exenatide, in the modified release formulation Presendin, 
for treatment of IIH will be within the approved dose range of Byetta, achieving a level 
of total systemic exposure comparable with the immediate release Byetta formulation. 
Therefore, safety data available from the Byetta clinical development program are 
considered relevant and supportive of exenatide development in IIH.  
The efficacy of exenatide (Byetta) was evaluated in a Phase 2 randomised, placebo 
controlled, double-blind trial of exenatide in patients with active IIH (IIH:Pressure Trial). 
Sixteen patients with a diagnosis of active IIH (LP opening pressure >25 cm CSF and 
papilloedema) were identified and recruited to the trial. Participants had a telemetric ICP 
monitor implanted and were randomised to either exenatide (first dose was 2. 0 mcg 
followed by 10 mcg BD sub-cutaneous) or a matched placebo; allocation was 1:1. The 
treatment duration was 12 weeks. The trial was powered to seek significance to at least 
alpha < 0.1 and power at least 80% using equal group sizes. Data was analysed by 
hierarchical regression analysis. 16 participants were recruited, 15 were randomised and 
completed the study. At baseline the mean age was 28 ± 9 years, BMI 38.1 ± 6.2 kg/m2, 
ICP 23.5 ± 3.9 (equivalent to 32.0 ± 5.3 cm CSF). The primary outcome, change in 
intracranial pressure between arms, was significant: at 2.5 hours -4.2 ± 2.1 mmHg 
(equivalent to 5.7 ± 2.9 cm CSF), p=0.04, at 24 hours -4.7 ± 2.1 mmHg (equivalent to 6.4 
± 2.9 cm CSF), p=0.03, and at 12 weeks -4.1 ± 2.2 mmHg (equivalent to 5.6 ± 3.0 cm 
CSF), p=0.05. A significant reduction in monthly headache days was also observed 
amongst those on exenatide (-7.7 ± 9.2, p-0.069). LogMar visual acuity also significantly 
improved in the exenatide treated arm (-0.1 ± 0.05, p=0.036). No significant weight loss 
was observed in either arm and hence weight change is unlikely to have contributed to 
the reduction kin ICP observed. Exenatide was safe and well tolerated: no treatment 
related SAE’s were reported, 8 adverse events were reported in those taking exenatide. 
The most frequent adverse event, amongst those taking exenatide, was nausea (7 reports), 
the majority of these were mild and all reports were self-limiting. There were no patient 
withdrawals due to adverse events.  
 
1.1.4. 
Trial Conduct 
This trial will be conducted in accordance with the requirements of this document (the 
Clinical Trial Protocol), the Trial Reference Manual and also in accordance with the 
following as per country specific requirements:  
• 
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013) 
• 
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016) 
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• 
The United Kingdom Statutory Instrument 2004 No. 1031 and UKSI 2006 No.1928 
• 
European Union Directives 2001/20/EC and 2005/28/EC 
• 
United States Code of Federal Regulations Title 21 
• 
The Australian Therapeutic Goods Act, 1989, amended December 2020 and 
Therapeutic Goods Regulations, 1990, amended January 2021 
• 
Other country specific laws and regulations 
• 
Any amendments to these regulations  
1.2. 
Risk/Benefit Assessment 
Current treatments for IIH have limited efficacy and can cause disabling side effects. 
Acetazolamide, the most commonly used drug (off licence) has a high side effect profile 
(48% discontinued in a clinical trial due to intolerable side effects) [Ball, 2011]. 
Although IIH is a rare condition, incidence is rising with rising obesity trends. Improving 
IIH morbidity with new therapeutics is clearly an unmet need.  
Safety data for Presendin (exenatide) is based on the IB (Peptron Inc.). Warnings include 
pancreatitis, hypoglycaemia when used in combination with a sulfonylurea, renal 
impairment, severe gastrointestinal disease and hypersensitivity.  
Invex Therapeutics has considered these warnings and has defined eligibility criteria to 
ensure patient safety is paramount. As such patients with known contraindications to 
GLP-1 agonists, such as pancreatitis, ketoacidosis, severe gastrointestinal disease and 
renal impairment, will not be included. Additionally, diabetic patients receiving glucose 
lowering medication will be excluded. 
An Independent Adjudication Committee (IAC), as described in Section 14.5, will assist 
the Investigators when required with the eligibility criteria of the patients to be enrolled 
to ensure patient safety and the efficacy of the trial. 
The most common adverse reactions experienced with exenatide are nausea, 
hypoglycaemia (only when used with other glucose lowering drugs, but these patients are 
excluded from the trial), vomiting, diarrhoea, feeling jittery, dizziness, headache and 
dyspepsia. 
Patients receiving the active treatment during the randomised period may benefit by 
experiencing an improvement in their IIH symptoms, although this cannot be guaranteed. 
2. 
OBJECTIVES 
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2.1. 
Primary Objective 
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. 
2.2. 
Secondary Objectives 
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 (optic nerve head size and 
retinal nerve fibre layer (RNFL) thickness)  
• 
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 
2.3. 
Safety Objective 
To determine the safety of Presendin administered subcutaneously once weekly as 
determined by vital signs, the occurrence of adverse events (AEs), electrocardiogram 
(ECG) and routine laboratory assessments. 
2.4. 
Exploratory Objectives 
To determine the effect of Presendin on: 
• 
Ganglion cell layer thickness 
• 
Retinal nerve fibre layer thickness 
• 
Headache responder rate: ≥30% reduction in monthly headache days  
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• 
Headache responder rate: ≥30% reduction in moderate to severe monthly headache 
days  
• 
Patient Reported Outcomes 
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint is the change in ICP from baseline to Week 24 measured by LP. 
3.2. 
Secondary Endpoints 
• 
Perimetric Mean Deviation  
• 
Optic nerve head size 
• 
Retinal nerve fibre layer (RNFL) thickness 
• 
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 
• 
Treatment failure, defined as initiation of either medical therapy or a surgical 
intervention to lower ICP.* 
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*criteria defined in rescue therapy section 10.1.1 
3.3. 
Safety Endpoints 
• 
Vital Signs 
• 
Adverse events: Treatment-emergent adverse events (TEAEs), adverse events of 
special interest (AESIs), serious adverse events (SAEs) 
• 
Resting 12-lead electrocardiogram  
• 
Routine laboratory assessments (haematology, biochemistry and urinalysis) 
3.4. 
Exploratory Endpoints 
• 
Ganglion cell layer thickness 
• 
Responder rate monthly headache days (defined as ≥30%) 
• 
Responder rate moderate to severe monthly headache days (defined as ≥30% 
reduction) 
• 
Patient Reported Outcomes (PRO): 
• 
Visual Function Questionnaire-25 and 10-item supplement 
• 
Headache Impact Test-6 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
• 
Patient Global Impression of Change  
• 
Body Mass Index 
• 
Body Weight 
• 
Health Utilisation  
4. 
TRIAL DESIGN 
4.1. 
Summary of Trial Design 
4.1.1. 
Trial Design 
This will be a randomised, placebo-controlled, double-blind, multi-centre clinical trial in 
approximately 240 randomised patients with IIH.  
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The trial will begin with a 1-week screening period. Although a headache diary is 
typically over 28 days, it was felt unethical to have patients off treatment for this more 
prolonged period. Headache diaries designed to measure headache frequency have been 
successfully utilised over shorter time periods in previous IIH trials and noted to be 
representative [NORDIC, 2018; Mollan, 2021b]. Hence the baseline headache frequency 
will be calculated over 1 week. Patients will be provided with training on the self-
administration of the trial medication from the site trial coordinator and provided with a 
leaflet to take home at the screening visit. Patients will be asked to self-administer 
placebo during the screening visit to ensure they are comfortable with self-injection. 
Patients who are not comfortable with self-administration will be deemed screen failures, 
and not be randomised into the trial. The purpose of the screening period will be to 
establish baseline measurements and assess trial eligibility.  
The 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 SC dose of either Presendin 
(containing 2mg 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. Four weeks after the end of that treatment visit, an end of trial 
safety follow-up telephone visit will be performed. In the event of any abnormal safety 
assessments or ongoing adverse event(s) identified at end of treatment; for example, an 
abnormal ECG or abnormal routine laboratory results, this visit may be performed at the 
clinic and a safety follow-up performed as appropriate.  
The duration of the randomised treatment period was felt to be appropriate as the 
previous phase 2 trials of Exenatide in IIH demonstrated efficacy by 3 months. 
Additionally, an alternative off label drug used in IIH (acetazolamide) was evaluated over 
a 6-month period. Hence efficacy is relevant over this time frame. A longer period of 
randomisation would not be ethical if patients were expected to remain on placebo for 12 
months as this could place their overall health at risk. 
Assessments will be performed as outlined in Table 1. 
A schematic diagram of the trial can be seen in Figure 1. 
 
 
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Figure 1: Schematic Diagram 
 
4.1.2. 
Randomisation and Blinding 
At the end of the Screening period, eligible patients will be randomised to receive either 
Presendin or matching placebo in a 1:1 ratio using a computer system to generate 
randomisation codes. 
Investigators and other site personnel, patients, contract research organisation and 
Sponsor personnel will be blinded regarding the treatment during the randomised period. 
Only designated unblinded staff, not involved in the operational conduct of the trial, will 
be aware of the randomisation codes. 
The placebo will have the same appearance and reveal no differences, during 
administration, to either the Investigator or the patient. 
4.1.3. 
Duration of Patient Participation 
The duration of the trial for each patient will be up to 29 weeks, which includes a 1-week 
screening period, a 24-week randomised treatment period and a treatment follow-up 
period of 4 weeks.  
4.2. 
Stopping Rules 
4.2.1. 
Trial Stopping Rules 
There are no trial-specific stopping rules. The Sponsor maintains the right to stop the trial 
at any point. If this is done, then the Sponsor will provide the Investigators with the 
rationale for such early termination. 
Screening 
1 week 
screening 
period 
,-
Presendin 
Treatment 
/ __ _ 
r 
Endof 
Placebo 
24 weeks randomised 
double-blind treatment 
period 
Treatment 
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4.2.2. 
Individual Stopping Rules 
Patients will be withdrawn from the trial medication if they are unable to tolerate the trial 
medication and will continue to attend trial visits as per protocol. See Section 11 for 
further details. A Data Safety Monitoring Committee (DSMC) will be involved in 
decisions for patient safety (Section 14.6). 
4.3. 
End of Trial 
The end of trial is defined as last patient last visit. 
5. 
TRIAL POPULATION 
5.1. 
Number of Patients 
It is anticipated that approximately 300 patients will be required to enter the screening 
phase for 240 patients to be randomised into the treatment phase. 
5.2. 
Eligibility Criteria 
5.2.1. 
Inclusion Criteria 
Patients must not be enrolled unless they meet all the following criteria: 
1. Age >18 years at the time of consent 
2. Diagnosis of IIH by consensus criteria (see Section 16.1, Appendix 1), 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. Lumbar puncture opening pressure ≥ 25 cm H2O CSF at baseline 
4. Screening commenced no more than 4 weeks after the diagnostic LP  
5. Presence of bilateral papilloedema established from OCT imaging by the 
reading centre (Frisén grade ≥1). Where there is uncertainty fundus photography 
and/or ultrasound scan (B scan) of the optic nerve should be conducted for 
evaluation by the reading centre 
6. Perimetric mean deviation (PMD) (with mild/moderate visual loss) -2 to -7 
decibels (dB) 
7. Reproducible visual loss present on automated perimetry including no more than 
15% false positive responses (reliability confirmed by the reading centre) 
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8. Greater than 3 days headache 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 – see Section 16.7, Appendix 7 for 
further details) 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. Greater than 2 weeks prior to screening since COVID-19 vaccination (for 
patients that have received the Covid-19 vaccination)  
12. Able to provide written informed consent 
5.2.2. 
Exclusion Criteria 
Patients must not be enrolled if they meet any of the following exclusion criteria: 
IIH related exclusions 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 nerve palsy or palsies) 
5. Treatment to lower ICP within 1 week prior to screening visit (e.g., 
acetazolamide, topiramate, diuretics, glucocorticoids (oral dexamethasone and 
oral prednisolone)) 
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Vision related exclusion criteria: 
6. Patients with a past ophthalmic history or diseases causing visual loss, other than 
cataract extraction, or pre-existing optic disc or retinal diseases that may (in the 
opinion of the Independent Adjudication Committee [IAC]) affect interpretation 
of the visual outcomes (e.g., ischaemic optic neuropathy, optic neuritis, 
pronounced optic disc drusen, optic atrophy, retinal, or choroidal diseases) 
7. Existing clinically relevant optic atrophy which, in the opinion of the IAC, may 
affect interpretation of the visual outcomes  
8. Refractive error > +/- 6.00 sphere or > +/- 3.00 cylinder in either eye. In 
addition, participants with myopia of >-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. Poor Humphrey Visual Field (HVF) test quality which, in the opinion of the 
IAC, may affect interpretation of the HVF that is not rectified through repeat 
testing 
Headache related exclusion criteria: 
10. Has received botulinum toxin or monoclonal antibodies targeting calcitonin 
gene­related peptide (CGRP) or CGRP antagonist injections within the last 4 
months for headache or has intention to initiate such injections during the trial 
11. Has undergone nerve block (occipital or other) in the head or neck within the 
last 4 weeks or has intention to undergo nerve block in the head or neck during 
the trial 
12. Does not complete ≥6 days of electronic/paper trial diary during the 7 day 
screening period 
Other exclusion criteria: 
13. Untreated documented obstructive sleep apnoea with historically recorded 
apnoea­hypopnea index greater than 15 
14. Allergy/known hypersensitivity to the active substance and/or excipients of the 
investigational product 
15. Has known contraindications to GLP-1 receptor agonists (e.g., ketoacidosis, 
severe gastrointestinal disease, pancreatitis, renal impairment) which, in the 
opinion of the investigator or the IAC, may affect the safety of the patient 
16. Currently taking or has received a GLP-1 receptor agonist within the last 4 
weeks 
17. Using any glucose-lowering medication 
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18. Currently taking warfarin 
19. 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) 
20. Kidney disease (as defined by serum cystatin C-based estimated glomerular 
filtration rate [eGFR] <55 mL/min/1.73 m2, calculated at investigator site)  
21. 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) 
22. Using recreational (including cannabidiol) or illicit drugs (including marijuana) 
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 
23. Is unable to self-administer the trial medication (or unable to administer trial 
medication with support) after receiving training during the Screening period 
24. 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 
25. Has participated in any other interventional trial within 1 month prior to the 
screening visit. COVID vaccination trials are not considered an exclusion 
criteria provided the COVID vaccination has occurred > 2 weeks prior to 
screening visit. 
26. Is pregnant or breastfeeding 
6. 
TRIAL ASSESSMENTS AND PROCEDURES 
6.1. 
Procedures at Each Visit 
Trial procedures and timings are presented in the Time and Events Table, Table 1. 
No procedures should be performed prior to obtaining informed consent. All visits 
(except telephone call visits) should be performed at the clinic. Should a clinic visit not 
be possible, due to a patient self-isolating, the visit will be conducted at the earliest 
opportunity and will not constitute a protocol deviation. 
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6.1.1. 
Visit 1 Screening 
The screening period must be a minimum of 7 days, up to a maximum of 10 days. Visit 
procedures can be performed in a single visit or over a number of visits during the 
screening period. Ideally all screening procedures should be performed on the same day.  
• 
Obtain patient’s written informed consent 
• 
Eligibility criteria 
• 
Including confirmation that diagnostic LP occurred within the last 4 weeks with 
an opening pressure ≥ 25 cm CSF in lateral decubitus position  
• 
Demographics (sex, age and ethnicity) 
• 
Medical and ophthalmic history 
• 
Concomitant mediation history 
• 
Headache history 
• 
Headache preventative medication review 
• 
Headache diary dispensed and diary training – to be performed on first day of 
screening. 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Height, body weight and BMI 
• 
Full physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
Frisén grading will be inferred from the OCT imaging by the visual reading centre. 
Where there is uncertainty, fundus photos and or ultrasound scan (B scan) of the 
optic nerve should be conducted for evaluation by the reading centre 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
• 
Visual Acuity (LogMAR score) 
Visual assessments should be uploaded to the visual reading centre at the earliest 
opportunity during the visit to ensure satisfactory quality. Quality reports would be 
received within 24 hours and those visual tests failing to meet criteria would be 
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repeated at the earliest opportunity with in the screening timeframe (up to 7 days)  at 
an unscheduled visit 
• 
Laboratory assessments 
• 
Trial medication training. Patients will be asked to self-administer 1 dose of placebo 
at the screening visit to ensure they are comfortable with self-injection. Patients who 
are not comfortable will be excluded 
6.1.2. 
Visit 2 Baseline 
• 
Review eligibility criteria 
• 
Concomitant medications review 
• 
Headache preventative medication review 
• 
Review headache diary (Patient must meet required number of headache days as per 
inclusion criteria. If the headache diary exceeds 7 days, then eligibility will be based 
on the last 7 days of the screening period, i.e. the 7 days prior to randomisation visit) 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI 
• 
Adverse events review 
• 
Targeted physical examination 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Electrocardiogram 
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
 
Optical coherence tomography Imaging will be used to confirm equivalent 
or increased papilloedema from visit 1. Where papilloedema has reduced, 
Frisén grading must be re-performed (by the visual reading centre) to 
confirm eligibility prior to randomisation  
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
A quality assessment should take place at site to ensure no more than 15% 
false positives in line with eligibility criteria. Where the visual field quality 
lies outside this parameter it should be repeated 
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• 
Visual Acuity (LogMAR score) 
Visual assessments should be uploaded to the visual reading centre at the earliest 
opportunity during the visit. If the quality is insufficient they should be repeated at 
an unscheduled visit 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary 
• 
Health Utilisation Form 
• 
Laboratory assessments 
• 
Pharmacokinetic sampling (pre-dose) 
• 
Anti-Drug Antibodies (ADA) blood sampling  
• 
Patient randomised  
• 
Trial medication training 
• 
Trial medication dispensed and first dose self-administered at clinic. Patients will 
then be instructed to administer subsequent doses once weekly. 
6.1.3. 
Visit 3 Telephone call 
All patients will receive a telephone call at visit 3 to conduct headache preventative 
medication review, check for any AEs or changes in medication, procedures outside of 
protocol, health utilisation, to remind them to complete their diary and to answer any 
questions they may have on administration or storage of the trial medication.  
6.1.4. 
Visits 4, 5, 6, 7, 8 and 9 Clinic visits 
• 
Concomitant medication review 
• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI (not visit 4) 
• 
Adverse event review 
• 
Targeted physical examination (visit 6, 8 and 9 only) 
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
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• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging  
• 
Humphrey Visual Field (24-2 SITA-Standard)  
 
A quality assessment should take place at site to ensure no more than 15% 
false positives. Where the visual field quality lies outside this parameter it 
should be repeated. 
• 
Visual Acuity (LogMAR score) 
Visual assessments should be uploaded to the visual reading centre at the earliest 
opportunity during the visit to ensure satisfactory quality. Quality reports would be 
received within 24 hours and those visual tests failing to meet criteria would be 
repeated at the earliest opportunity at an unscheduled visit. 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary (not visit 4)  
• 
Health Utilisation Form 
• 
Laboratory assessments  
• 
Pharmacokinetic blood sampling  
• 
Anti-Drug Antibodies blood sampling  
• 
Trial medication dispensing (not Visit 4) and accountability -patients should be 
reminded by the trial site to self-administer the trial medication weekly and to return 
used and unused trial medication at clinic visits. 
6.1.5. 
Visit 10 
In the 4 weeks prior to visit 10, patients must not have missed more than one dose of trial 
medication and must have self-administered their final dose within 7 days of visit 10. 
Patients will be reminded by the trial site to self-administer trial medication weekly, to 
continue this until the completion of visit 10 and to bring their trial medication with them 
at visit 10 for return.  
Where more than one dose has been missed during the 4 weeks preceding visit 10, visit 
10 should be delayed. Self-administration of trial medication should continue at 7-day 
intervals and then visit 10 rescheduled to ensure no more than one dose of the trial 
medication has been missed in the previous 4 weeks. Visit 10 should be delayed no more 
than 14 days. 
• 
Concomitant medication review 
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• 
Headache preventative medication review 
• 
Headache diary review 
• 
Vital signs (triplicate readings for blood pressure and heart rate will be taken at 1-
minute intervals) 
• 
Body weight and BMI  
• 
Adverse event review 
• 
Targeted physical examination  
• 
Urine pregnancy test for women of child-bearing potential  
• 
Electrocardiogram  
• 
Visual Assessments to both eyes 
• 
Optical coherence tomography Imaging 
• 
Humphrey Visual Field (24-2 SITA-Standard)  
• 
Visual Acuity (LogMAR score) 
Visual assessments should be uploaded to the visual reading centre at the earliest 
opportunity during the visit to ensure satisfactory quality. Where the quality is 
insufficient the test should be repeated at the earlier opportunity. 
All visual imaging assessments should ideally be performed prior to LP. 
• 
Lumbar puncture (within 7 days of last dose of trial medication) 
• 
Lumbar puncture to be performed after visual assessments 
• 
Patient reported outcomes: VFQ-25 & 10-item supp, HIT-6, SF-36 and EQ-5D-5L in 
diary  
• 
Health Utilisation Form 
• 
Patient global impression of change question 
• 
Laboratory assessments 
• 
Pharmacokinetic  blood sampling 
• 
Anti-drug antibodies blood sampling  
• 
Trial medication accountability 
Where it is not feasible to conduct all of visit 10 procedures on the same day, these could 
be split provided visual assessments are performed before the LP and the patient remains 
on trial medication with the last dose within 7 days of the LP. 
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6.1.6. 
Visit 11 Follow-Up  
This visit will be performed as a telephone call to conduct headache preventative 
medication review and check for any AEs or changes in medication. In the event of any 
abnormal safety assessments identified at the end of treatment, e.g., abnormal ECG, 
abnormal routine laboratory results or ongoing adverse events, this visit may be 
performed at the clinic to repeat or follow up safety assessments. 
6.1.7. 
Unscheduled visit for repeat visual assessments 
Optional visit for patients that perform visual assessments inadequately (OCT and/or 
HVF and/or LogMar) or where there is technical failure (more than 15% false positive 
response for HVF or OCT imaging not amenable to segmentation (even when manually 
corrected) which, in the opinion of the IAC, may affect interpretation of the OCT 
imaging). Imaging of eye in which there is inadequate performance only. 
• 
Optical coherence tomography (as required) 
• 
Humphrey Visual Field (24-2 SITA-Standard) (as required) 
• 
Visual Acuity, LogMAR score (as required) 
6.2. 
Trial Procedures 
6.2.1. 
Screening Procedures 
6.2.1.1. 
Demographics 
The Investigator, or designee, should record the patient’s sex, ethnicity, age, height, body 
weight and BMI at screening. 
Ethnicity data will be collected in order to monitor any response differences in IIH 
disease progression/symptoms in different ethnicities. 
6.2.1.2. 
Medical, Headache and Ophthalmic History 
The Investigator, or designee, should record any ongoing co-morbidities and significant 
medical, headache and ophthalmic history along with the year in which such 
co-morbidities began (where known).  
6.2.1.3. 
Reporting of Prior and Concomitant Medication 
Concomitant treatment is any medication or therapeutic intervention being continued by 
the patient at trial entry and any new medication received during the trial. Prior treatment 
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includes previous medications, treatments and interventions received in the past but no 
longer ongoing. 
For this trial, only relevant prior concomitant medications within the last 4 months will 
be recorded. These include: 
• 
Headache preventative medications 
• 
Intracranial pressure lowering drugs 
• 
Botulism toxin or monoclonal antibodies targeting CGRP or CGRP antagonist 
injections 
• 
Oral dexamethasone and oral prednisolone 
• 
Nerve block (occipital or other) in the head or neck 
• 
Glucose lowering medication 
• 
Recreational drugs 
At every visit the Investigator or a qualified designee will ask the patient about relevant 
concomitant medication. 
No new medication should be started during the trial, unless medically necessary. The 
patient should be advised to consult the Investigator or designee before taking any 
prescribed or over-the-counter medications. In the case of headache preventative 
medications or ICP lowering medications please see details in the rescue therapy section. 
Acute headache analgesics are permitted and should be reported in the diary. 
6.2.2. 
Safety Procedures 
6.2.2.1. 
Physical Examination 
A full physical examination will be performed at the screening visit. At a minimum the 
following will be assessed: ear, nose and throat, cardiovascular system, pulmonary 
system, skin, abdomen and neurological system. At all other time points a targeted 
(symptom directed) examination will be performed at the Investigator’s discretion. 
6.2.2.2. 
Twelve- Lead Electrocardiogram  
Twelve lead ECGs should be performed at the times outlined in the Time and Events 
table (Table 1) in a standardized manner, i.e., after the patient has rested in the semi-
supine position for at least 10 minutes. Measurements will be made using an ECG 
machine that automatically calculates the heart rate and measures PR, RR, QRS, and QT 
intervals.  
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All ECG traces will be reviewed and signed by the Investigator or designee and any 
abnormalities will be marked as clinically significant or not clinically significant. 
6.2.2.3. 
Vital Signs 
Vital signs, including: systolic and diastolic blood pressure and heart rate, will be 
measured at the time points specified in Table 1. 
Patients should rest in a supine position for 10 minutes before the vital signs are assessed. 
Three recordings will be taken and the average taken.  
6.2.2.4. 
Laboratory Assessments 
Blood and urine samples will be processed at the site. Routine biochemistry and 
haematology samples will be evaluated at the trial appointed central laboratory. PK, ADA 
and CSF samples will be stored at the central laboratory and evaluated at a qualified 
international laboratory. Details of handling and shipping are described in the Laboratory 
Manual.  
6.2.2.4.1. Haematology 
Blood for the assessment of haematology parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
• 
Total blood count; consisting of: 
• 
Red blood cells  
• 
Haematocrit 
• 
Mean cell volume 
• 
Mean cell haemoglobin 
• 
Mean cell haemoglobin concentration 
• 
Glycated haemoglobin (HbA1C) 
• 
Blood glucose (non-fasting) 
• 
Platelets 
• 
White blood cells 
• 
Neutrophils 
• 
Lymphocytes 
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• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
6.2.2.4.2. Clinical Chemistry 
Blood for the assessment of clinical chemistry parameters will be collected at the times 
outlined in the Time and Events table (Table 1). The following parameters will be 
assessed during the trial: 
• 
Sodium  
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Total bilirubin 
• 
Total protein 
• 
Albumin 
• 
Alanine transaminase 
• 
Aspartate aminotransferase 
• 
Alkaline phosphatase 
6.2.2.4.3. Urinalysis 
Urine samples will be collected at the times outlined in the Time and Events table 
(Table 1). The following parameters will be assessed at each time point: 
• 
Glucose 
• 
Ketones 
• 
Specific gravity 
• 
Blood 
• 
pH 
• 
Protein 
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• 
Urobilinogen 
6.2.2.4.4. CSF 
CSF sample from visit 10 LP will be retained for future potential analysis of disease and 
drug related biomarkers. 
6.2.2.4.5. Pregnancy 
Urine will be collected from female patients of childbearing potential at the times 
outlined in the Time and Events table (Table 1) to enable urine-based pregnancy tests to 
be performed. Female patients who are identified as being pregnant during the trial will 
be withdrawn from further treatment but will continue to attend safety follow-up visits.  
The Investigator or designee should report any pregnancies in female patients to the 
Sponsor or designee, using the Pregnancy Report Form, within 24 hours. The contact 
details for reporting are: 
 
Female patients or partners of patients who become pregnant should be followed until 
delivery, stillbirth or termination. The outcome of the pregnancy and, if applicable, the 
health of the baby, should be reported to the Sponsor using the Pregnancy Report Form. 
6.2.2.4.6. Pharmacokinetic sampling 
Pharmacokinetic sampling is to characterize the pharmacokinetics of exenatide after once 
weekly subcutaneous administration of Presendin at the times outlined in the Time and 
Events table (Table 1). 
The primary purpose of the pharmacokinetic sampling is to characterize the steady state 
concentrations of exenatide. All actual sampling times and dosing times will be recorded. 
Sampling and processing will be performed as described in the Laboratory Manual. 
6.2.2.4.7. Anti-drug Antibodies sampling 
Anti-drug antibodies sampling will be performed in all subjects at the times outlined in 
the Time and Events table (Table 1). 
Sampling and processing will be performed as described in the Laboratory Manual. 
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6.2.2.5. 
Adverse Events 
Patients will be asked non-leading questions to assess how they are feeling at each clinic 
visit. Adverse events will be assessed and reported as outlined in Section 12. 
6.3. 
Efficacy Procedures 
6.3.1. 
Intracranial Pressure 
Assessment of ICP will be measured by LP in the lateral decubitus position, according to 
LP standard operating procedure (SOP). Lumbar puncture will ideally be performed after 
visual assessments as outlined in the Time and Events table (Table 1).  
Any additional LP procedures, outside of the protocol would constitute a protocol 
deviation and ideally should be discussed with the Investigator before the procedure is 
performed.  
Non-protocol LPs should be recorded in the Case Report Form. 
6.3.2. 
Visual Assessments 
Visual assessments should be performed on both eyes. All visual assessments should be 
uploaded on the day of the visit at the earliest opportunity to the visual reading centre. In 
all cases the site is responsible for initial checks of data quality: 
i. Humphrey Visual Field false positives <15%;  
ii. Optical coherence tomography displays accurate segmentation (either through the 
automated software or manually corrected)  
The visual reading centre will provide a definitive quality report and in some cases 
assessments will need repeating at the earliest opportunity. 
6.3.2.1. 
Optical Coherence Tomography 
Imaging may be acquired using Heidelberg or Cirrus platforms according to the OCT 
SOP. Key measures are optic nerve head size, RNFL and ganglion cell layer thickness. 
• 
At screening OCT will be reviewed by the central ophthalmic reading facility to 
confirm eligibility. 
• 
Frisén Grade will be inferred from the OCT imaging by the visual reading centre. 
During screening, where there is uncertainty a fundus photo and or ultrasound scan 
(B scan) of the optic nerve should be conducted for evaluation by the reading centre. 
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• 
Whilst optic disc drusen that effects the interpretation of the OCT imaging is an 
exclusion criterion, those with minimal optic disc drusen at screening identified on 
OCT by the central ophthalmic reading facility will be reported to the IAC to review 
and confirm eligibility. 
• 
Any OCT with findings that suggest the patient may require rescue therapy will be 
prioritised and the report expedited to the IAC and site for review, to determine if 
rescue therapy is indicated. 
6.3.2.2. 
Humphrey Visual Field 
Visual field will be measured by Humphrey Visual Field analysis (24-2 SITA-Standard) 
according to PMD SOP. 
• 
At screening HVF will be reviewed by the central ophthalmic reading facility to 
confirm eligibility 
• 
Un-correctable poor performance (including >15% false positives) is an exclusion 
criterion. HVF can be repeated to obtain as assessment with reliable performance. 
• 
Any HVF with findings that suggest the patient may require rescue therapy will be 
prioritised and the report expedited to the IAC and site for review, to determine if 
rescue therapy is indicated. 
6.3.2.3. 
Visual Acuity  
Assessment of corrected visual acuity will be recorded using a LogMAR scoring chart. 
6.3.3. 
Headache Assessments 
Patients will be provided with an electronic/paper diary at screening to complete during 
the course of the trial. Information collected will be used to assess the following 
headache parameters: 
• 
Monthly headache days 
• 
Monthly moderate to severe headache days 
• 
Responder rate 
• 
Monthly acute analgesic use 
• 
Headache severity (11-point NRS) 
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6.3.3.1. 
Headache Preventative Medication Review 
A review of any headache preventative medications taken by the patient will be 
undertaken at each clinic visit. If the Investigator alters the headache preventative 
medication, this will be considered rescue medication (Section 10.1.1) and the IAC 
consulted. This will be considered a protocol deviation. Use of headache preventative 
medication will be recorded at trial visits as outlined in the Time and Events table 
(Table 1). 
Patients will record their acute headache analgesic use in their trial diary. 
6.3.4. 
Patient Reported Outcomes 
6.3.4.1. 
Visual related 
Assessment of visual related quality of life will be derived from self-reported responses 
to the VFQ-25-10 item supp (see Section 16.5 Appendix 5). 
6.3.4.2. 
Health-related 
Assessment of health-related quality of life will be derived from self-reported responses 
using the following questionnaires: 
• 
36-item short form survey  
• 
EuroQol -5 dimension -5 level survey  
A Healthcare Utilisation Form will be completed by the trial site staff at clinic visits. 
All questionnaires can be found in Section 16, Appendix 2 for SF-36 and Appendix 3 for 
the EuroQoL- 5D-5L survey. 
6.3.4.3. 
Headache related Quality of Life 
Assessment of headache-related quality of life will be derived from self-reported 
responses to the Headache Impact Test-6 questionnaire and performed at time points as 
outlined in the Time and Events table (Table 1). A copy of this questionnaire can be 
found in Section 16.4, Appendix 4. 
6.3.4.4. 
Patient Global Impression of Change  
The Patient Global Impression of Change will be conducted at visit 10, as outlined in the 
Time and Events table (Table 1).  
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It is a single item questionnaire using a seven-point verbal response scale to assess 
overall change in the patient’s status since taking trial medication. A copy of this 
questionnaire can be found in Section 16.6, Appendix 6 
6.3.5. 
Body Weight and Body Mass Index 
The patient’s body weight and BMI will be measured at the time points as outlined in the 
Time and Events table (Table 1).  
The patient’s height will be measured at Screening (shoes off).  
 
 
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7. 
SAFETY MEASURES DUE TO A GLOBAL CRISIS 
The COVID-19 global pandemic presents numerous challenges to the conduct of ongoing 
clinical trials. In line with the FDA and European Medicines Agency's Guidance on the 
Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic 
(EMA, 2021), the following protocol considerations are provided to ensure patients 
safety is maintained and adequate benefit/risk analyses are applied relative to the 
completion of study procedures and maintaining the investigational product supply chain.  
Other unforeseen global crises may occur during the conduct of the study, similar to the 
COVID-19 global pandemic, in which case the following protocol considerations may 
also be applied. 
Recognizing the flexibility required to manage the impact of the pandemic (or other 
global crisis) on this clinical study, additional details will be added to respective study 
manuals, project plan documents, and communicated to the investigative sites as needed.  
For any additional questions, the investigator should confer with the sponsor. 
Number of Trial Patients 
The evolving situation of the pandemic (or other global crisis) may result in a substantial 
number of patients’ early withdrawal from the study, which could affect the data integrity 
of the study.  Because of this risk, the sponsor may decide to recruit additional patients in 
the study, beyond the expected number, to mitigate such risk. 
Study Visits 
There are a number of on-site visits that would be required to ensure study validity.  If 
there are local travel restrictions, isolation requirements, or the investigator determines it 
to be unsafe for patients to attend their scheduled study visits, the site staff may conduct 
certain visits via telemedicine (phone or video calls) to minimize patient risk as follows. 
Screening Period 
The following visit must be performed in person: 
• Screening/Visit 1 
Note:  To minimize direct, in-person contact between site personnel and patients, 
certain screening procedures may be performed remotely via telemedicine.  All 
other procedures should be done in-person while the subject is on-site.  
Specifically, the following procedures may be done remotely: 
o Informed consent (where applicable, per approved IRB/IEC process) 
o Demography 
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o Medical and ophthalmic history 
o Concomitant medication history 
o Headache history 
o Headache preventative medication review 
o Train and dispense headache diary 
o Trial medication training 
Randomised period 
• Baseline (Visit 2) 
There are essential aspects to the baseline visit which must be performed in 
person. 
If the baseline visit is delayed the headache diary should utilise the preceding 7 
days data. Where the visit is delayed by more than 10 days due to a global crisis 
the patient will be considered to have failed screening.  Patients who screen failed 
due to the pandemic (or other global crisis) may be rescreened at a later time, if 
feasible. 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 4, 5, 6, 7, and 8 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
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o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
 
To minimize direct, in-person contact between site personnel and patients, certain 
procedures may be performed remotely via telemedicine.  All other procedures 
should be done in-person while the subject is on-site.  Specifically, the following 
procedures may be done remotely: 
o Concomitant medication review 
o Headache preventative medication review 
o Headache diary review 
o Adverse events 
o Patient reported outcomes 
o Health utilisation form 
 
• Visit 10 
There are essential aspects to these visits which must be performed in person. 
Where this is not possible due to the pandemic or other global crisis the following 
components of the visit should be performed at the next available opportunity in 
line with the schedule of assessments table: 
o Vital signs 
o Body weight and BMI 
o Physical examination  
o Urine pregnancy test 
o Electrocardiogram 
o Optical coherence tomography imaging 
o Humphrey Visual Field 
o Visual acuity testing 
o Laboratory assessments 
o Pharmacokinetic sampling 
o Anti-drug antibodies sampling 
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o Lumbar puncture* 
 
* Lumbar puncture to be performed after visual assessments. In the 4 weeks prior to visit 
10, patients must not have missed more than one dose of trial medication and must have 
self-administered their final dose within 7 days of visit 10. Patients will be reminded by 
the trial site to self-administer trial medication weekly, to continue this until the 
completion of visit 10 and to bring their trial medication with them at visit 10 for return.  
Where more than one dose has been missed during the preceding 4 weeks, visit 10 should 
be delayed. Self-administration of trial medication should continue at 7-day intervals and 
then visit 10 rescheduled to ensure no more than one dose of the trial medication has been 
missed in the previous 4 weeks. Visit 10 should be delayed no more than 14 days if 
possible, but this can be extended according to local government policy if a patient is 
unable to attend (for example if a patient is self-isolating) as long as medication use is 
maintained as above. 
 
• Follow up/ Visit 11 
This should be performed as a telephone visit unless clinical contact is necessary, as 
per protocol. Where face to face contact is required this should be conducted at the 
earliest available opportunity.  
 
Study Drug Dispensation and Distribution 
If a patient is not able to attend a clinic visit, in order to ensure the continuity of 
providing patients’ study drug within the constraints imposed by the pandemic (or other 
global crisis), the site staff may decide to supply study drug to patient as follows: 
o Adequate supplies of study drug can be shipped to the patient by the study staff 
using a third-party service with approval from the patient.  The third-party vendor 
will be agreed upon with the sponsor. 
o The patient may request, with prior arrangement/agreement with the site, an 
authorized individual (a relative or delegate) to retrieve the study drug from the 
study site if the patient is unable to personally to do so. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed; however, the site monitor will continue to 
employ off-site monitoring practices such as routine communication methods (e.g., phone 
calls, emails, video visits) with the sites to get information on study progress, patient 
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status, and information on issue resolution as detailed in the Data Monitoring Guidelines, 
Remote source data verification. 
If the trial site monitor cannot be on-site to carry out the final drug accountability for 
reconciliation purposes, and the operation cannot be postponed, it may be carried out by a 
pharmacist from the site pharmacy or by the study coordinator/data manager with suitable 
training. The study drug can be returned to the sponsor by the site pharmacy directly, or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 
Direct Contracts with Third Parties/Specialized Service Companies 
If necessary, direct contracts can be established with third-party local physicians to 
conduct activities related to the clinical management of patient for whom the investigator 
is responsible and maintains oversight.  In such situations, the investigator is required to 
provide the local physician with a delegation letter listing all delegated activities.  The 
sponsor, through the study investigator or institution, will reimburse the local physician 
for the test/procedures conducted outside of the standard of care. 
Clinic visits should take place to the extent possible and usual protocol requirements 
adopted for all subjects as soon as the crisis-related limitations permit. 
All safety data that are possible to obtain locally should be collected at a remote visit. 
These measurements may include the use of local practitioners and resources. 
Exceptional measures taken in response to a crisis (e.g., COVID-19) and their impact on 
study results, such as tests done in a local laboratory, will be explained, assessed and 
reported in the clinical study report following ICH E3 guidance. 
8. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS 
Patients will receive lifestyle advice as per routine care from their treating physician. 
9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Dosage and Administration 
9.1.1. 
Randomised Period 
During the 24-week randomised treatment period (Figure 1) patients will be randomised 
in a 1:1 ratio to receive active treatment or placebo. 
Either 
Presendin (2.0mg exenatide) as a SC injection, self-administered once weekly. 
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Presendin is supplied as 2 parts, one vial consisting of a drug part (white or grayish 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 as a 
suspension.  
or 
Placebo as a SC injection, self-administered once weekly. 
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 as a suspension. 
9.2. 
Dose Rationale 
The proposed 2mg weekly dose was based on the pharmacokinetic performance of the 
Peptron formulation (PT320). Pharmacokinetic profiles obtained after repeated once 
weekly dosing of 2mg of PT320 s.c. (as specified in the Presendin IB phase 2 clinical 
study in patients with type 2 diabetes) were comparable to those predicted by the 
population PK model developed for weekly s.c. administration of the recommended dose 
of the 2mg Bydureon extended-release formulation [Cirincione 2017],with time to reach 
the steady state slightly shorter for PT320 than for Bydureon (7-8 weeks vs 8-10 weeks) 
and with steady state plasma concentrations remaining within a comparable range for 
both products. Based on the same molecule and dose, comparable plasma concentrations 
for PT320 and Bydureon and the established safety profile of Bydureon a similarly 
acceptable safety and tolerability profile for PT320 is expected. 
9.3. 
Maintaining the Blind 
This is a double-blind trial.  
A computer/website system will be used to maintain the blind for this trial. The site will 
be provided with website login details for the system. In the event that the Investigator 
needs to unblind a patient’s treatment, due to a medical emergency, the website should be 
accessed to unblind for that patient. If possible, the Investigator should discuss this with 
the IAC and Sponsor prior to unblinding. 
9.4. 
Treatment Assignment 
Patients will be randomised in a ratio of 1:1 to receive active treatment (Presendin) or 
placebo. A computer/website system will be used to randomly assign each patient to a 
treatment arm.  
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9.5. 
Packaging and Labelling 
Individual supplies of trial medication will be provided to the sites in a double-blind 
format. The labels will contain all information required to meet the applicable local 
regulatory requirements. 
Further information on packaging, labelling and dispensing are included in the Pharmacy 
Manual. 
9.6. 
Preparation 
Each dose of trial medication is provided as two parts, a single use vial and a pre-filled 
syringe of diluent. Patients will receive training and be provided with an instruction sheet 
with details, on how to store, prepare, self-administer and discard/keep used trial 
medication.  
9.7. 
Handling and Storage 
Presendin, the active trial medication, contains the active ingredient, exenatide, which is 
hygroscopic and light sensitive and must be protected from light during storage. Prior to 
use, all trial medication should be stored refrigerated at 2-8ºC. 
9.8. 
Product Accountability and Assessment of Compliance 
In accordance with International Council of Harmonisation – Good Clinical Practice 
(ICH-GCP), each trial centre will account for all supplies of trial medication. Details of 
receipt, storage, assembly, and return will be recorded. The unit of accountability will be 
one single active or placebo vial. Both the pre-filled syringe and needle will be disposed 
of in a sharps box. 
All unused supplies will either be destroyed or returned to the trial Sponsor at the end of 
the trial in accordance with instruction by the Sponsor. 
All trial medication will be self-administered by the patients. If a dose is not administered 
as planned, patients will record the missed dose in their electronic/paper diaries and it 
will be documented in the electronic case report form (eCRF). 
9.9. 
Treatment of Investigational Product Overdose 
In the event a patient overdoses on trial medication the Investigator should be notified as 
soon as possible. If symptoms appear, the Investigator will treat the patient according to 
their clinical judgement depending on the type of clinical signs and symptoms exhibited 
by the patient.  
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Effects of overdose that may be seen include severe nausea, severe vomiting and rapidly 
declining blood glucose concentrations. 
If a patient receives an overdose of the trial medication, the Sponsor should be notified in 
writing within 24 hours of the Investigator becoming aware. 
9.10. 
Occupational Safety 
There are no known occupational safety risks to staff. The Material Safety Data Sheet 
will be made available where required by local regulations. 
10. 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
10.1. 
Recording Prior and Concomitant Medication 
All relevant medication taken within 4 months of screening should be recorded in the 
eCRF along with all relevant medication taken from the start of the screening period until 
the final follow-up visit (Section 6.2.1.3). 
At a minimum the following information will be collected: 
• 
Generic name 
• 
Dose 
• 
Frequency 
• 
Date started 
• 
If ongoing (or if not, then the date stopped will be recorded) 
• 
Reason for taking the medication  
10.1.1. 
Treatment Failure 
Rescue therapy can be initiated when there is a treatment failure.  
• 
Possible treatment failure is defined as those with baseline PMD between -2 and -
3.5dB who experience a decline of > or equal to 2dB. In those with a baseline PMD 
between -3.5 and -7 dB those who experience a decline of > or equal to 3 dB.  
When possible treatment failure is identified, perimetry should be repeated. 
• 
Treatment failure is defined as those with baseline PMD between -2 and -3.5dB 
experience a decline of > or equal to 2dB which remains after repeat perimetry. Or in 
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those with a baseline PMD between -3.5 and -7 dB who experience a decline of > or 
equal to 3 dB which remains after repeat perimetry.  
These cases should be reviewed urgently by the IAC (who will review all visual and 
ancillary measures) to confirm or refute a treatment failure 
10.1.2. 
Rescue Therapy/Rescue Intervention for Progressive Visual Loss 
When a treatment failure occurs, rescue therapy can be initiated based on the medical 
judgement of the trial Investigator. Decisions should always be discussed with the IAC as 
soon as possible and if possible before any action is taken, unless in the opinion of the 
Investigator there is no time to do so as it is judged to be a medical emergency. In all 
cases the final decision lies with the trial Investigator. 
Patients showing progressive visual loss will be considered for rescue therapy with 
acetazolamide or an alternative diuretic. In cases where the visual loss is severe and 
“rapid”, and believed by the Investigator to necessitate surgical intervention, the 
intervention will be conducted in accordance with local emergency practice. 
10.1.2.1. 
Rescue Therapy for Headache 
If the Investigator wishes to alter the headache preventative medication (any drug can be 
considered), this decision should always be discussed with the IAC before any action is 
taken, unless in the opinion of the Investigator there is no time to do so as it is judged to 
be a medical emergency. Addition or changing a headache preventive therapy will be 
considered a protocol deviation. Use of headache preventative medication will be 
recorded at trial visits. 
Use of acute headache analgesics is not considered as rescue medication and is permitted 
but must be documented in the headache diary (monthly analgesic use). 
10.2. 
Prohibited Medications 
10.2.1. 
Prior to enrolment 
• 
Treatment to lower ICP within 1 week prior to screening (e.g., Acetazolamide, 
topiramate, diuretics and oral or IV glucocorticoids (including oral dexamethasone 
and oral prednisolone, excluding inhaled and topical formulations) 
• 
Exposure to fluoroquinolones, lithium, vitamin A, or tetracyclines within 2 months 
of diagnostic LP 
• 
Botulism toxin or monoclonal antibodies against CGRP or CGRP antagonist 
injections within previous 4 months 
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• 
Greater occipital nerve block within the last 4 weeks 
• 
Glucagon like peptide-1 receptor agonist within last 4 weeks 
10.2.2. 
Prior to randomisation (visit 2) 
• 
Greater occipital nerve block 
• 
Recreational (including cannabidiol) or illicit drugs (including marijuana) 
10.2.3. 
During the trial 
• 
Acetazolamide, topiramate, diuretics and oral or IV glucocorticoids (including oral 
dexamethasone and oral prednisolone, excluding inhaled and topical formulations). 
These will be considered rescue medication (Section 10.1.2) and the IAC consulted. 
This will be considered a protocol deviation. 
• 
If the Investigator alters the headache preventative medication (oral or Botulism 
toxin or monoclonal antibodies against CGRP or CGRP antagonist injections) this 
will be considered rescue medication (Section 10.1.2) and the IAC consulted. This 
will be considered a protocol deviation. 
• 
Greater occipital nerve block 
• 
Glucagon like peptide-1 receptor agonists 
• 
Recreational (including cannabidiol) or illicit drugs (including marijuana)Glucose-
lowering medication 
• 
Prescribed weight loss medication 
• 
Regarding COVID-19 vaccination, the risks of receiving or not receiving the 
vaccination have been considered in relation to the IMP and no additional risks are 
envisaged. Hence patients may choose to have or not have COVID-19 vaccination or 
booster during this trial. 
11. 
PATIENT COMPLETION AND WITHDRAWAL 
11.1. 
Patient Completion 
Patients will be classed as having completed the trial once they have completed all 
required trial visits. See Section 10.2.1 for early discontinuations. 
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11.2. 
Patient Withdrawal 
11.2.1. 
Patient Withdrawal from Trial Treatment 
A patient will be withdrawn from treatment for any of the following reasons: 
• 
Withdrawal of consent to continue in the trial. The reason for this will be 
documented if provided 
• 
The Investigator or Sponsor, for any reason, decides the patient should be withdrawn 
from the treatment 
• 
Lack of compliance with the trial medication is classified as <75% or >125% of 
scheduled doses over the course of the trial, excluding supply issues 
• 
Adverse events, which cannot be tolerated by the patient 
• 
Pregnancy during the treatment period 
Patients will be encouraged to continue in the trial to the end of the randomised treatment 
period even if they stop trial medication so that data can be collected for the Intention-
To-Treat (ITT) population.  
If a patient is withdrawn from treatment during the randomised treatment period they will 
be encouraged to return for all trial visits up to visit 10. If a patient does not want to 
return then at a minimum they should be encouraged to attend for visit 11 procedures as a 
safety follow-up visit.  
11.3. 
Treatment after the End of the Trial 
Patients will not be provided with trial medication following the end of the trial. 
11.4. 
Screen and Baseline Failures 
Information will be collected on all patients who sign the Informed Consent Form (ICF). 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
12.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
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temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
12.1.1. 
Causal Relationship 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs. To promote consistency, the following guidelines should be taken into 
consideration along with good clinical and scientific judgment when determining the 
relationship of drug treatments to an AE: 
• 
Probable relationship: event occurs in a plausible time relationship to the medication 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals; the response to the withdrawal of the drug should be clinically plausible 
• 
Possible relationship: event occurs with a reasonable time sequence to the 
medication administration, but could also be explained by concurrent disease or 
other drugs or chemicals; information on the drug withdrawal may be lacking or 
unclear 
• 
Unlikely relationship: event occurs with little temporal relationship to the medication 
administration and other factors such as drugs, chemicals or underlying disease 
provide plausible explanations 
• 
Not related: event has no temporal relationship to the medication administration or 
there is a definite alternative aetiology 
12.1.2. 
Severity Criteria 
An assessment of severity grade will be made using the following categorical descriptors: 
• 
Grade 1 means a relatively minor side effect 
• 
Grade 2 means a moderate side-effect  
• 
Grade 3 means a severe or medically significant but not immediately life-threatening 
side-effect  
• 
Grade 4 means life-threatening consequences 
• 
Grade 5 death related to AE 
The exact definition of each number in the scale depends on the particular side effect 
according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
[CTCAE].  
The Investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the patient (e.g., laboratory abnormalities). 
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Adverse events occurring as a result of LP should be specifically recorded. Occurrence of 
post lumbar headache will be specifically reported. 
12.1.3. 
Reporting Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated informed consent form is obtained until completion of 
the patient's last trial-related procedure (which may include contact for follow-up of 
safety). The Sponsor will evaluate any safety information that is spontaneously reported 
by an Investigator beyond the time frame specified in the protocol. Adverse events 
reported after dosing will be classed as treatment emergent AEs. 
All AEs, regardless of seriousness, severity, or presumed relationship to trial therapy, 
must be recorded using medical terminology in the source document and the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common aetiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). Investigators must record in the 
source documents and the eCRF their opinion concerning the relationship of the AE to 
trial therapy. All measures required for AE management must be recorded in the source 
document and reported according to Sponsor instructions. 
The patient must be provided, on the first day of trial medication (Day 1), with a "patient 
card" indicating the following: 
• Patient number 
• Name of the investigational product 
• Investigator's name and 24-hour contact information 
• Statement that the patient is participating in a clinical trial 
12.2. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
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Medical and scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not reach the 
above definition but may jeopardise the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive or malignant 
cancers, intensive treatment in an accident and emergency department or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse. 
Deterioration of IIH necessitating CSF shunting or optic nerve sheath fenestration or 
dural venous sinus stenting will be recorded as an SAE and reported. 
Deterioration of IIH necessitating hospital admission will be recorded as an SAE and 
reported. 
Pre-defined exclusions: 
• 
Hospitalisation for unrelated elective procedures 
• 
Post LP headache 
12.2.1. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to 
be related to the trial medication and are both unexpected (i.e., the nature or severity is 
not expected from the information provided in the Investigator Brochure) and serious. 
12.2.2. 
Expected Adverse Events 
Perceived deterioration of IIH necessitating attendance or admission to hospital will not 
be reported as an SAE, but these events will be reported and recorded at follow-up. Non-
protocol LPs will be reported at follow-up. 
12.2.3. 
Reporting Serious Adverse Events 
All SAEs occurring during clinical studies must be reported to the appropriate Sponsor 
designee (contract research organisation) within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the Sponsor’s safety contact using the 
SAE Form, which must be completed and signed by the Investigator, and transmitted to 
the Sponsor’s safety contact within 24 hours.  
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The contact details are: 
 
The Sponsor assumes responsibility for appropriate reporting of SAEs or SUSARs to the 
regulatory authorities. The Investigator (or Sponsor where required) must report these 
events to the appropriate Independent Ethics Committee (IEC) that approved the protocol 
unless otherwise required and documented by the IEC. 
An annual safety report will be submitted to the Institutional Review Board once a year 
via the Investigator. 
12.3. 
Reporting and Handling of Pregnancies 
Pregnant patients will be withdrawn from the trial. 
Female patients will be instructed to notify the Investigator immediately if they become 
pregnant during the trial and up to 12 weeks after discontinuation/completion of trial 
medication. Pregnant patients will be withdrawn from further trial treatment. The patients 
will also be instructed to report pregnancies discovered after the last visit, if they believe 
that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the trial medication 
has interfered with the efficiency of any contraceptive measures. The Investigator should 
report all pregnancies to the Sponsor contact or designee within 24 hours of being 
informed of them. The pregnancy report form should be used instead of the SAE form. 
The pregnant patients will be followed until the end of the pregnancy. Any complication 
during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, 
stillbirth, birth defect/congenital anomaly, death, or other serious infant condition must be 
reported and followed up as an SAE. 
Patients will give consent on enrolment that the Investigator will report any pregnancy to 
the Sponsor and that further information will be collected until delivery. 
 
 
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13. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Before patients are enrolled, a Statistical Analysis Plan (SAP) will be finalised providing 
detailed methods for the analyses outlined below. 
13.1. 
Hypotheses 
This trial compares outcomes in IIH patients under Presendin and matched placebo. The 
primary hypothesis that will be tested is: 
• 
The ICP measurement in the Presendin group is equal to the ICP measurement in the 
placebo group at Week 24; against the alternative that the outcomes differ 
13.2. 
Trial Design Considerations 
13.2.1. 
Sample Size Assumptions 
The target sample size for the trial is 240 randomised patients, i.e., 120 patients per arm. 
We justify this figure in the following sections. The two outcomes for which we sought to 
power the study are ICP and MHD. It transpired from the study of previous literature and 
trials that MHD was subject to relatively more variability and required the greater sample 
size to achieve nominal power to detect the sought difference. Thus, it was the powering 
of the test of MHD that determined the sample size for the trial. For that reason, we 
commence the justification of the sample size below using MHD, even though it is not 
the primary outcome measure. In a following section, we convey power at this sample 
size for the test of ICP. 
Operating performance at the target sample size for testing differences in MHD was 
assessed by computer simulation. Vectors for the daily probability of headache during 
months 0, 1, …, 6 were specified for the placebo and experimental arms, and the logits of 
these vectors were used as the intercepts in the data-generating models (DGMs). Patient-
level susceptibilities were sampled from a N(0, 0.72) distribution and fixed throughout the 
simulated trial, performing the role of patient-level adjustments to the intercept on the 
log-odds scale in the DGM. Random patient-level gradients were sampled from a N(0, 
0.22) distribution and used to reflect patient-level trends in the log-odds of headache. 
Random errors were sampled from a N(0, 0.72) distribution, performing the role of 
independent homoskedastic random errors on the log-odds scale. The probability of 
headache is the inverse logit of the sum of these terms (with the gradients scaled by time) 
and the number of headache days was sampled as a binomial random variable between 0 
and 28. The parameters in the DGMs were chosen to yield repeated measures outcomes 
that have similar variability and serial correlation to those observed in previous IIH trials. 
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Data missingness was incorporated into our simulations using a method we describe as 
“randomly sampled departures”. The method can be visualised using the following table 
where white cells reflect that a measure was obtained and orange cells reflect that data is 
missing: 
Patient 
t0 
t1 
t2 
t3 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
 
In this method, patients reliably provided data up until the time that they departed the 
trial, and then never provided data again. Under such a scheme, later time-points are 
more likely to be missing than earlier time-points, some patients provide full data, and 
some patients provide no data, despite being randomised. Each of these features is 
possible in data we expect to collect in our trial. 
The method takes a data set and arrives at a state where 100 × ω% of the data is missing 
by invoking the following iterative algorithm: 
1. Randomly sample a patient for which some data will be missing. 
2. Randomly sample a time-point from the list of protocol-specified assessment 
times. This is the patient’s departure point. 
3. Remove all observations for the patient at or after their departure point. 
4. If the percentage of missing data is less than 𝜔𝜔, go to step 1 
Using this algorithm, we removed 20% of data in the simulations used to infer statistical 
performance. The 20% value was adjudged to be realistic by the sponsor based on 
previous trials in IIH. 
For each simulated dataset, we then tested the presence of treatment effects using a 
likelihood ratio test of nested models. Let i index patients and j index time so that yij 
represents the measured outcome for the ith patient at the jth protocol-specified 
assessment time. Let N be the total number of patients and J the total number of 
assessment times. Furthermore, let zi be an indicator variable, taking the value 1 when 
patient i is allocated to the experimental arm or 0 when they are allocated to placebo.  
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The main analysis model was: 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝑎𝑎𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑡𝑡 +  𝛽𝛽1𝐼𝐼(𝑗𝑗= 1) + ⋯+ 𝛽𝛽𝑗𝑗𝐼𝐼(𝑗𝑗= 𝐽𝐽) + 𝛾𝛾1𝐼𝐼(𝑗𝑗= 1)𝐼𝐼(𝑧𝑧𝑖𝑖= 1) + ⋯ 
+ 𝛾𝛾𝐽𝐽𝐼𝐼(𝑗𝑗= 𝐽𝐽)𝐼𝐼(𝑧𝑧𝑖𝑖= 1) + 𝜖𝜖𝑖𝑖𝑖𝑖 
and the alternative model was: 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝑎𝑎𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑡𝑡 +  𝛽𝛽1𝐼𝐼(𝑗𝑗= 1) + ⋯+ 𝛽𝛽𝑗𝑗𝐼𝐼(𝑗𝑗= 𝐽𝐽) + 𝜖𝜖𝑖𝑖𝑖𝑖 
where 𝜖𝜖𝑖𝑖𝑖𝑖∼𝑁𝑁(0, 𝜎𝜎2), 𝑎𝑎𝑖𝑖∼𝑁𝑁൫0, 𝜎𝜎𝑎𝑎2൯, 𝑏𝑏𝑖𝑖∼𝑁𝑁(0, 𝜎𝜎𝑏𝑏
2) and I(A) is the indicator function, 
taking the value 1 when A is true, else taking the value 0. That is, we used a mixed effects 
model where time is treated as a factor variable for estimating treatment effects, with 
normally distributed patient-level intercepts, normally distributed patient-level gradients 
with respect to continuous time, and normally distributed errors. 
In this model, the 𝛽𝛽𝑗𝑗terms represent the mean changes from baseline in the placebo 
group. The 𝛾𝛾𝑗𝑗  terms represent the treatment effects, being the mean difference in 
outcome between the arms at time j. In a scenario where the drug has effects 
indistinguishable from placebo, 𝛾𝛾1 = ⋯= 𝛾𝛾𝐽𝐽= 0 
Using this method, we observed by simulation that the type I error rate was controlled at 
the nominal 5% level when there were no differences in probability of headache between 
the two arms. Furthermore, we observed that power was approximately 88% when the 
mean MHD in the experimental arm was (0.0, 2.4, 2.5, 2.6, 2.8, 2.9, 3.0) days lower than 
placebo in months 0 to 6. 
13.2.1.1. Intracranial Pressure Power 
Initially, for the purposes of estimating power, we assume that ICP standard deviation is 
6.0 cm H2O CSF in placebo and Presendin treated patients at baseline, 6.0 in placebo 
patients at 24-weeks, and 7.0 in Presendin treated patients at 24-weeks. By way of 
justification of these assumptions, we note that baseline standard deviations of ICP in 
previous trials were: 5.4 (n=10) and 6.3 (n=17) in the Drug Trial [Markey, 2017]; 5.0 
(n=16) (data on file); and 5.7 (n=32) and 5.3 (n=30) in the Weight Trial [Ottridge, 2017]. 
Post-baseline standard deviations were slightly lower (and less than 6.0) in three of these 
five arms; and increased slightly in one (but remained less than 6.0). The post-baseline 
standard deviation however increased to over 8.0 in the surgery arm of the Weight Trial, 
because the surgical intervention dramatically impacted ICP in some patients. 
Conservatively, we therefore estimate that post-baseline standard deviation will be 6.0 in 
the control arm. We anticipate that the standard deviation will be slightly higher in the 
experimental arm as treatment effects will potentially manifest changes in ICP. However, 
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we do not expect variability to be as inflated in this trial relative to control as it was in the 
Weight Trial, because of the likely difference in effect between surgical and drug 
interventions. For this reason, we have predicted in the Presendin arm that post-baseline 
standard deviation will be 7.0.  
Under this parameterisation, when testing for a difference between arms at 24-weeks of 5 
cm H2O CSF using a total sample size of 240, assuming that up to 30% of observations 
are missing, using a 5% significance level by Analysis of Covariance (ANCOVA) 
adjusted for baseline ICP, the two stratification variables, and treatment arm, we expect 
to have approximately 99% power. This has been inferred by computer simulation. 
In the NORDIC trial [Wall, 2014], the standard deviation of baseline ICP was higher, at 
9.4 cm H20 in the treatment arm (n=86). To stress-test the power analysis presented 
above, we investigated the following values: control arm baseline and 24-week ICP SD 
equals 9.4, Presendin baseline ICP SD equals 9.4, and Presendin 24-week ICP SD equals 
10.4. These values assume the variability of ICP measures in untreated patients is as high 
as has been seen in an IIH trial, and assumes that the variability in treated patients is 
slightly higher still. Mimicking the above method with these revised values, when testing 
for a difference between arms at 24-weeks of 5 cm H2O CSF using a total sample size of 
240, assuming that 30% of observations are missing, using a 5% significance level by 
Analysis of Covariance (ANCOVA) adjusted for baseline ICP, the two stratification 
variables, and treatment arm, we expect to have at least 90% power. 
Outcomes from previous trials show that baseline and post-baseline distributions of ICP 
show central tendency with approximate symmetry, so we conclude that normality is a 
reasonable assumption and therefore ANCOVA is a defensible analysis method. 
13.2.1.1. Perimetric Mean Deviation Power 
We convey here estimated power for detecting differences between arms in the PMD 
outcome measure. In the NORDIC trial [Wall, 2014], the authors observed that the 
decrease from baseline to 6-months in PMD was 0.71dB greater in the experimental arm 
than the control arm. Cross-sectional SD of PMD was 1.1-1.2 at baseline. Table 2 in their 
publication shows that the standard error of mean PMD is higher at 6m than at baseline, 
likely reflecting a combined effect of missing data at 6m and greater variability of post-
baseline measures. We plan to take repeated measures of PMD at baseline, 2m, 4m and 
6m. Assuming that the overall SD of PMD scores is 1.5, thus introducing some inflation 
on Wall et al.’s baseline for the reasons identified, using the formula given on p.31 of 
Diggle, Liang & Zeger (1994), we would expect to require 138 patients in total to detect a 
difference of 0.71dB with 90% power  at a 5% significance level, if the serial correlation 
between repeated measures is 0.5 (we expect a value in this region) [Diggle, 1994]. If the 
serial correlation parameter is as low as 0.3, the required sample size increases to 192. 
Note that these methods assume full follow-up and data collection. Naturally, some 
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missing data is expected but we expect the aggregate data from the n=240 group to make 
up any shortfall. This section assumes a longitudinal analysis method like hierarchical 
regression. 
13.2.2. 
Stratification 
At the outset, it is expected that duration of symptoms attributed to IIH will be prognostic 
of potential efficacy. For this reason, it is proposed to stratify randomisation by duration 
of diagnosis (≥ 2 weeks from diagnostic LP), previous diagnosis of migraine, baseline 
ICP (≥35 cm), baseline Body mass index (≥30 kg/m2). 
13.2.3. 
Sample Size Sensitivity 
13.2.3.1. Clinically Meaningful Effect Sizes 
Minimally relevant effect sizes have not been fully determined in IIH given it is a rare 
disease with relatively few previous trials.  
The ICP diagnostic threshold in IIH is 25 cm H2O [Mollan, 2018]. However, it is not 
necessary to reduce ICP <25 cm H2O to achieve remission from signs and symptoms of 
IIH in all patients [Sinclair, 2010]. The clinical importance of a particular change in ICP 
will vary depending on the starting ICP and the impact this pressure has on vision and 
headache. Changes in ICP of 5 cm H2O are generally considered meaningful when 
treating IIH patients. For example, in a clinical study evaluating the benefits of weight 
loss in IIH patients, a 16.5% (6.2 cm H2O) reduction in ICP resulted in a statistically 
significant improvement in headache and vision measures as well as quality of life 
[Sinclair, 2010]. In the IIH Treatment trail (n=165), a study evaluating the drug treatment 
acetazolamide against placebo, a reduction of -5.9 cm H2O was seen in association with 
significant improvement in PMD, OCT measures of papilloedema and quality of life 
measures [Wall, 2014]. 
The minimally clinically important change in the perimetric mean deviation adopted into 
clinical practice was stablished by the Neuro-Ophthalmology Research Disease 
Investigator Consortium (NORDIC) group and the IIH Treatment Trial (IIHTT). The 
investigators found a 0.71dB difference in the PMD between the two trial arms 
(comparing acetazolamide with placebo) that was clinically meaningful. The change of 
0.71dB was interpreted as clinically meaningful as this was in the setting of significant 
changes in LP opening pressure, papilloedema (measured by OCT), general quality of life 
and visual related quality of life [Wall, 2014, Bruce, 2016].  
The clinically meaningful effect size for MHD reflects that for a phenotypically similar 
headache, chronic migraine. Recent randomised trials in patients with chronic migraine 
[Tepper, 2017; Silberstein, 2017], episodic migraine [Goadsby, 2017], or both 
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[Camporeale, 2018] have shown in post-baseline months 1–3, odds of migraine relative 
to baseline of 0.5–0.8 with placebo and 0.5–0.3 with experimental drugs. Decreases in 
MHD relative to baseline grew in time, and placebo responses were stronger in chronic 
migraine than episodic migraine. In the three placebo-controlled, blinded trials, these 
equated to odds-ratios of migraine compared with placebo of 0.8–0.6, or absolute 
differences of 1.5–2.5 MHD [Sinclair, 2010; Tepper 2017; Silberstein, 2017; 
Goadsby, 2017].  
13.2.4. 
Sample Size Re-estimation 
No sample size re-estimation of the overall sample size will be performed. 
13.2.5. 
Trial Stopping Criteria 
There are no trial-specific stopping rules.  
13.3. 
Data Analysis Considerations 
13.3.1. 
Estimands 
We have specified intercurrent events that are material to the measurement of our 
primary and secondary outcomes, and unbiased estimation of treatment effects 
attributable to Presendin. 
ICP-lowering medication include:  acetazolamide, topiramate, diuretics, glucocorticoids 
(oral dexamethasone and oral prednisolone). Headache-preventative medications include: 
amitriptyline, topiramate, nortriptyline, beta blockers, candesartan, sodium valproate, 
pizotifen, botox, CGRP-therapy. 
13.3.1.1. 
Outcome: Intracranial pressure (ICP) 
13.3.1.1.1. Intercurrent event: ICP-lowering medications 
All patients are expected to have elevated ICP because it is a defining characteristic of 
the disease. ICP is a physiological variable that is unlikely to show spontaneous 
improvement without treatment. For these reasons, we expect ICP-lowering medication 
use to be greater in the placebo arm. If a patient takes medication that is intended to 
reduce their ICP, it is logical to expect that their ICP will be reduced. Outcomes from 
patients that take ICP-lowering medications will confound the estimation of the causal 
treatment effect of Presendin. We have no data to estimate the length of effects of ICP-
lowering medications. For these reasons, we propose to remove 24-week ICP outcomes 
from all patients that have used ICP-lowering medications and replace these observations 
with arm-specific imputations. This will allow estimation of the treatment effect that is 
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purely and causally attributable to Presendin. Patients will consent at enrolment to forgo 
the use of ICP-lowering medications, and be informed that taking ICP-lowering 
medications during the trial would constitute rescue therapy and be a protocol deviation. 
13.3.1.1.2. Intercurrent event: Off-protocol lumbar punctures 
Lumbar punctures are commonly conducted to reduce intracranial pressure [Weisberg, 
1977; Johnston, 1981; De Simone, 2005]. In some centres, they are given routinely 
although this has now been advised against in the International IIH Guidelines (Soler, 
1998; Mollan, 2018). As such, they remain a material therapeutic option. LP is expected 
to reduce ICP mean opening pressure 32 (28-37) cm CSF to 19 (17-21) cm CSF post LP 
[Yiangou, 2019]. Beneficial effects dissipate with time and whilst there has been no 
longitudinal assessment to quantify change in ICP after an LP, it is expected that effects 
in the majority of change would have dissipated completely within two months [Yiangou, 
2019]. Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove 24-week ICP outcomes from all patients that have had an off-protocol LP within 
two months of the protocol-scheduled 24-week LP, and replace these observations with 
arm-specific imputations. Where patients require off-protocol LP this would be a protocol 
deviation. 
13.3.1.1.3. Inter-current event: Dramatic weight-loss following surgery 
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in ICP [Sinclair, 2010]. We do not regard gradual weight-
loss arising from changes to diet, lifestyle or exercise to be intercurrent events. However, 
sudden dramatic weight loss arising from a surgical procedure will likely yield material 
changes to IIH symptoms. This will confound the estimation of the causal treatment 
effect of Presendin. For these reasons, we propose to remove 24-week ICP outcomes 
from all patients that experience weight loss exceeding 10% of baseline weight after a 
surgical weight-loss procedure and replace with arm-specific imputations. Patients will 
be ineligible for the trial if they have had a surgical weight-loss procedure within 3 
months of randomisation or fail to confirm that they do not intend to undertake such a 
procedure during the trial. They will also be informed at enrolment that undergoing a 
surgical weight-loss procedure would be a protocol deviation. 
13.3.1.2. 
Outcome: Perimetric Mean Deviation (PMD) 
13.3.1.2.1. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication, it is logical to expect that their ICP will decrease 
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and that papilledema will reduce as a result, allowing visual fields to improve. As stated, 
we expect ICP-lowering medication use to be greater in the placebo arm. Outcomes from 
patients that take these medications will confound the estimation of the causal treatment 
effect of Presendin. For these reasons, we propose to remove the PMD outcomes 
following the administration of ICP-lowering medications, and replace these observations 
with imputations generated by a method suitable for longitudinal data imputation. This 
will allow estimation of the treatment effect that is purely and causally attributable to 
Presendin. 
13.3.1.2.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilledema, allowing visual fields to improve. Patients that have LPs are expected to 
experience less pressure on the optic nerve, less papilledema, and have better chances of 
visual fields improving. Beneficial effects dissipate with time and whilst there has been 
no longitudinal assessment to quantify papilledema after an LP the consensus of 
clinicians would predict that effects of the LP on papilledema and therefore visual fields 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
PMD outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove PMD outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.2.3. Intercurrent event: Dramatic weight-loss following surgery 
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including improvements in visual fields [Sinclair, 2010]. We do not regard 
gradual weight-loss arising from changes to diet, lifestyle or exercise to be intercurrent 
events. However, sudden dramatic weight loss arising from a surgical procedure will 
likely yield material changes to IIH symptoms. This will confound the estimation of the 
causal treatment effect of Presendin. For these reasons, we propose to remove PMD 
outcomes of patients that experience weight loss exceeding 10% of baseline weight after 
a surgical weight-loss procedure from the date of procedure. These outcomes will be 
replaced with patient-within-arm imputations generated by a method suitable for 
longitudinal data imputation. 
 
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13.3.1.3. 
Outcome: Papilledema measured by OCT (including central thickness, 
CT, retinal nerve fibre layer, RNFL) 
13.3.1.3.1. Intercurrent event: ICP-lowering medications 
All patients will suffer from papilledema at enrolment and it is the hallmark feature of the 
disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient takes ICP-lowering 
medication, it is logical to expect that their ICP will decrease and that the papilledema 
will reduce in turn. As stated, we expect ICP-lowering medication use to be greater in the 
placebo arm. Outcomes from patients that take these medications will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove the OCT outcomes following the administration of ICP-lowering medications, 
and replace these observations with imputations generated by a method suitable for 
longitudinal data imputation. This will allow estimation of the treatment effect that is 
purely and causally attributable to Presendin. 
13.3.1.3.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilledema. Patients that have LPs are expected to experience less pressure on the optic 
nerve and therefore relatively less papilledema. Beneficial effects dissipate with time and 
whilst there has been no longitudinal assessment to quantify papilledema after an LP the 
consensus of clinicians would predict that effects of the LP on papilledema would have 
dissipated by one month. Outcomes from patients that have undergone off-protocol LPs 
will confound the estimation of the causal treatment effect of Presendin. OCT outcomes 
will be recorded repeatedly during the trial. For the reasons stated, we propose to remove 
OCT outcomes recorded in the 4-weeks following an off-protocol LP, and replace these 
observations with patient-within-arm imputations generated by a method suitable for 
longitudinal data imputation. 
13.3.1.3.3. Intercurrent event: Dramatic weight-loss following surgery 
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in papilledema [Sinclair, 2010]. We do not regard gradual 
weight-loss arising from changes to diet, lifestyle or exercise to be intercurrent events. 
However, sudden dramatic weight loss arising from a surgical procedure will likely yield 
material changes to IIH symptoms. This will confound the estimation of the causal 
treatment effect of Presendin. For these reasons, we propose to remove OCT outcomes of 
patients that experience weight loss exceeding 10% of baseline weight after a surgical 
weight-loss procedure from the date of procedure. These outcomes will be replaced with 
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patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4. 
Outcome: Monthly headache days (MHD)  
13.3.1.4.1. Intercurrent event: Headache-preventative medications 
The great majority of patients are expected to suffer from headache because it is a 
common symptom of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a patient 
takes medication that is intended to prevent headache, it is logical to expect that their 
headache burden will be decreased. Despite the widely-observed short-term placebo-
effect observed in headache outcomes, we expect headache-preventative medication use 
to be greater in the placebo arm. Outcomes from patients that take headache-preventative 
medications will confound the estimation of the causal treatment effect of Presendin. For 
these reasons, we propose to remove the headache outcomes following the administration 
of headache-preventative medications, and replace these observations with imputations 
generated by a method suitable for longitudinal data imputation. This will allow 
estimation of the treatment effect that is purely and causally attributable to Presendin. 
Patients will consent at enrolment to forgo the use of Headache-preventative medications, 
and be informed that taking such medicines during the trial would be regarded as rescue 
therapy and be a protocol deviation. 
13.3.1.4.2. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing the frequency and intensity of 
headache. Beneficial effects dissipate with time. Prospective data documents alterations 
in headache for at least 7 days and whilst there is no prospective longitudinal data over a 
longer time period consensus amongst clinicians would widely acknowledge that 
headache in some individuals can be influenced for up to a month [Yiangou, 2019]. 
Outcomes from patients that have undergone off-protocol LPs will confound the 
estimation of the causal treatment effect of Presendin. MHD outcomes will be recorded 
daily via diaries. For the reasons stated, we propose to remove MHD outcomes recorded 
in the 4-weeks following each off-protocol LP, and replace these observations with 
patient-within-arm imputations generated by a method suitable for longitudinal data 
imputation. 
13.3.1.4.3. Intercurrent event: Dramatic weight-loss following surgery 
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including decreases in headache frequency and severity [Sinclair, 2010]. We 
do not regard gradual weight-loss arising from changes to diet, lifestyle or exercise to be 
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intercurrent events. However, sudden dramatic weight loss arising from a surgical 
procedure will likely yield material changes to IIH symptoms. This will confound the 
estimation of the causal treatment effect of Presendin. For these reasons, we propose to 
remove MHD outcomes of patients that experience weight loss exceeding 10% of 
baseline weight after a surgical weight-loss procedure from the date of procedure. These 
outcomes will be replaced with patient-within-arm imputations generated by a method 
suitable for longitudinal data imputation. 
13.3.1.4.4. Intercurrent event: ICP-lowering medications 
All patients are expected to suffer from some visual field loss at enrolment because it is 
the hallmark feature of the disease [Wall, 2014; Ottridge, 2017; Markey, 2020]. If a 
patient takes ICP-lowering medication, it is logical to expect that their ICP will decrease 
and that papilledema will reduce as a result, allowing visual fields to improve. As stated, 
we expect ICP-lowering medication use to be greater in the placebo arm. Outcomes from 
patients that take these medications will confound the estimation of the causal treatment 
effect of Presendin. For these reasons, we propose to remove the PMD outcomes 
following the administration of ICP-lowering medications, and replace these observations 
with imputations generated by a method suitable for longitudinal data imputation. This 
will allow estimation of the treatment effect that is purely and causally attributable to 
Presendin. 
13.3.1.4.5. Intercurrent event: Off-protocol lumbar punctures 
As discussed above, LPs are a material and widespread intervention in the treatment of 
IIH, given with the intention of reducing intracranial pressure and improving the 
associated symptoms of the disease, including reducing pressure on the optic nerve and 
papilledema, allowing visual fields to improve. Patients that have LPs are expected to 
experience less pressure on the optic nerve, less papilledema, and have better chances of 
visual fields improving. Beneficial effects dissipate with time and whilst there has been 
no longitudinal assessment to quantify papilledema after an LP the consensus of 
clinicians would predict that effects of the LP on papilledema and therefore visual fields 
would have dissipated by one month. Outcomes from patients that have undergone off-
protocol LPs will confound the estimation of the causal treatment effect of Presendin. 
PMD outcomes will be recorded repeatedly during the trial. For the reasons stated, we 
propose to remove PMD outcomes recorded in the 4-weeks following an off-protocol LP, 
and replace these observations with patient-within-arm imputations generated by a 
method suitable for longitudinal data imputation. 
13.3.1.4.6. Intercurrent event: Dramatic weight-loss following surgery 
Research has shown that weight loss in IIH is associated with reductions in IIH 
symptoms, including improvements in visual fields [Sinclair, 2010]. We do not regard 
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gradual weight-loss arising from changes to diet, lifestyle or exercise to be intercurrent 
events. However, sudden dramatic weight loss arising from a surgical procedure will 
likely yield material changes to IIH symptoms. This will confound the estimation of the 
causal treatment effect of Presendin. For these reasons, we propose to remove PMD 
outcomes of patients that experience weight loss exceeding 10% of baseline weight after 
a surgical weight-loss procedure from the date of procedure. These outcomes will be 
replaced with patient-within-arm imputations generated by a method suitable for 
longitudinal data imputation. 
13.3.1.5. 
Primary Estimand (Hypothetical assuming no concurrent procedures, 
irrespective of adherence to treatment) 
The primary estimand is defined as the following for the primary endpoint: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect ICP. 
The primary estimand for the initial secondary endpoint will be handled similarly to the 
primary endpoint using the “Hypothetical” approach. The initial secondary endpoint is 
defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, regardless of adherence to 
randomised treatment, where patients did not have medications or procedures likely 
to materially affect PMD. 
13.3.1.6. 
Secondary Estimand (Hypothetical) 
The secondary estimand for the primary endpoint is defined as follows: 
• 
Treatment difference in ICP measurement between Presendin and placebo at Week 
24 for all patients who are randomised and start treatment, if all patients adhered to 
treatment, where patients did not have medications or procedures likely to materially 
affect ICP. 
The secondary estimand for the initial secondary endpoint will be defined as: 
• 
Treatment difference in PMD between Presendin and placebo over 24-weeks for all 
patients who are randomised and start treatment, if all patients adhered to treatment, 
where patients did not have medications or procedures likely to materially affect 
PMD. 
All details will be defined in the SAP. 
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13.3.2. 
Analysis Populations 
The following analysis populations are planned for this trial:  
• 
Safety Population: The Safety population includes all patients randomised to 
treatment who receive at least one dose of trial medication. This will be the 
population used for all safety analyses unless otherwise specified. 
• 
Intent-To-Treat Population (ITT): The ITT population includes all patients 
randomised to treatment. This will be the main population for all efficacy analyses 
unless otherwise specified. 
• 
Per Protocol (PP): The PP population includes all patients randomised to treatment 
who complete the trial without important non-evaluable protocol deviations. Only 
protocol deviations with the potential to affect the trial results significantly, or to 
invalidate the interpretation of the data obtained, will lead to exclusion of patients 
from the PP population. Protocol deviations to be considered will include (but will 
not be limited to): 
• 
Failure to meet inclusion/exclusion criteria 
• 
Wrong treatment or incorrect volume of drug administration 
• 
Prohibited concomitant medications 
• 
Compliance of less than 75% and >125% with trial drug administration 
• 
Use of rescue procedures, including, off-protocol LPs, LP shunts or bariatric 
surgery 
Assignment of patients to populations will be confirmed at a blinded data review meeting 
to be held before the trial database is locked. 
If a patient is randomised incorrectly or is administered the incorrect trial medication, 
analyses of the ITT will be based on the assigned treatment, whereas all other analyses 
will be based on the actual treatment received. 
13.3.3. 
Treatment Comparisons 
Treatment comparisons will be undertaken between active and control groups.  
13.3.4. 
Safety Analyses 
Safety will be evaluated from reported AEs, changes in clinical laboratory values, 
changes in vital signs, and ECG results. 
All safety analyses will be performed on the Safety population. 
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13.3.4.1. Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (the most recent 
version before starting the trial will be used).  
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of trial medication. 
Guidance for programmers on how to handle missing fields relating to AEs will be given 
in the SAP. 
The number and percentage of patients reporting TEAEs, grouped by MedDRA system 
organ class and preferred term will be tabulated by treatment group and observation 
period. Summaries will be presented for all TEAEs, TEAEs by severity and TEAEs by 
relationship to trial medication. 
In the case of multiple occurrences of the same TEAE within the same patient, each 
patient will only be counted once for each preferred term. If a patient experiences’ more 
than one TEAE within a preferred term, only the TEAE with the strongest relationship or 
the maximum intensity, as appropriate, will be included in the summaries of relationship 
and intensity. 
In the summaries showing severity and relationship to trial medication, the event with the 
maximum severity or strongest relationship will be reported. If a particular event is 
missing the severity and/or relationship, then the strongest possible severity or 
relationship will be assumed for analysis (severity = Grade 4/life-threatening, relationship 
= probable relationship). 
Adverse event table summaries will be split by observation period. Adverse events with a 
start date after first dose of trial drug and up to and including date of Week 24 assessment 
will be presented in the randomised treatment period.  
In the AE data listings, all AEs will be displayed. Adverse events that are not treatment-
emergent will be flagged. The observation period in which an AE started will also be 
provided. 
Non-protocol LPs, interventions for IIH, hospital admission for IIH exacerbation will be 
displayed. Treatment failures will be displayed by trial arm. 
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13.3.4.2. Clinical Laboratory Evaluations  
Laboratory test results for each biochemistry and haematology parameter will be 
summarized descriptively by treatment group and time point as both observed values and 
change from baseline values. 
The number of patients with clinical laboratory (biochemistry, haematology, and 
urinalysis) values categorized as below, within, or above the normal ranges (or as either 
normal or abnormal for urinalysis variables that do not have quantitative ranges), will be 
tabulated in relation to baseline (shift tables), for each clinical laboratory analyte by 
treatment group and time point. 
Laboratory values will be displayed in the data listings and those that are outside the 
reference ranges will be flagged, along with corresponding normal ranges. Any patients 
with any markedly abnormal laboratory results will also be provided in a listing. 
All laboratory summaries will be prepared for the period of randomised treatment. 
Pregnancy test results including reason, if not performed, will be listed. 
13.3.4.3. Vital Signs and Body Mass Index Evaluations 
Descriptive summaries of observed values and changes from baseline will be calculated 
for systolic blood pressure, diastolic blood pressure and heart rate by treatment group and 
time point.  
Body mass index will be derived at Screening, Baseline and Weeks 4, 8, 16, 24, 32 and 
48 using height captured at Screening and weight at the respective assessment. Body 
mass index and weight will be summarized descriptively by treatment group and time 
point as both observed values and change from baseline values for Safety and ITT 
populations. 
Summaries will be prepared for the period of randomised treatment. 
13.3.4.4. Electrocardiogram 
Descriptive statistics of observed values and change from baseline will be presented for 
ECG measures of PR interval, QRS interval, QT interval, QT interval corrected 
according to Fridericia’s formula (QTcF). These summaries will be presented by 
treatment and time point for the Safety population.  
The number and percentage of patients with values beyond clinically important limits 
will be summarised including those with an increase in QTcF >30 msec increase from 
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baseline and >60 msec increase from baseline or those with an absolute QTcF value of 
>450 msec (male patients) or >470 msec (female patients). 
Summaries will be prepared for the period of randomised treatment. 
13.3.5. 
Patient Reported Outcomes Analyses 
All patient reported outcome endpoints (VFQ-25, HIT-6, SF-36, EQ-5D-5L) will be 
analysed as observed and presented with change from baseline in a descriptive summary 
of treatment and visit for the period of randomised treatment.  
The number and percentages of PGIC responses will be tabulated by treatment and visit. 
13.3.6. 
Missing Data 
Although every effort will be made to collect responses from all patients at all scheduled 
time points, there undoubtedly will be some missing data. The SAP will describe detailed 
steps for dealing with missing data using an iterative regression based multiple 
imputation strategy that adjusts for treatment arm, centre, baseline value, and 
stratification variables. 
13.3.7. 
Reporting Deviations from the Statistical Plan 
Any deviations from the planned analyses will be described and justified in the final 
clinical trial report. 
14. 
TRIAL ADMINISTRATION 
14.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Before initiation of a trial site, the Sponsor will obtain approval from the appropriate 
regulatory agency to conduct the trial in accordance with ICH-GCP and applicable 
country-specific regulatory requirements. 
The trial will be conducted in accordance with all applicable regulatory requirements. 
The trial will be conducted in accordance with ICH-GCP, all applicable patient privacy 
requirements and the ethical principles that are outlined in the Declaration of Helsinki 
2013, including, but not limited to: 
• 
An IEC/Institutional Review Board review and approval of trial protocol and any 
subsequent amendments and all ICFs or other information given to the patient 
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• 
Patient informed consent 
• 
Investigator reporting requirements 
The Sponsor will provide full details of the above procedures, either verbally, in writing, 
or both. 
Written informed consent must be obtained from each patient before participation in the 
trial. Written informed consent will be collected following a review of the patient’s 
information leaflet by the potential patient and a discussion between the patient and the 
Investigator or suitably qualified designee. 
The Investigator will cooperate with all regulatory inspections and will notify the 
Sponsor as soon as they are aware of an inspection which may involve this trial. With the 
exception of statutory regulatory authority inspections, the Sponsor will be consulted in 
the event of inspection of the clinical site(s) by an outside authority before the Inspectors 
are permitted access to any of the trial records or the trial areas. 
14.2. 
Trial Monitoring 
In accordance with applicable regulations, ICH-GCP, the monitoring plan and the 
Sponsor’s and/or delegate procedures, monitors will contact the site before the start of the 
trial to review with the site staff the protocol, trial requirements, and their responsibilities 
to satisfy regulatory, ethical, and the Sponsor’s requirements. When reviewing data 
collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. 
The Sponsor and or delegated monitors will perform risk-based monitoring during the 
conduct of the trial to ensure that: 
• 
The data are authentic, accurate and complete 
• 
The patient’s safety and rights are being protected 
• 
The trial is conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH-GCP and all applicable regulatory requirements 
14.2.1. 
Access to Source Data 
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor, Sponsor-appointed auditors and regulatory inspectors direct access to 
all relevant documents. 
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14.2.2. 
Data Handling and Record Keeping 
Following closure of the trial, the Investigator or head of the medical institution (where 
applicable) must maintain all site trial records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
Investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The Investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
The Sponsor will inform the Investigator of the time period for retaining the site records 
in order to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, the Sponsor SOPs and/or institutional requirements. 
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the Investigator is no longer associated with the 
site. 
14.3. 
Provision of Trial Results and Information to Investigators 
and Publications 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical trial report. The Investigator will be provided 
reasonable access to statistical tables, figures and relevant reports and will have the 
opportunity to review the complete trial results at a mutually agreeable location. 
The Sponsor will also provide the Investigator with the full summary of the trial results. 
The Investigator is encouraged to share the summary results with the trial patients, as 
appropriate. 
If the Sponsor decides to publish the results, then they will provide the Investigator with 
an opportunity to review the manuscript. If the Investigator wishes to publish anything 
related to the trial, then they must provide the Sponsor with the draft publication and 
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allow them no less than 14 days to review the document. The Investigator cannot publish 
without written authorisation from the Sponsor. 
14.4. 
Data Management 
For this trial, patient data will be collected using an eCRF and combined with data 
provided from other sources in a validated data system. Patient’s identifiable data (e.g., 
name, initials, address etc.) will not be collected in the eCRF or transferred to Invex 
Therapeutics. Clinical data management will be performed with the objective of 
removing errors and inconsistencies in the data which would otherwise impact on the 
statistical analysis or the credibility of the Clinical Study Report. Original CRFs will be 
retained by Invex Therapeutics; the Investigator will also retain a copy. 
Management of clinical data will be performed in accordance with the applicable Sponsor 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using the Medical Dictionary for Regulatory Affairs and World Health 
Organisation Drug dictionary.  
When using electronic trial data handling and/or remote electronic trial data systems, the 
Sponsor or designee will:  
a. 
Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation) 
b. Maintain SOPs for using these systems 
c. 
Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail) 
d. Maintain a security system that prevents unauthorised access to the data 
e. 
Maintain a list of the individuals who are authorised to make data changes 
f. 
Maintain adequate backup of the data 
g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing) 
Training on the use of the electronic data collection system will be provided to all 
relevant trial site staff. 
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14.5. 
Independent Adjudication Committee 
The IAC will consist of three international medical experts in neurology or 
ophthalmology who are independent of the Sponsor team and Investigators running the 
trial.  
The role of the IAC will be: 
• 
To support the Investigators with opinions on the eligibility of potential patients 
• 
To provide opinions regarding rescue medications required during the trial 
Further details on the composition, activities and responsibilities of the IAC can be found 
in the IAC charter. 
14.6. 
Data Safety Monitoring Committee 
Details on the composition, activities and responsibilities of the DSMC can be found in 
the DSMC charter. 
14.7. 
Insurance, Indemnity and Finance 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
The Sponsor will indemnify all Investigators participating in this trial against future 
claims by trial patients; the terms of this will be detailed within a separate letter of 
indemnification. The indemnity will only apply where all trial procedures have been 
carried out according to this protocol. 
The financial aspects of the trial are addressed in a separate agreement. 
 
 
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Community Weight Management Intervention for the Treatment of Idiopathic 
Intracranial Hypertension: A Randomized Clinical Trial. JAMA Neurol. 2021b Jun 
1;78(6):678-686.  
Moreno JL, Willett KC, Desilets AR. Exenatide as a novel weight loss modality in 
patients without diabetes. Ann Pharmacother. 2012 Dec;46(12):1700-6. 
Mulla Y, Markey KA, Woolley RL, Patel S, Mollan SPS, Sinclair AJ. Headache 
determines quality of life in idiopathic intracranial hypertension. J. Headache Pain. 
2015;16:521. 
Ney JJ, Volpe NJ, Liu GT, Balcer LJ, Moster ML, Galetta SL. Functional Visual Loss in 
Idiopathic Intracranial Hypertension. Ophthalmology, 2009 Sep;116(9):1808–1813.e1. 
NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee; Wall M, 
McDermott MP, Kieburtz KD et al. Effect of acetazolamide on visual function in patients 
with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial 
hypertension treatment trial. JAMA, 2014 Apr 23-30;311(16):1641-51. 
Olesen, J. Headache Classification Committee of the International Headache Society 
(IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 
2018 Jan;38(1):1-211. 
O’Reilly MW, Westgate CS, Hornby C et al. A unique androgen excess signature in 
idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. JCI insight. 
2019 Mar 21;4(6). 
Ottridge R, Mollan SP, Botfield H et al. Randomised controlled trial of bariatric surgery 
versus a community weight loss programme for the sustained treatment of idiopathic 
intracranial hypertension: The Idiopathic Intracranial Hypertension Weight Trial 
(IIH:WT) protocol. BMJ Open. 2017 Sep 27;7(9):e017426. 
Petzold A, de Boer JF, Schippling S et al. Optical coherence tomography in multiple 
sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010 Sep;9(9):921-32. 
Piper RJ, Kalyvas AV, Young AMH, Hughes MA, Jamjoom AAB, Fouyas IP. 
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Interventions for idiopathic intracranial hypertension. Cochrane Database of Systematic 
Reviews. 2015 Aug 7;2015(8):CD003434. 
Pujante Alarcón P, Hellín Gil MD, Román LM, Ferrer Gómez M, García Zafra MV, 
Tébar Massó J. Metabolic control and weight loss in patients with obesity and type 2 
diabetes mellitus, treated with exenatide. Med Clin (Barc). 2012 Dec 1;139(13):572-8. 
Raphael BA, Galetta KM, Jacobs DA et al. Validation and test characteristics of a 10-
item neuro-ophthalmic supplement to the NEI-VFQ-25 Am J Ophthtalmol 2006 
Dec;142(6):1026-35 
Rebolleda G, Munoz-Negrete FJ. Follow-up of mild papilledema in idiopathic 
intracranial hypertension with optical coherence tomography. Invest Ophthalmol Vis Sci. 
2009 Nov;50(11):5197-200. 
Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, Trautmann 
M. Effects of exenatide and lifestyle modification on body weight and glucose tolerance 
in obese subjects with and without pre-diabetes. Diabetes Care. 2010 Jun;33(6):1173-5. 
Salgarello T, Falsini B, Tedesco S, Galan ME, Colotto A, Scullica L. Correlation of optic 
nerve head tomography with visual field sensitivity in papilledema. Invest Ophthalmol 
Vis Sci. 2001 Jun;42(7):1487-94. 
Scotton WJ, Mollan SP, Walters T et al. Characterising the patient experience of 
diagnostic lumbar puncture in idiopathic intracranial hypertension: a cross-sectional 
online survey. BMJ Open 2018 May 30;8(5):e020445. 
Scotton WJ, Botfield HF, Westgate CSj et al. Topiramate is more effective than 
acetazolamide at lowering intracranial pressure. Cephalalgia. 2019 Feb;39(2):209-218. 
Silberstein S, Tfelt-Hansen P, Dodick DW et al. Guidelines for Controlled Trials of 
Prophylactic Treatment of Chronic Migraine in Adults. Cephalalgia. 2008 
May;28(5):484-495. 
Silberstein SD, Dodick DW, Bigal ME et al. Fremanezumab for the preventive treatment 
of chronic migraine. N. Engl. J. Med. 2017 Nov; 377(22):2113–2122. 
Sinclair AJ, Burdon MA, Nightingale PG et al. Low energy diet and intracranial pressure 
in women with idiopathic intracranial hypertension: Prospective cohort study. BMJ. 2010 
Jul 7;341:c2701. 
Sina F, Razmeh S, Habibzadeh N, Zavari A, Nabovvati M. Migraine headache in patients 
with idiopathic intracranial hypertension; Neurology international 2017 Oct 2;9(3):7280. 
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Soler D, Cox T, Bullock P, Calver DM, Robinson RO. Diagnosis and management of 
benign intracranial hypertension. Arch Dis Child. 1998 Jan;78(1):89-94. 
Sørensen PS, Thomsen AM, Gjerris F. Persistent disturbances of cognitive functions in 
patients with pseudotumor cerebri. Acta Neurologica Scandinavica, 1986 Mar;73(3)264–
268. 
Tassorelli C, Diener H-C, Dodick DW et al. Guidelines of the International Headache 
Society for controlled trials of preventive treatment of chronic migraine in adults. 
Cephalalgia. 2018 Apr;38(5):815–832.  
Tepper S, Ashina M, Reuter U et al. Safety and efficacy of erenumab for preventive 
treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 
trial. Lancet Neurol. 2017 Jin;16(6):425–434. 
Vernieri F, Paolucci M, Altamura C et al. Onabotulinumtoxin-A in chronic migraine: 
should timing and definition of non-responder status be revised? Suggestions from a real-
life Italian multicentre experience. Headache. 2019 Sep;59(8):1300–1309. 
Vijay V, Mollan SP, Mitchell JL et al. Utilising optical coherence tomography measures 
as surrogates for raised intracranial pressure in idiopathic intracranial hypertension. 
JAMA Opthalmology, 2020 Dec 1;138(12):1264-1271 
Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 
patients. Brain, 1991 Feb;114 (Pt 1A):155-80. 
Wall M, Woodward KR, Brito CF. The effect of attention on conventional automated 
perimetry and luminance size threshold perimetry. Invest Ophthalmol Vis Sci. 2004. 
Jan;45(1):342-50.  
Wall M, McDermott MP, Kieburtz KD et al. Effect of acetazolamide on visual function 
in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic 
intracranial hypertension treatment trial JAMA 2014 Apr 23-30;311(16):1641-51  
Wall M, Johnson CA, Cello KE et al. Visual Field Outcomes for the Idiopathic 
Intracranial Hypertension Treatment Trial (IIHTT). Invest Ophthalmol Vis Sci. 2016 
Mar;57(3):805-812. 
Websky von K, Reichetzeder C, Hocher B. Physiology and pathophysiology of incretins 
in the kidney. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):54–60.  
Westgate CS, Botfield HF, Alimajstorovic Z et al. Systemic and adipocyte transcriptional 
and metabolic dysregulation in idiopathic intracranial hypertension. JCI insight 
2021:24;6(10). 
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Weisberg LA, Chutorian AM. Pseudotumor cerebri of childhood. Am J Dis Child. 1977 
Nov;131(11):1243–8. 
Wright BLC, Lai JTF, Sinclair AJ. Cerebrospinal fluid and lumbar puncture: a practical 
review. J Neurol. 2012 Aug;259(8):1530-45.  
Yiangou A, Mitchell JL, Fisher C et al. Erenumab for headaches in idiopathic intracranial 
hypertension: A prospective open-label evaluation. Headache. 2021 Jan;61(1):157-169. 
Yiangou A, Mitchell J, Markey KA et al. Therapeutic lumbar puncture for headache in 
idiopathic intracranial hypertension: Minimal gain, is it worth the pain? Cephalalgia. 
2019 Feb;39(2):245-253.  
Yri HM, Rönnbäck C, Wegener M, Hamann S, Jensen RH. The course of headache in 
idiopathic intracranial hypertension: A 12-month prospective follow-up study. Eur. J. 
Neurol. 2014 Dec;21(12):1458–1464. 
Yri HM, Jensen RH. Idiopathic intracranial hypertension: Clinical nosography and field-
testing of the ICHD diagnostic criteria. A case-control study. Cephalalgia. 2015 
Jun;35(7):553-62. 
 
 
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16. 
APPENDICES PROVIDED FOR TRIAL INVEX-CLIN-IIH-
301 
16.1. 
Appendix 1: IIH Diagnostic criteria [Mollan, 2018] 
A. Papilloedema 
B. Normal neurological examination (except sixth cranial nerve palsy) 
C. Neuroimaging: normal brain parenchyma (no hydrocephalus, mass, structural 
lesion or meningeal enhancement). Venous thrombosis excluded in all. 
D. Normal CSF constituents (less than or equal to 7 white cells per mm3 with normal 
protein and glucose  
E. Elevated lumbar puncture pressure ≥ 25cmCSF  
 
 
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16.2. 
Appendix 2: 36-item short from survey  
 
HEALTH 
• • 
RAND > RAND Health > Surveys > RAND Medical Outcomes Study > 36-ltem Short Form Survey (SF-36) > 
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-m 
36-ltem Short Form Survey Instrument 
(SF-36) 
RAND 36-ltem Health Survey 1.0 Questionnaire Items 
Choose one option for each questionnaire item_ 
L In general, would you say your health is: 
,,...... 1- Excellent 
,....,_ 2 - Very good 
0 3- Good 
0 4-Fair 
"
5-Poor 
2. Compared to one year ago, how would you rate your health in general now? 
0 
1- Much better now than one year ago 
0 2 - Somewhat better now than one year ago 
0 3 -About the same 
" 
4 - Somewhat worse now than one year ago 
n s - Much worse now than one year ago 


 
 
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The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so. how much? 
Yes. 
Yes. 
No.not 
limited a 
limited a 
limited at 
lot 
little 
all 
3. Vigorous activities, such as running. lifting heavy objects. 
0
1 
0 
2 
0 
3 
participating in strenuous sports 
4. Moderate activities. such as moving a table, pushing a 
0
1 
r'\ 2 
3 
vacuum cleaner, bowling, or playing golf 
s. Lifting or carrying groceries 
1'""'1 1 
2 
,...., 3 
6. Climbing several flights of stairs 
n
1 
r'\ 2 
r'\ 3 
7. Climbing one flight of stairs 
0
1 
2 
3 
8. Bending. kneeling. or stooping 
0
1 
r, 2 
0
3 
9. Walking more than a mile 
0
1 
r'\ 2 
!'""' 3 
10. Walking several blocks 
0
1 
2 
3 
u. Walking one block 
r- 1 
r'\ 2 
3 
12. Bathing or dressing yourself 
n
1 
r'\ 2 
r, 3 


 
 
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During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
13. Cut down the amount of time you spent on work or other activities 
14. Accomplished less than you would like 
1s. Were limited in the kind of work or other activities 
16. Had difficulty performing the work or other activities (for example, it took extra 
effort) 
Yes 
No 
0 
0 
() 
2 
,-... 
2 
,-... 
2 
2 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
Yes 
No 
17. Cut down the amount of time you spent on work or other activities 
("') 2 
18. Accomplished less than you would like 
19. Didn't do work or other activities as carefully as usual 
20. During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family. friends. neighbors. or 
groups? 
r- I - Not at all 
2 - Slightly 
,..._ 3 - Moderately 
'"" 4 - Quite a bit 
,..._ s - Extremely 


 
 
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21. How much bodily pain have you had during the past 4 weeks? 
(' 1-None 
"" 2 - Very mild 
"" 3 -Mild 
"" 4 - Moderate 
,.... 5- Severe 
r- 6 -Very severe 
22. During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
1 - Not at all 
r,, 2 - A little bit 
"" 3 - Moderately 
"" 4 - Quite a bit 
,-.. 5 - Extremely 
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These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question. please give the one answer that comes closest to the way 
you have been feeling. 
How much of the time during the past 4 weeks ... 
All of 
Most 
A good 
Some 
A little 
None 
the 
of the 
bit of the 
ofthe 
of the 
ofthe 
time 
time 
time 
time 
time 
time 
23. Did you feel full of pep? 
,...... l 
") 2 
,..... 3 
,,..... 4 
'"" s 
r\ 6 
24. Have you been a very nervous 
,--. l 
ll 2 
3 
,,..... 4 
r"\ 5 
"") 6 
person? 
25. Have you felt so down in the 
1 2 
3 
4 
5 
6 
dumps that nothing could cheer you 
up? 
26. Have you felt calm and peaceful? 
1 2 
3 
4 
5 
6 
27. Did you have a lot of energy? 
l 2 
3 
4 
5 
6 
28. Have you felt downhearted and 
0 1 
"") 2 
3 
,,..... 4 
'1 5 
'"' 6 
blue? 
29. Did you feel worn out? 
"
l 
<'I 2 
"
3 
"
4 
r"\ 5 
"
6 
30. Have you been a happy person? 
,--. l 
"") 2 
r\ 3 
,, 4 
0
5 
"") 6 
31. Did you feel tired? 
r"\ l 
I") 2 
"
3 
"
4 
"
5 
6 
32. During t he past 4 weeks. how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
,...._ 1 - All of the time 
,..... 2 - Most of the time 
,...._ 3 -Some of the time 
4 - A little of the time 
5 - None of the time 


 
 
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How TRUE or FALSE is each of the following statements for you. 
Definitely 
Mostly 
Don't 
Mostly 
Definitely 
true 
true 
know 
false 
false 
33. I seem to get sick a little easier than 
,,..., l 
,...._ 2 
I""' 3 
""" 4 
,...._ 5 
other people 
34. I am as healthy as anybody I know 
0 1 
2 
3 
4 
5 
35. I expect my health to get worse 
0 1 
,..._ 2 
,.._ 3 
,..._ 4 
,..._ 5 
36. My health is excellent 
2 
3 
4 
5 
ABOUT 
The RAND Corporation is a research organization that develops solutions to public policy challenges to help make 
communities throughout the world safer and more secure. healthier and more prosperous. RAND is nonprofit, nonpartisan, 
and committed to the public interest. 
1776 Main Slreel 
Sonia Monico, Colifornio 90401 -3208 
RAND• is a registered trademark. Copyright ie 1994-2016 RAND Corporation. 


 
 
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16.3. 
Appendix 3: EuroQol -5 dimension-5 level survey  
 
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UK (English} © 2009 EuroQof Group EQ-5O'" is a trade mark of/he EuroQol Group 


 
 
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Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, hou 
leisure activities) 
I have no problems doing my usual 
I have slight problems doing my usu 
lh 
s or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
UK (English) <Ill 2009 EuroQol Group E0-5D"' is a trade marl< of Iha EuroQol Group 
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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
O means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TOD 
• 
Now, please write the number you marked on the scale in the 
below. 
3 
UK (English) <Ill 2009 EuroQol Group E0-5D"' is a trade marl< of Iha EuroQol Group 
The best health 
you can imagine 
100 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The WO rst hea Ith 
you can imagine 
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16.4. 
Appendix 4: Headache Impact Test-6 
 
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HIT-6Thl 
(VF R 10 
I.I ) 
~
HE 
This questionnaire was designed to help you describe and communicate 
the way you feel and wha t you cannot do because of headaches. \ 'i£'1T 
TESTN 
To complete, please circle one answer for each question. 
V When you have headaches, how often is the pain severe? 
Never 
Rarely 
Sometimes 
,...How often do headaches limit your ability to do usual daily activities in 
T 
work, work, school, or social activities? 
Never 
Rarely 
Never 
Rarely 
Always 
In the past 4 weeks, how often have yo 
e 
do work or daily activities because 
of your headaches? 
Never 
Very Often 
Always 
ed up or irritated because of your headaches? 
Vuy Often 
Always 
.... 
Int 
y 
da· 
ften did headaches limit your ability to concentrate on work or 
Som etimes 
+ 
COLUMN 1 
COLUMN 2 
COLUMN 3 
(6 points each) 
(8 points each] 
( 10 points each) 
To score, add points for answers in each column. 
Please share your HIT-6 results with your doctor. 
HH~~ IJS.jlJ>tlrt,tv.n.c,,1 1 
QXh, lo:11 ~c.N.~ GINSai11hJl11ewi:q,ctG:iripai,a. 
+ 
Very Often 
COLUMN 4 
I 11 points each] 
+ 
Always 
COLUMN 5 
(13 points each) 
Total Score ~I---~ 
Higher scores indicate 
greater impact on your life. 
Score range i 36-78. 


 
 
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HEADACHE 
IMPACT TESTn, 
What Does Your Score Mean? 
T If You Scored 60 or More 
Your hen.dachcs nrc having a vc:ry severe imp.lei on your life. You mny be experiencing disnblir 
arc more severe lhan lhosc of other hcad~1chc sufferers. Don't let your headaches: slOp you Ir< 
your life. like family. work. school or social ac1ivi1ies. 
1nkc an ,1ppoimmen1 today 10 discuss your HIT-6 rcsuils: and your hcadnchcs wilh your d 
T lf You Scored 56 - 59 
Your headaches arc having a ubst.:uuial impacl on your life. A a re uh y 
symptoms, <.omsiug yuu 10 utiss some lilnc from fmuily. work. Mcbool. or soc 
fake an appoimmenl today to discuss your I IIT-6 results and y 
T If You Scored 50 - 55 
Your hc.1dachcs seem 10 be having some impacl on your 
work. school. or social ac1ivi1ics. 
lake sure you discuss your I llT-6 results ond yo, 
T If You Scored 49 or 
ur 
1.--o.1usc rc~.;m:h si.Jows lhal when c.kx.:Lo~ unc.lcrsuu1d exactly ltow badly 
ien1s. they are much m re li.kcly to provide u successful 1rcau11cn1 program. which may 
a special derni led version for your doctor. 
,1gnin or try lhc Internet version 10 con linuc to moni1or your progress. 
·nit! I lt:adachc Impact Tt:sl (I IIT) is a tool ust:d lo lllt:asun: the ill1pact lit:ad;H.:hcs have un yuur abili ty 10 fu11cliu11 on ll1cjub. ill 
school. al home ancl in social situa.tions. Your score shows you lhe effect that headaches have on nonni3 1 daily life and your 
o.bili1y to funclion. I UT was developed by an i11ternn1t011nl re.om of headache expertS rrom neurology and prim3r)· co.re medicine 
in collabomtion with lhc psyclxm1clricians who developed the SF-36• · llcahh asscs~mcnl Loo i. 
I HT is 1101 intended lo offer UlCdical advice rcg;.udiug mc<licnl tli;.1gi.1& is or Lrcalmcnl. You should talk 10 your bc.a11hcarc 
provider for ad\•icc pccilic to your itualiou. 
SF-36' is a registered trademark of Medical Outcomes Trusl and John E. Ware, Jr. 
II IT•6 ScorinJ? 1111.crprtlalion 1-:ngJish Vention I.I 
elOOJ Qua.Jlt}'~le1'rif,. lnc. and GlaxoSmUhKHne Group of Compan.les. All rights reserved. 
V X 


 
 
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16.5. 
Appendix 5: Visual Function Questionnaire-25 & 10-item 
Supplement 
 
 
National Eye institute 
Visual FunctioninrJ Questionnaire - 25 
{VFQ-25) 
version 2000 
PB/SA 
"•ti s 
0'ftt1l5 r-Jf l v:,· 
S - July 1996 accept!; fu!I resp::>n!;ibi!lt~•. and Jgree!: to hold RAr-m harmlt£!;, tor 1hca 
·rac.y of any trar.slat:01 
".' t:,e NEJ VFQ-ZC. k st Version - July 1396 into ar,ott,cr :,mguc.gc ~nd for ,lily errors, 
liSSiC>rl~:;~~-ttiQ •~::-<./ COli!'oP.(IUeltCltS lhHE:-(if. 
·~tnts,.L
00 -Q.i°f . July 1995 lt.:Ce-pts !U!I re~ponst!Jility, J!ld a;irn-~s ~o t!O!d RANU Mrml::!SS, fer .:my 
J~~Ces resulti 
om lhe..ise ufthe NEI 'JFQ-26. 
4. The IJ~('.'r of ttlt: • 
• HJ-:li - .July ·\~iiJ •vl!I pro>nd~ cl. crectic line w!lE'r! printing tJ.nd cHstr!l,!IUng: th!s Oor::ument 
.::,r in pu~W,esultt or 1rna11s-es Mse-d en this tnetrum2-nt ac!<new\Mging tt!Jt it WJ$ dc•1etop~d .lt RAND 
unocr u,~·~Sh:p of tt.c Notkmc.l Eve Institute. 
1:w:sc 
@ HAND 1996 
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- 1 -
version 2000 
The following is a survey with statements about problems which involve your 
vision or feelings that you have about your vision condition. After each question 
please choose the response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
Please take as much time as you need to answer each question. 
answers are confidential. In order for this survey to improve our 
about vision problems and how they affect your quality of life, 
be as accurate as possible. Remember, if you wear glasses 
please answer all of the following questions as though you wer 
INSTRUCTIONS 
1. 
In general we would like to have people tr 
their own. If you find that you need 
project staff and they will assist y 
2. 
Please answer every question 
because they don't apply 
3. 
4. 
5. 
6. 
efore leaving the center and give it to 
Do not take it home. 
lease feel free to ask a member of the project 
I be glaa to help you. 
would permit identification of any person who completed this 
e regarded as strictly confidential. Such information will be 
purposes of this study and will not be disclosed or released for 
poses without prior consent, except as required by law. 
©RAND 1996 
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- 1 -
version 2000 
Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEAL TH AND VISION 
1. 
2. 
One) 
1 
2 
3 
......................................... 4 
........................................ 5 
ou say your eyesight using both eyes (with 
ou wear them) is excellent. good, fair, 
u completely blind? 
(Circle One) 
Excellent............................... 1 
Good ...................................... 2 
Fair ......................................... 3 
Poor ........................................ 4 
Very Poor .............................. 5 
Completely Blind................ 6 
©RAND 1996 
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3. 
How much of the time do you worry about your eyesight? 
(Circle One) 
None of the time............................. 1 
A little of the time ........................... 2 
Some of the time .............. . 
3 
Most of the time .......... . 
All of the time? ...... . 
4. 
How much pain or discomfort have you h 
(for example, burning, itching, or achin 
2 
3 
4 
5 
The next 
• 
difficulty, if any, you have doing 
or contact lenses if you use them 
certain ac 
for that ac 
5. 
have reading ordinary print in 
ould you say you have: 
(Circle One) 
ifficulty at all ......................................................... 1 
le difficulty ............................................................. 2 
3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
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6. 
How much difficulty do you have doing work or hobbies that require 
you to see well up close, such as cooking, sewing, fixing things 
around the house, or using hand tools? Would you say: 
(Circle One) 
No difficulty at all ......................................................... 1 
A little difficulty ............................................................ . 
Moderate difficulty ...................................................... . 
Extreme difficulty .................................................... .. 
Stopped doing this because of your eyesigli ... 
Stopped doing this for other reasons or not 
interested in doing this .......................................... . 
7. 
Because of your eyesight, how much 
something on a crowded shelf? 
8. 
Mod era 
• • 
.................. 3 
Extre 
.................. 4 
Stop ,CN:JloiJ:1o't 
5 
Sto 
have reading street signs or the names of 
(Circle One) 
lty at all ......................................................... 1 
culty ............................................................. 2 
3 
4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
9. 
Because of your eyesight, how much difficulty do you have gQi.ng 
down steps, stairs, or curbs in dim light or at night? 
©RAND 1996 


 
 
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(Circle One) 
No difficulty at all ......................................................... 1 
A little difficulty............................................................. 2 
Moderate difficulty....................................................... 3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your eyesight ..... 
Stopped doing this for other reasons or not 
interested in doing this ................................... ., ... 6 
10. Because of your eyesight, how much diffi 
ob·ects off to the side while ou are walkin 
No difficulty at all ............ .. . 
3 
Extreme difficul 
4 
Stoppe 
• 
~:a1.1rSEt 
5 
Stopp 
int 
11. 
ow much difficulty do you have seeing 
u say? 
(Circle One) 
at all ......................................................... 1 
ulty ............................................................. 2 
ifficulty ....................................................... 3 
e difficulty......................................................... 4 
<i;.;·.;;;;;t pped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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12. Because of your eyesight, how much difficulty do you have picking out 
and matching your own clothes? 
(Circle One) 
No difficulty at all......................................................... 1 
A little difficulty............................................................. 2 
Moderate difficulty ...................................................... . 
Extreme difficulty ....................................................... . 
Stopped doing this because of your eyesigh .. . 
Stopped doing this for other reasons or not 
interested in doing this ........................................ . 
13. Because of your eyesight, how much 
with eo le in their homes at arti 
Mod era 
• • 
.................. 3 
Extre 
.................. 4 
Stop 
,CN:JloiJ:1o't 
5 
Sto 
w much difficulty do you have going out 
s events? 
(Circle One) 
1 
2 
3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this .......................................... 6 
15. Are you currently driving, at least once in a while? 
©RAND 1996 


 
 
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(Circle One) 
Yes ........................ 1 Skip To Q 15c 
No ......................... 2 
15a. 
IF NO: Have you never driven a car or have you~ ~'-'-".,, 
15b. 
driving? 
(Circle One) 
Never drove........ 1 
e of your 
of both your 
1 Skip To Part 3, Q 17 
2 Skip To Part 3, Q 17 
3 Skip To Part 3, Q 17 
NTL Y DRIVING: How much difficulty do you have 
the da time in familiar laces? Would you say 
(Circle One) 
No difficulty at all ................................. 1 
A little difficulty..................................... 2 
Moderate difficulty............................... 3 
Extreme difficulty................................. 4 
©RAND 1996 


 
 
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16. How much difficulty do you have driving at night? Would you say you 
have: 
(Circle One) 
No difficulty at all....................................... 1 
A little difficulty........................................... 2 
Moderate difficulty..................................... 3 
Extreme difficulty......................... ... ....... 4 
Have you stopped doing 
of your eyesight.. ....... . 
Have you stopped doing 
reasons or are you no 
doing this ........................... . 
16A. How much difficulty do you have ,,dL!..!ril-!.vµ.· J¥C"'¼--'"'-lli~"¼'--'<>!.'--'--"'!'--"."~"--"-s"'-uc,,,__,h 
as in bad weather durin rush ho 
traffic? 
Would you say you have: 
(Circle One) 
.................................. 1 
2 
3 
....................................... 4 
u s opped doing this because 
r eyesight.................................... 5 
ave you stopped doing this for other 
easons or are you not interested in 
doing this ................................................ 6 
©RAND 1996 


 
 
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PART 3 RESPONSES TO VISION PROBLEMS 
The next questions are about how things you do may be affected by your 
vision. For each one, please circle the number to indicate whether for you 
the statement is true for you all, most, some, a little, or none of the time. 
READ CATEGORIES: 
17. Do you accomplish less 
than you would like 
because of your vision? 
18. Are you limited in how 
long you can work or do 
other activities because of 
your vision? ...................... . 
19. How much does pain or 
discomfort in or around 
your eyes, for 
burning, itchin 
aching, keep 
doing w 
bedoi 
(Circle One On ach Line) 
All of 
the 
Most of 
Some 
None of 
the 
of the 
the 
time 
time 
1 
2 
3 
5 
2 
3 
4 
5 
©RAND 1996 


 
 
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For each of the following statements, please circle the number to indicate 
whether for you the statement is definitely true, mostly true, mostly false, 
or definitely false for you or you are not sure. 
(Circle One On Each Line) 
Definitely Mostly 
Not 
Definitely 
True 
True 
Sure 
False 
20. I stay home most of the time 
because of my eyesight. .... 
1 
2 
3 
21. I feel frustrated a lot of the 
time because of my 
eyesight. ................................. 
1 
22. I have much less control 
over what I do, because of 
my eyesight. .......................... 
5 
23. Because of my eyesight, 
have to rely too much on 
what other 12eo12le tell me ... 
3 
4 
5 
24. I need a lot of h 
2 
3 
4 
5 
25. 
1 
2 
3 
4 
5 
©RAND 1996 


 
 
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Appendix of Optional Additional Questions 
SUBSCALE: GENERAL HEAL TH 
A1 . How would you rate your overall health, on a scale where 
bad as death and 10 is best possible health? 
0 
Worst 
2 
3 
SUBSCALE: GENERAL VISION 
(Circle One) 
4 
5 
6 
7 
A2. How would you rate your eyesig 
on, if you wear them), on a sea 
worst possible eyesight, a 
ad 
means the 
, and 10 
means the best possible 
ht? 
0 
Worst 
7 
8 
9 
10 
Best 
o 
h difficulty do you have reading the small 
ne book on a medicine bottle or on le al forms? 
(Circle One) 
. o ifficulty at all......................................................... 1 
~-rA little difficulty............................................................. 2 
Moderate difficulty....................................................... 3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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A4. Because of your eyesight, how much difficulty do you have figuring 
out whether bills you receive are accurate? 
(Circle One) 
No difficulty at all......................................................... 1 
A little difficulty ............................................................ . 
Moderate difficulty ...................................................... . 
Extreme difficulty .................................................... . . 
Stopped doing this because of your eyesigti .. . 
Stopped doing this for other reasons or not 
interested in doing this .......................................... . 
AS. Because of you 
• 
things like ""sh'""a,._v...,_,_,...,__,.......,_,_,_,.......,'-"'-",_,_,_,._....,."-"',.,.11--'-",._,, ...... ....,,,.=;,_. 
Mod era 
.................. 3 
.................. 4 
5 
. ........................................... 6 
r eyesight, how much difficulty do you have 
le ou know from across a room? 
ing 
(Circle One) 
ifficulty at all ......................................................... 1 
2 
Moderate difficulty....................................................... 3 
Extreme difficulty......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 


 
 
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A7. Because of your eyesight, how much difficulty do you have taking part 
in active sports or other outdoor activities that you enjoy (like golf, 
bowling, jogging, or walking)? 
(Circle One) 
No difficulty at all......................................................... 1 
A little difficulty ............................................................ . 
Moderate difficulty .................................................... . 
Extreme difficulty.................................................. .. . 
Stopped doing this because of your eyesight ... . 
Stopped doing this for other reasons or not 
interested in doing this.............. 
. ...................... 6 
AS. Because of your eyesight, how much 
enjoying programs on TV? 
Mod era 
• • 
.................. 3 
Extre 
.................. 4 
Stop 
,CN:JloiJ:1o't 
5 
Sto 
r eyesight, how much difficulty do you have 
ds and famil in our home? 
(Circle One) 
ifficulty at all ......................................................... 1 
ittle difficulty............................................................. 2 
3 
Extreme difficulty ......................................................... 4 
Stopped doing this because of your eyesight..... 5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
©RAND 1996 
and 


 
 
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SUBSCALE DRIVING 
A10. [This item, "driving in difficult conditions", has been included as part 
of the base set of 25 items as item 1 Sa.] 
SUBSCALE ROLE LIMITATIONS 
A11. The next questions are about things you may do be 
a. 
b. 
vision. For each item, please circle the number to ind1~,~
,p 
you this is true for you all, most, some, a little, or none o 
Do l£OU have more helg 
from others because of 
3 
4 
your vision? ....................... 
Are l£OU limite 
kinds of things 
3 
4 
because 
©RAND 1996 
None of 
the 
time 
5 
5 


 
 
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SUBSCALES WELL-BEING/DISTRESS (#A12) and DEPENDENCY (#A13) 
The next questions are about how you deal with your vision. For each 
statement, please circle the number to indicate whether for you it is 
definitely true, mostly true, mostly false, or definitely false for you or you 
don't know. 
Definitely 
Mostly 
Not 
True 
True 
Sure 
A 12.1 am often irritable because 
of my eyesight....................... 
1 
2 
A 13.1 don't go out of my home 
alone, because of my 
eyesight. ................................ . 
©RAND 1996 
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10-ITEM NEURO-OPHTHALMIC SUPPLEMENT TO THE NEI-VFQ-2S 
The following are additional questions and statements about problems that involve your vision or 
feelings you may have about your vision condition. After each question, there will be a list of possible answers. 
Please choose the response that best describes your situation. 
Please answer all questions as if you were wearing your glasses or contact lenses (if any). Please take as much 
time as you need to answer each question. 
1. How much difficulty do you have performing tasks when your eyes are tired? 
/Circle One) 
None 
Mild 
Moderate 
Severe, or 
Very severe? 
2. Because of your vision, how much difficulty do you have identify; 
sunlight? 
/Circle One) 
None 
Mild 
Moderate 
Severe, or 
Very severe? 
3. Because of your vision, how much difficul,v., • .,.,..,,,,,n 
/Circle One) 
No difficulty at all 
A little difficulty 
Moderate difficulty 
Extreme difficulty 
Stopped doing this because of your ey 
Stopped doing this! r 
4. Because of y 
/Cir 
E 
s 
2 
3 
4 
5 
3 
4 
5 
6 
2 
3 
4 
5 
6 
For each o 
I wing statements, please indicate if it is definitely true, mostly true, mostly false, or 
definitely false for you or if you are not sure. 
5. I have a feeling that my two eyes see differently, even with correction (glasses or contact lenses). 
(Circle One) 
Definitely true 
Mostly true 
2 
Not sure 
3 
Mostly false 
4 
Definitely false 
5 
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6. I have a feeling that my eye or eyelid appearance is unusual. 
/Circle One) 
Definitely true 
Mostly true 
Not sure 
Mostly false 
Definitely false 
2 
3 
4 
5 
For each of the following, please indicate if it is true for you all, most, some, a little, or none of the time. 
7. My vision is blurry, not clear, or "fuzzy." 
/Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
8. I have trouble focusing on or following moving objects. 
/Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
9. I have double vision with both eyes open t 
/Circle One) 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
2 
3 
4 
5 
3 
4 
5 
2 
3 
4 
5 
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16.6. 
Appendix 6: Patient Global Impression of Change  
 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
Since the start of the study, my overall status is 
one box only: 
[1] 
Very much Improved 
[2] 
Much Improved 
[3] 
Minimally Improved 
[4] D No change 
[5] D Minimally Worse 
[6] 
Much Worse 
[7] 
Very much Worse 
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16.7. 
Appendix 7: Contraception 
Birth control methods which may be considered as highly effective (that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are 
considered as highly effective birth control methods).  
Patients should be instructed not to take their oral contraceptive within 1 hour prior to 
administration of trial medication. 
Such methods include: 
• combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system ( IUS)  
• bilateral tubal occlusion  
• vasectomised partner 1 
• sexual abstinence 2 
 
1. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the trial participant.  
2. In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
 
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SAP_001.pdf: 
Study 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 
 
ClinicalTrials.gov ID: NCT05347147 
 
 
 
Statistical Analysis Plan: Abbreviated Final Analysis, Final Version 1.0, dated 02-Nov-2023 
 
 


 
AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 1 of 10 
 
   Statistical Analysis Plan 
Sponsor 
Invex Therapeutics 
Protocol 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 
Protocol Number: 
INVEX-CLIN-IIH-301 
Premier Research PCN: 
213492 
Document Version: 
Abbreviated Final Analysis, Final Version 1.0 
Document Date:  
02NOV2023 
Approvals 
Role 
Signatures 
Biostatistician 
Print Name: Karola Köhler 
Sign Name: 
 
 
 
 
Peer Reviewer 
Print Name: Lucia Rodrigo 
Sign Name: 
 
 
 
 
Invex Therapeutics 
Representative 
Print Name: Carol Parish 
Sign Name: 
 
 
 
 
 
 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 2 of 10 
 
 
Document History 
Version 
Date 
Change(s) 
Author 
Final Version 1.0 
02NOV2023 
Initial final version 
Karola Köhler 
 
 
 
 
 
 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 3 of 10 
 
 
Table of Contents 
Approvals................................................................................................................................ 1 
Document History ................................................................................................................... 2 
Table of Contents .................................................................................................................... 3 
List of Abbreviations ............................................................................................................... 4 
1. 
Overview ..................................................................................................................... 5 
2. 
Study Objectives and Endpoints.................................................................................... 5 
3. 
Overall Study Design and Plan ..................................................................................... 5 
3.1. 
Overall Design ....................................................................................................... 5 
3.2. 
Study Population .................................................................................................... 5 
3.3. 
Treatments Administered ........................................................................................ 6 
3.4. 
Schedule of Events ................................................................................................. 6 
4. 
Statistical Analysis and Reporting................................................................................. 6 
4.1. 
Introduction............................................................................................................ 6 
4.2. 
Interim Analysis and Data Monitoring..................................................................... 6 
5. 
Analysis Populations .................................................................................................... 7 
6. 
General Issues for Statistical Analysis ........................................................................... 7 
6.1. 
Statistical Definitions and Algorithms ..................................................................... 7 
6.1.1. Baseline ................................................................................................................. 7 
6.1.2. Analysis Visits ....................................................................................................... 7 
7. 
Study Patients and Demographics ................................................................................. 7 
7.1. 
Disposition of Patients and Withdrawals.................................................................. 7 
7.2. 
Demographics and Other Baseline Characteristics ................................................... 8 
7.3. 
Exposure and Compliance....................................................................................... 8 
8. 
Safety and Tolerability Analysis ................................................................................... 8 
8.1. 
Adverse Events ...................................................................................................... 8 
8.2. 
Adverse Events Leading to Withdrawal ................................................................... 9 
8.3. 
Serious Adverse Events .......................................................................................... 9 
8.4. 
Adverse Events of Special Interest .......................................................................... 9 
8.5. 
Clinical Laboratory Evaluations ............................................................................ 10 
9. 
Changes from Planned Analysis.................................................................................. 10 
10. 
Other Planned Analysis .............................................................................................. 10 
11. 
Tables and Listings..................................................................................................... 10 
11.1. Planned Table and Listing Shells........................................................................... 10 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 4 of 10 
 
 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
eCRF 
electronic case report form 
CSR 
clinical study report 
DSMC 
data safety monitoring committee 
IIH 
idiopathic intracranial hypertension  
MedDRA 
medical dictionary for regulatory activities 
PT 
preferred term 
SAE 
serious adverse event 
SAF 
Safety population 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 5 of 10 
 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned abbreviated analysis and reporting for 
Invex Therapeutics protocol number INVEX-CLIN-IIH-301 (A Phase III randomised, placebo-
controlled, double-blind, multi-centre, clinical trial to determine the efficacy and safety of 
PresendinTM in idiopathic intracranial hypertension), protocol version 4.0, dated 09JUL2022, and 
protocol version 5.0 (countries of the European Union), dated 08DEC2022.  
The study was early terminated due to commercial reasons in Aug 2023, with only a very small 
number of patients enrolled. All patients finally consented were in countries working with protocol 
version 4.0. 
This analysis plan only covers the analysis that is finally planned to be conducted for this early 
terminated study. 
The statistical plan described hereafter is an a priori plan. It will be approved before any unblinded 
inferential or descriptive analysis of data pertaining to Invex Therapeutics’s study INVEX-CLIN-
IIH-301. 
2. 
Study Objectives and Endpoints 
Original study objectives and endpoints are listed in protocol section 2. It was decided to restrict 
the planned analysis to the most relevant safety endpoints only (adverse events and safety 
laboratory data). 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a randomised, placebo-controlled, double-blind, multi-centre clinical trial, initially planned 
in approximately 240 randomised patients with idiopathic intracranial hypertension (IIH). 
The trial is designed as follows: 
The trial begins with a 1-week screening period. The screening period is 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 2mg 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 have an end of treatment clinic visit. Five weeks after the 
end of that treatment visit, an end of trial safety follow-up telephone visit is performed. For full 
details of the study design, please see the protocol. 
3.2. 
Study Population 
Patients with a diagnosis of IIH according to the protocol and meeting the eligibility criteria. 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 6 of 10 
 
 
3.3. 
Treatments Administered 
There are two treatment groups with patients randomised in a ratio of 1:1 to receive active 
treatment (Presendin) or placebo. 
3.4. 
Schedule of Events 
Please see protocol Table 1 for a detailed schedule of study assessments. 
4. 
Statistical Analysis and Reporting 
The final statistical analysis will be performed after the clinical study database is locked and the 
study is unblinded. A synoptic clinical study report (CSR) summarizing all planned analyses 
according to this analysis plan will be prepared. Other analyses as part of the protocol are finally 
not planned to be performed by statistics due to the early study termination. In addition, the medical 
writer may review relevant raw data and relevant conclusions based on raw data may be included 
in the CSR. 
4.1. 
Introduction 
Data processing and tabulation of descriptive statistics will primarily use SAS (release 9.4 or 
higher). If the use of other software is warranted, the final statistical methodology report will detail 
what software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of patients (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of patients 
who are in the particular category or each possible value. In general, the denominator for the 
percentage calculation will be based upon the total number of patients in the relevant analysis 
population for the treatment groups, unless otherwise specified. The denominator for by-visit 
displays will be the number of patients in the relevant analysis population with non-missing data 
at each visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will be 
reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Due to the early study termination all statistical analyses performed will be descriptive. 
4.2. 
Interim Analysis and Data Monitoring 
A Data Safety Monitoring Committee (DSMC) was planned to be established for this study. 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 7 of 10 
 
 
Finally due to early study termination, no DSMC meeting other than the DSMC kick-off meeting 
took place; thus, no unblinded data were presented to the DSMC. 
Also, no other formal interim analyses were planned or conducted. 
5. 
Analysis Populations 
Due to the early termination of the study, all tables and listings (except disposition information) 
are planned to be presented for the Safety population. No other analysis populations will be 
implemented. 
Safety Population (SAF): The Safety population includes all patients randomised to treatment 
(active or placebo) who received at least one dose of study medication. 
Due to the limited number of patients, it is likely that the unblinded randomized treatment will 
match the actual treatment in all cases. This will be re-checked based on the unblinded data. If 
there are no discrepancies, a footnote will be added to the output to indicate that actual and 
randomized treatment are the same for all patients. If any discrepancies occur between randomized 
and actual treatment, the actual treatment will be used for all tables/listings. Any patient who 
received Presendin at least once will be included under Presendin treatment for all tables/listings. 
In this case, the information about the randomized treatment will be added to the diposition listing. 
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
There is no specific baseline definition. Tables by visit will contain “Screening (Visit 1) – Week 
– 1” as well as “Baseline (Visit 2) – Week 0 (Day 1)” reported separately. Changes from baseline 
will not be calculated. 
6.1.2. Analysis Visits 
In general, scheduled visits as reported in eCRF will be used for analysis. No visit windowing is 
planned. 
7. 
Study Patients and Demographics 
7.1. 
Disposition of Patients and Withdrawals 
Disposition of patients will include tabulations of the number of screened patients, tabulated 
reasons for screen failure, number of patients randomised into each treatment group, the number 
of patients who received treatment, the number of patients completing 24-weeks of randomised 
treatment, the number of patients completing study, tabulated reasons for discontinuation from the 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 8 of 10 
 
 
study, tabulated reasons for discontinuation of study medication (without withdrawal from study) 
and number of patients in the Safety population. 
In addition, treatment and study completion status and reasons for study withdrawals will be listed. 
7.2. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, sex, race, and ethnicity will be presented by treatment group and 
overall. 
All demographic and baseline characteristics will also be displayed in a data listing. 
7.3. 
Exposure and Compliance 
Investigational product administration will be listed based on the exposure (study drug 
administration) page from the eCRF. 
8. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported adverse events (AEs) and clinical laboratory values. 
All safety analyses will be performed on the Safety population. 
8.1. 
Adverse Events 
All AEs, treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary (version 25.0 
or later). 
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of study medication. 
If the start date and time of an AE are partially or completely missing, the AE will be assumed to 
be treatment-emergent if it cannot be definitely shown that the AE did not occur or worsen during 
the treatment-emergent period (worst-case approach). 
For missing or partial AEs onset dates and times, the convention for replacing missing or partial 
dates will be the following based on the worst-case approach: 
For partial AE start dates: 
• If the year is unknown, then do not impute the date but assign a missing value. The AE 
will then be considered as a TEAE. 
• If the month and day are unknown, then: 
o If the year matches the year of first treatment date, and the end date (if present) is 
after first treatment date, then impute as the month and day of the first treatment 
date. 
o Otherwise, assign 1st of January. 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 9 of 10 
 
 
• If only the day is unknown, then: 
o If the month and year match the month and year of the first treatment date, then 
impute as the day of first treatment date. 
o If this produces a date after the AE end date, assign the start date to the 1st day of 
the month. 
o Otherwise, assign the 1st day of the month. 
 
Missing or partial AE end dates will not be replaced. 
If partial or missing times occur for AE at the day of first treatment, AE will be considered as 
TEAE, unless it cannot be definitely shown that the AE did not occur or worsen during the 
treatment-emergent period (worst-case approach). 
An overall summary table of TEAEs will be produced. 
The number and percentage of patients reporting TEAEs, grouped by MedDRA system organ class 
(SOC) and preferred term (PT), will be tabulated by treatment group. Summaries will be presented 
for all TEAEs and treatment-related TEAEs. 
In the case of multiple occurrences of the same TEAE within the same patient, each patient will 
only be counted once for each PT. 
If a particular event is missing the severity and/or relationship, then the strongest possible severity 
or relationship will be assumed for analysis (severity = Grade 4/life-threatening, relationship = 
probable relationship). 
In the AE data listings, all AEs will be displayed. Adverse events that are treatment-emergent will 
be indicated as such. 
8.2. 
Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages of patients) of TEAEs leading to 
withdrawal of study drug and/or study discontinuation by treatment group, SOC, and PT will be 
tabulated. 
8.3. 
Serious Adverse Events 
A summary of incidence rates (frequencies and percentages of patients) of SAEs by treatment 
group, SOC, and PT will be tabulated. 
A data listing of SAEs will also be provided, displaying details of the event(s) captured on the 
eCRF. 
8.4. 
Adverse Events of Special Interest 
No adverse events of special interest are defined in the protocol. 


 
Statistical Analysis Plan 
 
Sponsor Invex Therapeutics  
 
Protocol Number INVEX-CLIN-IIH-301  
 
PCN Number 213492 
 
-AD-ST-33.06 Effective date: 12-Nov-2020 
Final Version 1.0    |    Date 02-NOV-2023      |    AD-PR-109.02 Effective date: 17-Aug-2020 
 Page 10 of 10 
 
 
8.5. 
Clinical Laboratory Evaluations 
Laboratory test results for each biochemistry (including glucose) and haemotology parameters 
(including coagulation) will be summarized descriptively by treatment group and timepoint as 
observed values. 
The number of patients with clinical laboratory (biochemistry and haemotology) values 
categorized as below, within, or above the normal ranges will be tabulated in a frequency table for 
each clinical laboratory analyte by treatment group and timepoint. 
Abnormal laboratory values will be displayed in the data listings, along with corresponding normal 
ranges. 
9. 
Changes from Planned Analysis 
As the study is early terminated, only an abbreviated analysis will be conducted. Thus, not all 
analyses from the protocol will finally be conducted. 
10. 
Other Planned Analysis 
No other analyses are planned for this study. 
11. 
Tables and Listings 
11.1. 
Planned Table and Listing Shells 
Table of contents of planned tables and listings together with table and listing shells will be 
presented in a separate document.