The Water Drinking Test in Glaucoma Study
Conditions: Glaucoma
Sponsor: Imperial College London

Joint Research Compliance Office 
 
 
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                                                                  WIGS Protocol V1.8 14.09.2020 IRAS: 264273 
 
 
WIGS 
 
 
 
 
The Water Drinking Test in Glaucoma Study: WIGS 
 
 
 
 
V1.8   14.09.2020 
 
 
 
 
MAIN SPONSOR: Imperial College London  
FUNDERS: N/A 
STUDY COORDINATION CENTRE: N/A 
 
IRAS Project ID: 264273 
REC reference: 20/LO/0035 
ClinicalTrials.gov: NCT05283031 
 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Joint Research Compliance Office 
 
 
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                                                                  WIGS Protocol V1.8 14.09.2020 IRAS: 264273 
 
 

Joint Research Compliance Office 
 
 
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                                                                  WIGS Protocol V1.8 14.09.2020 IRAS: 264273 
Study Management Group 
 
Chief Investigator:                  Prof Francesca Cordeiro 
 
Co-investigators:                    Dr. Timothy Yap MA MBChB MRCP 
 
 
 
 
Clinical Research Fellow 
                                               
Dr. Eduardo Normando MD, PhD, FEBO 
Senior Clinical Lecturer 
 
 Fernanda Nicoleta Susanna 
 
 
 
 
Medical Student, University of São Paulo 
                                               Observer at Imperial College Healthcare NHS Trust 
 
Statistician:                             Dr Roger A’Hearn 
 
Study Management:               Serge Miodragovic 
 
 
Study Coordination Centre N/A 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator: Jessica Bonetti 
Address: Western Eye Hospital, Marylebone Road, London NW1 5QH, 
Tel: 023 312 3206  
E-mail:  Jessica.bonetti@nhs.net 
Fax:  0203 312 4388  
 
 
Clinical Queries 
 
Clinical queries should be directed to Serge Miodragovic who will direct the query to the 
appropriate person. 
 
 
Sponsor 
 
Imperial College Healthcare NHS Trust is the main research Sponsor for this study.  For 
further information regarding the sponsorship conditions, please contact the Head of 
Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust 

Joint Research Compliance Office 
 
 
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                                                                  WIGS Protocol V1.8 14.09.2020 IRAS: 264273 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 9459/ 0207 594 1862 
http://www3.imperial.ac.uk/clinicalresearchgovernanceoffice  
 
Funder 
 
WIGS study is not funded. 
 
 
This protocol describes the WIGS study and provides information about procedures for entering 
participants.  Every care was taken in its drafting, but corrections or amendments may be necessary. 
These will be circulated to investigators in the study.  Problems relating to this study should be referred, 
in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and Social Care 
Research. It will be conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate.  
 
 
 

Joint Research Compliance Office 
 
 
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Table of Contents                                                             Page No 
1. 
INTRODUCTION 
8 
1.1 
BACKGROUND 
8 
1.1.1. 
IOP and glaucoma 
8 
1.1.2. 
IOP measurement methods 
8 
1.1.3. 
The role of the WDT in glaucoma 
8 
1.1.4. 
OCT and glaucoma progression 
9 
1.1.5. 
Safety 
9 
1.1.6. Previous studies 
9 
1.2 
RATIONALE FOR CURRENT STUDY 
11 
2.  STUDY OBJECTIVES 
11 
3.  STUDY DESIGN 
12 
3.1 STUDY OUTCOME MEASURES 
12 
3.1.1. 
Premedication 
12 
3.1.2.  
Interventions 
13 
4. 
PARTICIPANT ENTRY 
13 
4.1  
INCLUSION CRITERIA 
13 
4.2 
EXCLUSION CRITERIA 
13 
4.3  
WITHDRAWAL CRITERIA 
14 
5. 
ADVERSE EVENTS 
14 
5.1 
DEFINITIONS 
14 
5.3 
REPORTING PROCEDURES 
14 
6. 
ASSESSMENT AND FOLLOW-UP 
15 
7.1  
SAMPLE SIZE 
15 
7.2  
RECRUITMENT 
15 
7.3  
FOLLOW-UP 
16 
7.4 
DATA ANALYSIS 
16 
7.4.1.  
Data Collection 
16 
7.4.2  
Data Management 
16 
7.4.3 
Statistical analysis 
16 
8. 
REGULATORY ISSUES 
16 
8.1 
ETHICS APPROVAL 
16 
8.2 
CONSENT 
17 
8.3 
CONFIDENTIALITY 
17 
8.4 
INDEMNITY 
17 
8.5 
SPONSOR 
17 
8.6 
FUNDING 
17 
8.7 
AUDITS 
17 
9. 
STUDY MANAGEMENT 
17 

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10. 
PUBLICATION POLICY 
17 
APPENDIX 1. 
PARTICIPANT TIMELINE 
18 
 
GLOSSARY OF ABBREVIATIONS 
DTC – Diurnal Tension Curve 
GCC – Ganglion Cell Complex 
IOP – Intraocular Pressure 
MD – Mean Deviation  
mDTC – modified Diurnal Tension Curve 
NFL – Nerve Fiber Layer 
NTG – Normal Tension Glaucoma 
OCT – Optical Coherence Tomography 
VF – Visual Field  
WDT – Water Drinking Test 
 
 
KEYWORDS 
Intraocular pressure, stress test, correlation, water drinking test, modified diurnal tension 
curve, glaucoma progression, OCT, VF, normal tension glaucoma 
 
 
 
 
 
 

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STUDY SUMMARY 
 
TITLE The Water Drinking Test (WDT) in Glaucoma Study: WIGS 
DESIGN Observational cohort study 
AIMS To investigate the correlation and agreement between the intraocular pressure 
peaks detected during the water drinking test and modified diurnal tension 
curve in glaucomatous eyes and to analyse whether this is associated with 
prognostic outcome. We will also measure autonomic nervous system 
activation during the test to investigate one possible mechanism behind it. 
OUTCOME MEASURES Peak IOP measurements from the two different methods 
POPULATION Primary open-angle and normal tension glaucoma patients 
ELIGIBILITY Primary open-angle and normal tension glaucoma patients, not on anti-ocular 
hypertensive therapy. 
- 
Able to give informed consent to participate in the study 
- 
Aged between 18 and 80 years of age 
- 
Clear optical media 
- 
Spherical equivalent +-10D 
DURATION Single visit  
 
 
REFERENCE DIAGRAM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1st contact: Clinic 
recruitment
Eligibility screening and 
informed consent
Study visit: 
mDTC (8 hours)                
Water drinking test (1 hour) 
Follow up: 
18 months routine follow up 
(minimum 6 monthly)

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
 
1.1.1. IOP and glaucoma 
 
Glaucoma is a progressive optic neuropathy characterised by progressive loss of retinal 
ganglion cells, leading to thinning of the retinal nerve fibre layer and visual field losseS[1]. It is 
the leading cause of irreversible blindness in the world [2] and affects more than 70 million 
people worldwide[3]. 
 
Intraocular pressure (IOP) is the main risk factor for the development and progression of 
glaucoma [4] [5]. The gold standard for intraocular pressure (IOP) measurement is applanation 
tonometry [6]. Routine office measurements may not detect IOP peaks in roughly 30% of 
patients due to variation throughout the day [7], and this detection failure may be responsible 
for visual field progression in apparently well-controlled patients [5]. 
 
1.1.2. IOP measurement methods  
 
To provide more reliable data, twenty-four hour diurnal tension curves (DTC) can be 
measured. However, 24-hour IOP monitoring is unfeasible and time consuming in the 
majority of circumstances. The modified diurnal tension curve (mDTC) involving IOP 
measurements every 2 or 3 hours during office hours is therefore often used as a shorter 
alternative.  
 
The water drinking test (WDT) is a tool that aims to indirectly evaluate the eye’s aqueous 
humor outflow facility[8] [9] by putting the drainage system under ‘stress’ in a test similar to 
that which may be used in cardiology or endocrinology. More recent research has suggested 
that water overload with the WDT may correlate well with the IOP peaks detected during a 
24-hour intraocular pressure measure[10].   
 
It remains unclear as to the physiological mechanism behind this observed IOP rise. Several 
hypotheses exist including increases in outflow resistance[11], episcleral venous pressure [12], 
choroidal expansion [13] and change in blood osmolality. However, it has been observed in 
one study that 20% of subjects developed change in IOP before change in osmolality could 
be detected.  
 
Centrally mediated causes, possibly triggered by gastric expansion have been postulated 
with regards to activation of the autonomic nervous system[14], but this has mainly been 
characterised in terms of cardiovascular physiology as oppose to intraocular pressure rise. 
Some evidence has been published to suggest the time course of the autonomic changes 
observed (rise in blood pressure, reduction in heart rate) are not consistent with reflex 
activity[15], however in this study only 500mls of water was ingested over 3-4 minutes. This 
aspect of the test requires further characterisation in relation to the time profiles of the IOP 
rise.  
 
1.1.3. The role of the WDT in glaucoma 
 
The WDT has been described as an independent risk factor for the development and 
progression of a glaucomatous field defect in patients with OAG [9,16]. In a prospective study 
of 5000 patients with open angle glaucoma, the authors found five potential risk factors for 
the development of glaucomatous visual field lesion: outflow facility, age, IOP, cup/disk ratio 

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and change in IOP after water ingestion[17]. These data have changed the concept of the 
WDT, which is now used as a useful tool to assess IOP peaks. Furthermore, the WDT is a 
reproducible [18,19] low-cost and feasible test in the clinical practice. 
 
1.1.4. OCT and glaucoma progression 
 
OCT has been widely used to measure the thickness of the NFL and GCC, which have 
strong correlation with glaucoma disease stages[20]. OCT can assist in the diagnosis of 
glaucoma to a certain extent, with faster rates of OCT progression associated with a higher 
risk of VF progression[21] . OCT is thought to be more sensitive than VF in detecting 
progression in the earlier stages of the disease, hense the term ‘pre-perimetric glaucoma’ 
[22]. Since OCT measurements have good repeatability and reproducibility, [23] it is clinically 
advantageous to monitor glaucoma progression using objective OCT structural 
measurements in the early stages prior to visual field defects appearing. 
 
1.1.5. Safety 
 
The water drinking test (WDT) is a safe test for the majority of the population since its 
intervention is drinking water. However, there are individual cases where it may be harmful; 
any person with contra-indication of drinking large amounts of water in a small amount of 
time should be excluded. This includes patients with heart or kidney failure, or those with 
swallowing difficulties associated with neurological disorders or gastrointestinal strictures or 
stasis.  
 
1.1.6. Previous studies 
 
Previous studies have shown correlation between the water drinking test and the modified 
diurnal tension curve [24]. Vasconcelos-Moraes CG et al. [24] showed that the WDT peak was 
significantly correlated with the mDTC peak (Person’s Correlation Coefficient r=0.780 for a 
95% confidence interval between 0.716 to 0.831, p<0.0001), however this has not yet been 
widely reproduced. However, this study was conducted on POAG patients who were on 
topical therapy for raised intraocular pressure, and therefore were required to undergo a 
washout period of no medication.  

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This study showed 95% limits of agreement between the WDT and mDTC IOP peaks 
ranging from −3.9 mmHg to 8.2 mmHg. In 52.5% of the tests, the agreement was within ± 2 
mmHg. 
 
 

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Figure 3 
Agreement between the WDT and mDTC peaks 
Eighty-two percent of eyes showed higher IOP peaks during the WDT than the mDTC (95% 
confidence interval between 0.0 and 6.99 mmHg).  
 
When analysing glaucomatous progression De Moraes et al. [9] showed that higher IOP 
peaks during the WDT were predictive of future visual field progression (hazard ratio=1.11; 
95% confidence interval, 1.02 to 1.21; P=0.013), but also that the average and peak IOP 
during office hours over the same follow-up period were not significantly associated with 
progression (P=0.651 and 0.569, respectively). This study showed that IOP peaks detected 
with the WDT were predictive of future visual field progression in a treated POAG population, 
while office hours measures were not. 
 
Another study performed by Yoshikawa et al. [16] in normal tension glaucoma patients 
showed that the maximum IOP levels after the water drinking test in patients with 
progressive visual field loss was significantly greater than the levels observed for the non-
progressive group. Given that a common indication for referring patients for the mDTC is 
disease progression despite normal pressures off-treatment (‘normal-tension glaucoma’), the 
agreement of the two tests in this specific cohort is currently under-documented. 
 
1.2 
RATIONALE FOR CURRENT STUDY 
 
 
The current method of using the mDTC is time consuming, labour intensive, and 
incomprehensive. Not only does the WDT have the potential to improve upon the time 
consuming and labour intensive nature of the test, but given the active element may improve 
diagnostic pickup and sensitivity for disease progression, given that the mDTC is only 
feasibly conducted during office hours.  
 
Further work comparing the currently used mDTC and the WDT to assess IOP peak and 
fluctuation is necessary. The study mentioned above [24] showed strong evidence of the 
clinical applicability of the WDT and its correlation with the mDTC. Furthermore, the IOP 
peak obtained by the WDT has been proved to be an independent risk factor for the 
development and progression of glaucoma [5,8]. However, to date, there are no studies 
focusing on OCT data that will indicate progression of ‘pre-perimetric’ glaucoma, or any 
studies focusing on the most commonly referred group of patients referred for the test. This 
will aid us to discern the best way to assess IOP peaks and manage glaucoma treatment 
and progression. 
 
Our hypotheses are: 
• 
The peak IOP during the WDT correlates with mDCT 
• 
Peak IOP during the WDT is associated with rate of glaucoma progression as 
measured with OCT 
• 
Changes in autonomic variables associated with IOP rise are consistent with a 
autonomic reflex as the physiological mechanism behind the test.  
 
 
2.  STUDY OBJECTIVES 
 

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- 
Primary research objective is to investigate the correlation and agreement between 
the intraocular pressure peaks detected during the water drinking test and the 
standard phasing test. 
 
Secondary research objective is to correlate the IOPs obtained with both tests and 
prognostic outcome of the patients enrolled in the study to see whether these 
methods have predictive value for glaucoma progression. We will also measure 
autonomic nervous system activation (pupil size, heart rate and postural BP) during 
the test to investigate one possible mechanism behind it.  
 
Lay summary 
 
Raised intraocular pressure (IOP) is the main risk factor for the development and 
progression of glaucoma. The mDTC is a test that consists of four to five eye pressure 
measurements taken thoughout office hours to check for rises in pressure that may be 
missed during their clinic appointment. To better try to assess the IOP peaks in a more time-
efficient way, the water-drinking test has been developed. This involves the patient drinking 
a weight-adjusted volume of water within 5 minutes which has the effect of testing the ability 
to cope with increased demand for fluid to leave the eye. It is unclear as to the physiological 
mechanism by which this occurs. In this study we aim to compare the eye pressure 
measurements with both tests, and to see if either have any bearing on whether the patient’s 
disease is getting worse. We also aim to show the changes in blood pressure and heart rate 
throughout the test. 
 
3.  STUDY DESIGN 
 
As described below active participation in the study (involving a single visit to the hospital) 
will last a total of 1 day, while the access (and analysis) of follow-up data generated as part 
of routine care pathway will go on for a period of 18 months in total. Participants are not 
required to do anything during this segment of the study. 
 
• 
Observational cohort study 
• 
40 Primary open-angle and normal tension glaucoma patients will be attending a 
single visit lasting 9 hours.  
• 
Their usual follow-up data will be tracked for 18 months 
 
 
3.1 STUDY OUTCOME MEASURES 
 
• 
Primary outcome measure:  
 
Intraocular pressures measured during the mDTC 
Intraocular pressures measured during the WDT  
 
• 
Secondary outcome measures: postural blood pressure, heart rate, pupil diameter, 
pulse oximetry, OCT imaging parameters (angiography and anterior segment angle 
size) including current and future rates of progression using nerve fibre layer 
thickness on optical coherence tomography (OCT) and visual field testing. 
 
3.1.1. Premedication 
 
No premedication is required in this study; however, the assessment of the intraocular 
pressure requires the surface of the eye to be anaesthetised by means of topical drops. 

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Proxymetacaine hydrochloride 0.5% drops are used for that purpose; the drops have been in 
approved use for a number of years and are part of standard of care. 
 
3.1.2.  Interventions 
 
Baseline and qualification assessments will take place on the day of the study. These 
include a medical, ophthalmic and drug history, ophthalmic examination, postural blood 
pressure measurement, testing of visual acuity, OCT/OCTA of the optic disc and macula and 
then IOP assessment. All ophthalmic assessments will be done on both eyes using the 
Heidelberg Spectralis® imaging system. The mDTC will be conducted as part of patient’s 
regular visit and is standard of care which consists of  5 IOP measurements beginning at 
8am and 2 hourly afterwards (+/- 15min) . Following completion of mDTC patients will have 
their WDT as detailed below.  
 
The water drinking test will occur following the mDTC and will involve the patient drinking 
800mL of water at room temperature, within a maximum of five minutes, after a period of no 
fluid intake of at least 2 hours. This will come after a period of no fluid intake of at least 2 
hours (2pm onwards). For the WDT, the first IOP measure will correspond to the last mDTC 
measure, and three IOP measurements will be made after water intake with a 15-minute 
interval between each. IOP measurements will be recorded using Goldmann Applanation 
Tonometry (GAT). At each 15 minute interval, postural blood pressure, heart rate, oxygen 
staurations and pupil diameter will be measured. The ambient light conditions will be 
monitored with a light meter. Imaging will then be repeated after one hour of the test. 
 
 
 
4. 
PARTICIPANT ENTRY  
 
After the fully informed consent has been obtained in writing with the opportunity to ask 
questions, patients’ participation will begin with the visit to the hospital where they will attend 
their phasing test, as part of their standard care. Following completion of the phasing they 
will proceed to do their water drinking test which will be followed by several measurements 
of their IOP and other relevant outcomes. Once they have completed the water drinking test 
and all necessary measurements their participation in the study will end and their care will 
continue as normal. Participation in this (active) part of the study will only last 1 day (single 
visit to the hospital).  
 
4.1  
INCLUSION CRITERIA 
 
-           Able to give informed consent to participate in the study 
- 
Aged between 18 and 80 years of age 
- 
Clear optical media 
- 
Spherical equivalent +-10D 
- 
Primary open-angle glaucoma or normal tension glaucoma proven by visual field 
testing or OCT imaging combined with clinical assessment. 
 
4.2 
EXCLUSION CRITERIA 
 
- 
Have any other known ocular disease (except glaucoma) 
- 
Have serious cardiac or kidney disease (WDT contra-indication) 
- 
Have swallowing difficulties associated with either a neurological or gastrointestinal 
condition. 

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- 
Patients with any contra-indication of drinking large amounts of water in a small 
period of time e.g. swallowing impairment, oesophageal stricture, gastric banding. 
- 
Have secondary or narrow/closed angle glaucoma 
- 
Patients submitted to any surgical procedure or laser intervention during the 
evaluation period 
-  
Participants who are involved in other current research  
 
4.3  
WITHDRAWAL CRITERIA 
 
Participants who lose mental capacity and those who may find it difficult to adhere to the 
study protocol will be withdrawn. Due to the short duration and low risk-profile of the study 
there are no stopping criteria. 
If a participant loses capacity to consent during the course of the study, they would be 
withdrawn from the study, while the identifiable data already collected with consent would be 
retained and used in the study. No further data would be collected or any other research 
procedures carried out on or in relation to the participant. 
 
 
5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 
• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2 Serious AEs 
 
All SAEs should be reported to the <name of REC> where in the opinion of the Chief 
Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; 
and 

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• 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
jrco@imperial.ac.uk 
CI email (Francesca.cordeiro@nhs.net ) 
Fax: 0203 312 4388, attention Serge Miodragovic 
Please send SAE forms to: ICORG CTU Western Eye Hospital, Marylebone Road 
London NW1 5QH 
Tel: 0203 312 3206  (Mon to Fri 09.00 – 17.00) 
 
6. 
ASSESSMENT AND FOLLOW-UP  
 
Following completion of the study, participants will be followed up in their usual clinic as part 
of their regular care. The participants' follow-up data such as OCT scans, Visual Field tests, 
mDTCs and WDTs, which is routinely generated as part of the glaucoma care pathway will 
be accessed for 18 months following completion of participation with a view of correlating 
initial results with possible disease progression and other related outcomes. This segment of 
the study is purely data-based and does not require any active involvement from patients 
Participation is optional, and patient’s decision (whether or not to grant access to the data) 
will be documented in the informed consent form. 
 
End of study is defined as last patient last visit (LPLV)  
 
7. 
STATISTICS AND DATA ANALYSIS 
 
7.1  
Sample size 
 
In this pilot study we aim to recruit a total of 40 glaucoma patients. 
This is based on a power calculation of of giving 80% power to detect a 2 mmHg difference 
in IOP peak (sd 2 mmHg) with ∝ = 5%. 
 
7.2  
Recruitment 
 
Recruitment sources will include: 
 
- 
opportunistic recruitment in glaucoma clinics at ICHNHST  
- 
electronic search of the patient database at the ICHNHST. The search criteria will 
include patients with a diagnosis of 'Primary open-angle glaucoma'. Potential patients will be 
contacted by telephone by a member of the usual care team and given the opportunity to 
receive more information about the research that we are undertaking. 
 
Study data and all appropriate documentation will be stored for a minimum of 10 years after 
the completion of the study. 

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7.3  
Follow-up 
 
Data generated as part of patients’ routine clinical care in their usual clinic will be accessed  
for 18 months following the study. We will include for OCT scans, Visual Field tests, mDTCs 
and WDTs, with a maximum interval of 6 months each. Permission to access the relevant 
data will be documented in the informed consent form; patients will be informed that this is 
optional. 
 
7.4 
Data analysis 
 
7.4.1.  Data Collection 
 
Data collection will occur solely on the premises of ICHNT and stored on secure Trust 
computers. 
 
7.4.2  Data Management 
 
. All identifiable study data will be pseudonymised by way of assignment of Study ID to each 
participant. Electronic data will be housed on trust protected dedicated servers while any 
hard copy data e.g. consent forms will be kept in dedicated locked cabinets at the ICORG 
Clinical Trials Unit at the Western Eye Hospital. 
 
7.4.3 Statistical analysis 
 
No interim analyses will take place as part of this pilot study. Data will be acquired using 
integrated Heidelberg® software packaged with the Heidelberg® Spectralis OCT system.  
Data for this initial pilot study will be collected using Microsoft® Excel, and analysed using R 
and GraphPad prism to compare IOPs between the mDCT and WDT. 
 
Specific analyses will include: 
 
- 
Generation of baseline data including mean and standard deviation of baseline 
characteristics 
- 
Bland-Altman agreement analysis of the primary outcome 
- 
Correlation analysis between WDT and rate of progression. 
- 
Analysis of change in OCT measurements 
- 
Change over time analysis for secondary outcomes compared to baseline 
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Study Coordination Centre has obtained approval from the xxx Research Ethics 
Committee (REC) and Health Regulator Authority (HRA). The study must also receive 
confirmation of capacity and capability from each participating NHS Trust before accepting 
participants into the study or any research activity is carried out. The study will be conducted 
in accordance with the recommendations for physicians involved in research on human 
subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions. 
 

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8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and a minimum of 24 hours time allowed for 
consideration.  Signed participant consent should be obtained.  The right of the participant to 
refuse to participate without giving reasons must be respected.  After the participant has 
entered the study the clinician remains free to give alternative treatment to that specified in 
the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons 
for doing so should be recorded.  In these cases the participants remain within the study for 
the purposes of follow-up and data analysis.  All participants are free to withdraw at any time 
from the protocol treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study. 
 
8.5 
SPONSOR 
Imperial College London will act as the main Sponsor for this study.  Delegated responsibilities 
will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
This study is not funded. Participants will not receive any payments, reimbursement of 
expenses or any other incentives for taking part in this research. 
No payments will be made to investigators not any members of the research team. 
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their remit 
as sponsor and other regulatory bodies to ensure adherence to GCP and the UK Policy Frame 
Work for Health and Social Care Research.  
 
 
9. 
STUDY MANAGEMENT 
 
The day-to-day management and coordination of the study will be done through Trial Manager 
Serge Miodragovic,Dr Timothy Yap and Research Coordinator Jessica Bonetti..   
 
 
 
 
10. 
PUBLICATION POLICY 
The study results will be published in peer reviewed scientific journals and presented at 
conferences. Participants’ anonymity will be fully respected as no identifiable information will 
be used in any of the publications or presentations. As stated in the participant information 
sheet, participants who express interest in finding out about the results will be contacted once 
the results are made available 
 
 
 
 
 

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Appendix 1. Participant timeline 
 
 
               
 
REFERENCES 
 
1. 
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: 
a review. JAMA. 2014;311(18):1901-1911. 
2. 
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 
and 2020. Br J Ophthalmol. 2006;90(3):262-267. 
3. 
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of 
glaucoma and projections of glaucoma burden through 2040: a systematic review 
and meta-analysis. Ophthalmology. 2014;121(11):2081-2090. 
4. 
Liu JH. Diurnal measurement of intraocular pressure. J Glaucoma. 2001;10(5 Suppl 
1):S39-41. 
5. 
Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal 
fluctuations in intraocular pressure are an independent risk factor in patients with 
glaucoma. J Glaucoma. 2000;9(2):134-142. 
6. 
Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular 
pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol. 
2011;95(8):1111-1114. 
7. 
Drance SM. Diurnal Variation of Intraocular Pressure in Treated Glaucoma. 
Significance in Patients with Chronic Simple Glaucoma. Arch Ophthalmol. 
1963;70:302-311. 
8. 
Susanna R, Jr., Hatanaka M, Vessani RM, Pinheiro A, Morita C. Correlation of 
asymmetric glaucomatous visual field damage and water-drinking test response. 
Invest Ophthalmol Vis Sci. 2006;47(2):641-644. 
9. 
De Moraes CG, Susanna R, Jr., Sakata LM, Hatanaka M. Predictive Value of the 
Water Drinking Test and the Risk of Glaucomatous Visual Field Progression. J 
Glaucoma. 2017;26(9):767-773. 
Type of procedure
Procedure
Clinic 
recruitm
ent
Study visit
Fr
Consent
PIS & Written consent
x
On
Screening
Inclusion criteria assessed
x
On
Screening
Exclusion criteria assessed
x
On
Baseline assessment
History (medical, ophthalmic, drug, allergy)
x
On
Baseline assessment
Slit-lamp examination
x
On
Baseline assessment
Visual acuity
x
On
Baseline assessment
Visual field test
x
On
Study Procedure
IOP measurements (phasing / mDCT)
x
2 h
Study Procedure
Water drinking (800mls in 5 minutes)
x
16
Study Procedure
IOP measurements (WDT)
x
15
Study Procedure
Postural blood pressure (BP) / Heart rate /
pupil diameter
x
14
Study procedure
OCT scan
x
15

Joint Research Compliance Office 
 
 
19 
                                                                  WIGS Protocol V1.8 14.09.2020 IRAS: 264273 
10. 
Li T, Hao Y, Zhu Y. Clinical study of water drinking test and 24-hour intraocular 
pressure monitoring in patients with primary open angle glaucoma. Pak J Pharm Sci. 
2017;30(4(Suppl.)):1461-1465. 
11. 
Kronfeld PC. Water drinking and outflow facility. Invest Ophthalmol. 1975;14(1):49-
52. 
12. 
Diestelhorst M, Krieglstein GK. The effect of the water-drinking test on aqueous 
humor dynamics in healthy volunteers. Graefes Arch Clin Exp Ophthalmol. 
1994;232(3):145-147. 
13. 
De Moraes CG, Reis AS, Cavalcante AF, Sano ME, Susanna R, Jr. Choroidal 
expansion during the water drinking test. Graefes Arch Clin Exp Ophthalmol. 
2009;247(3):385-389. 
14. 
Brown CM, Barberini L, Dulloo AG, Montani JP. Cardiovascular responses to water 
drinking: does osmolality play a role? Am J Physiol Regul Integr Comp Physiol. 
2005;289(6):R1687-1692. 
15. 
Cariga P, Mathias CJ. Haemodynamics of the pressor effect of oral water in human 
sympathetic denervation due to autonomic failure. Clin Sci (Lond). 2001;101(3):313-
319. 
16. 
Yoshikawa K, Inoue T, Inoue Y. Normal tension glaucoma: the value of predictive 
tests. Acta Ophthalmol (Copenh). 1993;71(4):463-470. 
17. 
Armaly MF, Krueger DE, Maunder L, et al. Biostatistical analysis of the collaborative 
glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field 
defects. Arch Ophthalmol. 1980;98(12):2163-2171. 
18. 
Hatanaka M, Alencar LM, De Moraes CG, Susanna R, Jr. Reproducibility of 
intraocular pressure peak and fluctuation of the water-drinking test. Clin Exp 
Ophthalmol. 2013;41(4):355-359. 
19. 
Babic M, De Moraes CG, Hatanaka M, Ju G, Susanna R, Jr. Reproducibility of the 
water drinking test in treated glaucomatous patients. Clin Exp Ophthalmol. 
2015;43(3):228-233. 
20. 
Kansal V, Armstrong JJ, Pintwala R, Hutnik C. Optical coherence tomography for 
glaucoma diagnosis: An evidence based meta-analysis. PLoS One. 
2018;13(1):e0190621. 
21. 
Lin C, Mak H, Yu M, Leung CK. Trend-Based Progression Analysis for Examination 
of the Topography of Rates of Retinal Nerve Fiber Layer Thinning in Glaucoma. 
JAMA Ophthalmol. 2017;135(3):189-195. 
22. 
Kuang TM, Zhang C, Zangwill LM, Weinreb RN, Medeiros FA. Estimating Lead Time 
Gained by Optical Coherence Tomography in Detecting Glaucoma before 
Development of Visual Field Defects. Ophthalmology. 2015;122(10):2002-2009. 
23. 
Mwanza JC, Chang RT, Budenz DL, et al. Reproducibility of peripapillary retinal 
nerve fiber layer thickness and optic nerve head parameters measured with cirrus 
HD-OCT in glaucomatous eyes. Invest Ophthalmol Vis Sci. 2010;51(11):5724-5730. 
24. 
Vasconcelos-Moraes CG, Susanna R, Jr. Correlation between the water drinking test 
and modified diurnal tension curve in untreated glaucomatous eyes. Clinics (Sao 
Paulo). 2008;63(4):433-436. 
 

 
 
                                                                                                WIGS Consent Form V1.5   07.10.2019   IRAS: 264273 
Participant Identification Number for this trial: 
CONSENT FORM 
Study Title: The Water Drinking Test In Glaucoma Study: WIGS 
Name of Principal Investigator: Prof Francesca Cordeiro Please initial box  
1. I confirm that I have read the information sheet dated.................... (Version............) for the above 
study. I have had the opportunity to consider the information, ask questions and have had these 
answered satisfactorily. 
2. I understand that my participation is voluntary and that I am free to withdraw at any time without 
giving any reason, without my medical care or legal rights being affected. 
3. I understand that relevant sections of my medical notes and data collected during the study, may be 
looked at by individuals from Imperial College London, from ICORG, from regulatory authorities or 
from the NHS Trust, where it is relevant to my taking part in this research. I give permission for these 
individuals to have access to my records.  
4. Optional: I agree to grant access to my follow-up data as specified in the patient information sheet. 
5. I consent to being contacted regarding potentially taking part in other research studies 
6. I give/do not give (delete as applicable) consent for information collected about me to be used to 
support other research in the future, , including those outside of the EEA. 
7. I consent to my GP being informed about my participation in the study  
8. I consent to take part in the above study 
 
 
 
 
_______  
 
 
 
 
 
 
 
 
Name of Participant 
 
 
Date 
 
 
 
Signature 
 
 
 
 
_______  
 
 
 
 
 
 
 
 
Name of Person taking consent 
 
Date 
 
 
 
Signature 
(If different from Principal Investigator) 
 
 
 
 
_______  
 
 
 
 
 
 
 
 
Principal Investigator taking consent 
Date 
 
 
 
Signature 
 
You will be given a copy of this consent form to keep; one copy will be filed in your medical notes, and one 
will be filed with the study records within the research folder at the Western Eye Hospital.