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Trial registered on ANZCTR


Registration number
ACTRN12622000104752
Ethics application status
Approved
Date submitted
3/09/2020
Date registered
24/01/2022
Date last updated
21/01/2024
Date data sharing statement initially provided
24/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Correlation between clinic-measured intraocular pressure (IOP) and disease progression in primary angle closure glaucoma (PACG)
Scientific title
Correlation between clinic-measured intraocular pressure (IOP) and disease progression in primary angle closure glaucoma (PACG)
Secondary ID [1] 302215 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary angle closure glaucoma 318911 0
Condition category
Condition code
Eye 316890 316890 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Participants will attend a study visit every 6 months for 5 years, in addition to their usual follow-up at Hong Kong Eye Hospital.

The following information will be collected for each patient:
- Hospital number (No Hong Kong ID number will be collected)
- Date of birth
- Date of diagnosis of PACG
- Date of any previous acute primary angle closure (APAC)
- Date of any previous argon laser peripheral iridoplasty (ALPI)
- Date of laser peripheral iridotomy (PI)
- Date of any previous cataract surgery
- Date of any previous glaucoma surgery
- Any co-existing cataract, diabetic retinopathy / maculopathy, age-related macular degeneration, or other eye diseases that may affect visual acuity or visual field

A systemic medical history is taken, with specific reference to history of:
- Hypertension (HT)
- Diabetes mellitus (DM)
- Hyperlipidemia (HL)
- Ischemic heart disease (IHD)
- Cerebrovascular accident (CVA)
- Cancer
- Smoking
- Number of cigarettes per day
- Number of years of smoking
- Number of years since quitting smoking
- Any secondary smoking
- Any family history of PACG / glaucoma

Ophthalmic examinations and investigations at recruitment by trained research personnel and optometrists:
- Date of study examination
- Best-corrected Snellen visual acuity and spherical refractive error
- Clinic-measured intraocular pressure (IOP) - measured with a Goldmann applanation tonometer on a slit-lamp biomicroscope. The reading in mm Hg is rounded to the next higher integer. Each measurement is repeated, and if the two readings differ by 3 mm Hg or more, a third measurement is taken. The median of the two or three measurements becomes the IOP determination.
- The number of IOP-lowering drugs (topical and systemic)
- Central corneal thickness and axial length by ultrasonography
- Central corneal endothelial cell count by specular microscopy (SM)
- Gonioscopic examination of angle structures, and grading by the Shaffer system
- Anterior segment imaging by Anterior Segment Optical Coherence Tomography (AS-OCT) using the Visante™ OCT (Carl Zeiss Meditec, Dublin, California, USA). The Irido-Corneal Tools Module of the Visante™ OCT will be used to document the following drainage angle parameters: Angle Opening Distance (AOD), the Trabecular Iris Space Area (TISA), the Angle Recess Area (ARA), the Scleral Spur Angle and the Trabecular Iris Contact Length (TICL).
- Vertical cup-to-disc ratio, and other optic disc changes suggestive of glaucoma
- Optic disc imaging by Cirrus™ Spectral Domain HD-OCT (Carl Zeiss Meditec, Dublin, California, USA)
- Automated perimetry using the Humphrey Field Analyzer II (Carl Zeiss Meditec, California, USA) (central 24-2 threshold test, Sita standard strategy, size III white stimulus, with the foveal threshold test turned on)
- Retinal nerve fiber layer thickness measurement by Optical Coherence Tomography III (OCT III) imaging system (Stratus OCT, Carl Zeiss Meditec, Dublin, California, USA)

Data collection at follow up
All recruited patients will be followed up in the Glaucoma Clinics at Hong Kong Eye Hospital and Prince of Wales Hospital for 5 years. Gonioscopy for angle assessment and documentation of optic nerve head appearances (including vertical cup-to-disk ratios) will be performed at least once a year as per hospital protocol. During follow up, patients will be prescribed IOP-lowering drugs, and advised surgery (phacoemulsification, trabeculectomy, or combined phaco-trabeculectomy), as clinically indicated. The goal of IOP-lowering treatment is to achieve an IOP of 21 mmHg or below, as per hospital protocol.

Documentation of IOP
All recruited PACG patients will be seen 3-monthly in the HKEH Glaucoma Clinic, with documentation of bilateral IOP. IOP is measured with a Goldmann applanation tonometer on a slit-lamp biomicroscope. The reading in mm Hg is rounded to the next higher integer. Each measurement is repeated, and if the two readings differ by 3 mm Hg or more, a third measurement is taken. The median of the two or three measurements becomes the
IOP determination.

Documentation of disease progression
All recruited PACG patients will attend 6-monthly study visits. Although patients may be seen between study visits, data from these examinations were not routinely collected. Examinations and investigations at each study visit will include:
1. Documentation of optic nerve head appearance, in particular the vertical cup-to-disc ratio (VCDR)
2. Automated perimetry using the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA) (central 24-2 threshold test, Sita standard strategy, size III white stimulus, with the foveal threshold test turned on)
3. Retinal nerve fiber layer thickness measurement by Optical Coherence Tomography III (OCT III) imaging system (Stratus OCT, Carl Zeiss Meditec, Dublin, California, USA)

All these examinations and investigations are non-invasive, and are standard follow-up routines for all glaucoma patients. Participation in this study would require performance of visual field examination and retinal nerve fiber layer thickness scan at slightly higher frequency than normally required for clinical management. In routine clinical management, such investigations are usually performed at least once a year, and often more frequently in advanced or unstable patients. Performing these investigations more frequently may allow earlier detection and confirmation of glaucomatous progression.

Three strategies will be employed to detect disease progression:
1. Structural assessment - Retinal nerve fiber layer thickness measurement by Optical Coherence Tomography III (OCT III) imaging system (Stratus OCT, Carl Zeiss Meditec, Dublin, California, USA)
The GPA™ Advanced Serial Analysis software (Advanced Analysis Package of Stratus OCT™ Software Version 5.0) in the Stratus OCT will be used to quantify the progressive thinning of the retinal nerve fiber layer thickness, and also for analysis of statistical significance.

2. Functional assessment 1 – Automated perimetry using the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA) (central 24-2 threshold test, Sita standard strategy) with Visual Field Defect Scoring (VFDS)
Visual Field Defect Scoring (VFDS), as defined and used in the Advanced Glaucoma Intervention Study (AGIS) for POAG, will be used to score Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA) printouts (central 24-2 threstold test, Sita standard strategy, size III white stimulus, with the foveal threshold test turned on). VFDS range from 0 (no defect) to 20 (end-stage). If an eye has insufficient vision for a patient to count fingers at 30 cm, the visual field defect score is recorded as 20.The method of analysis used in AGIS will be repeated to compare the correlations between IOP and disease progression in POAG and PACG.

3. Functional assessment 2 – Automated perimetry using the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA) (central 24-2 threshold test, Sita standard strategy) with Guided Progression Analysis (GPA™) software (Carl Zeiss Meditec, Dublin, California, USA)
The Humphrey Guided Progression Analysis (GPA™) software in the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA) is derived from the analysis used in the EMGT study. The GPA software uses the pattern deviation plot, point-by-point, to detect progression. It will be used in this study to quantify the progressive deterioration in visual field / retinal sensitivity to light, and also for analysis of statistical significance.
Intervention code [1] 318507 0
Early Detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325020 0
Mean change in retinal nerve fiber layer thickness per year by Optical Coherence Tomography III (OCT III) imaging system (Stratus OCT, Carl Zeiss Meditec, Dublin, California, USA)
Timepoint [1] 325020 0
Every 6 months for 5 years
Secondary outcome [1] 386571 0
Change from baseline in follow-up Visual Field Defect Scoring (VFDS) (range, 0 to 20 units)

Automated perimetry using the Humphrey Field Analyzer II (central 24-2 threshold test, Sita standard strategy) with Visual Field Defect Scoring (VFDS)

Visual Field Defect Scoring (VFDS), as defined and used in the Advanced Glaucoma Intervention Study (AGIS) for POAG will be used to score Humphrey Field Analyzer II printouts (central 24-2 threstold test, Sita standard strategy, size III white stimulus, with the foveal threshold test turned on).
Timepoint [1] 386571 0
Every 6 months for 5 years
Secondary outcome [2] 386572 0
Mean change in mean deviation (MD) per year determined by the Humphrey Guided Progression Analysis (GPA™) software in the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, California, USA)
Timepoint [2] 386572 0
Every 6 months for 5 years
Secondary outcome [3] 399387 0
Documentation of optic nerve head appearances (including vertical cup-to-disk ratios) by direct ophthalmoscopes
Timepoint [3] 399387 0
Every 6 months for 5 years
Secondary outcome [4] 399388 0
Documentation of bilateral IOP measured with a Goldmann applanation tonometer on a slit-lamp biomicroscope
Timepoint [4] 399388 0
Every 3 months for 5 years

Eligibility
Key inclusion criteria
- On darkroom gonioscopy, at least 180º of iridotrabecular contact (ITC) obliterating posterior pigmented part of trabecular meshwork, whether synechial or appositional, segmented or continuous, in the presence of a patent peripheral iridotomy;
- Requiring intraocular pressure (IOP)-lowering medications, or IOP of above 21 mmHg without IOP-lowering medications;
- Visual field loss compatible with glaucoma and / or glaucomatous optic disc changes;
- Minimal criteria for glaucomatous visual field defect as per published standard (Anderson et al., 2000): glaucoma hemifield test outside normal limits, pattern standard deviation with a P value less than 5%, or a cluster of greater than or equal to 3 points in the pattern deviation plot in a single hemifield (superior or inferior) with P value less than 5%, one of which must have a P value less than 1%. Any one of the preceding criteria, if repeatable, was considered sufficient evidence of a glaucomatous visual field defect;
- Characteristic optic disc changes include vertical cup-disc ratio greater than 0.5, discrepancy of vertical cup-disc ratios between the 2 eyes greater than 0.2, thin or notched neuroretinal rim, disc hemorrhage, and/or retinal nerve fiber layer wedge defect;
- Patient able and willing to give informed consent to participate.

Reference:
Anderson DR, Chauhan B, Johnson C, Katz J, Patella VM, Drance SM. Criteria for progression of glaucoma in clinical management and in outcome studies. Am.J Ophthalmol. 2000;130:827-829.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any secondary causes of angle closure or ocular hypertension, such as:
- Uveitis
- Neovascularization of iris / angle, e.g. from diabetes or central retinal vein occlusion (CRVO)
- Iris / ciliary body cysts
- Posterior segment mass effect, e.g. posterior segment hemorrhage or tumor
- Marfan syndrome
- Axenfeld-Rieger syndrome
- Trauma
- Steroid-induced
- Latrogenic, e.g. after vitreoretinal surgery

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Results analysis

The primary objective of this study is to examine the relationship between clinic IOP during follow-up and glaucoma progression. Adapted versions of the two analyses described and used in the AGIS study will be employed to address this objective.

The first, designated Predictive Analysis, is designed to assess whether IOP during early follow-up is predictive of subsequent change from baseline in the 3 outcome measures described above. Each eye is assigned to one of three categories in accordance with its IOP averaged over the 6-month, 12-month, and 18-month visits: less than 14 mm Hg, 14 to 17.5 mm Hg, and greater than 17.5 mm Hg. Then, for each subsequent 6-month follow-up visit, the mean change from baseline in the 3 outcome measures described above is calculated for each of the three IOP groups.

In the second analysis, designated Associative Analysis, the percent of visits over the first 3 years of follow-up for which an eye presented with IOP less than 18 mm Hg was determined. In accordance with this percent, each eye was assigned to one of four categories: 100% (group A); 75% to less than 100% (group B); 50% to less than 75% (group C); and 0% to less than 50% (group D). Then, for each group and for each visit starting with the 6-month visit, the mean changes from baseline in the 3 outcome measures are calculated.

Statistical analysis

SPSS 15.0 platform (SPSS Inc., Chicago, IL) will be used for statistical analysis.

Continuous variables are expressed as mean (± standard deviation), categorical variables as individual counts and proportions. Univariate analyses are performed using Wilcoxon signed-rank test as appropriate. We used P < 0.05 as the critical value to determine statistical significance.

In the AGIS study, the generalized estimating equations method of Liang and Zeger was used in both the Predictive and Associative analyses to estimate and test the association between IOP and change in visual field defect score. As we are using only one eye from each study subject, we will not employ the generalized estimating equations method of Liang and Zeger in our analysis. Instead, we will use the Jonckheere-Terpstra test as our groupings can be ordered.

In the Predictive Analysis, Pearson correlation coefficients will be calculated between average IOP over the first three 6-month visits and 1) IOP at baseline, 2) IOP at subsequent visits, and 3) change from baseline in our 3 outcome measures at subsequent visits.

We will further adjust the visual field parameters for the presumed effect of cataract, as per the AGIS. This is accomplished by first estimating the expected change in visual field parameters from before to after cataract surgery. Then for eyes with cataract not yet removed, we use the estimates of expected change to remove analytically the presumed effect of cataract on visual field parameters when cataract is present.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
4/09/2009
Date of last participant enrolment
Anticipated
Actual
20/12/2019
Date of last data collection
Anticipated
20/12/2024
Actual
Sample size
Target
575
Accrual to date
Final
575
Recruitment outside Australia
Country [1] 22920 0
Hong Kong
State/province [1] 22920 0

Funding & Sponsors
Funding source category [1] 306636 0
Government body
Name [1] 306636 0
Research Grants Council
Country [1] 306636 0
Hong Kong
Primary sponsor type
Individual
Name
Prof Clement Chee-yung THAM
Address
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong
4/F, Hong Kong Eye Hospital,
147K Argyle Street, Kowloon
Country
Hong Kong
Secondary sponsor category [1] 307187 0
University
Name [1] 307187 0
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong
Address [1] 307187 0
4/F, Hong Kong Eye Hospital,
147K Argyle Street, Kowloon
Country [1] 307187 0
Hong Kong

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306821 0
Research Ethics Committee (Kowloon Central / Kowloon East)
Ethics committee address [1] 306821 0
Ethics committee country [1] 306821 0
Hong Kong
Date submitted for ethics approval [1] 306821 0
20/08/2009
Approval date [1] 306821 0
01/09/2009
Ethics approval number [1] 306821 0
KC/KE-09-0121/ER-3
Ethics committee name [2] 306839 0
Joint CUHK-NTEC Clincial Research Ethics Committee
Ethics committee address [2] 306839 0
Ethics committee country [2] 306839 0
Hong Kong
Date submitted for ethics approval [2] 306839 0
12/10/2009
Approval date [2] 306839 0
08/12/2009
Ethics approval number [2] 306839 0
2009.519

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105126 0
Prof Clement Chee-yung THAM
Address 105126 0
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong
4/F, Hong Kong Eye Hospital,
147K Argyle Street, Kowloon
Country 105126 0
Hong Kong
Phone 105126 0
+85239435823
Fax 105126 0
+85227159490
Email 105126 0
clemtham@cuhk.edu.hk
Contact person for public queries
Name 105127 0
Jennifer Tsoi
Address 105127 0
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong
3/F, Hong Kong Eye Hospital,
147K Argyle Street, Kowloon
Country 105127 0
Hong Kong
Phone 105127 0
+85239435818
Fax 105127 0
+85227689565
Email 105127 0
jennifertsoi@cuhk.edu.hk
Contact person for scientific queries
Name 105128 0
Clement Chee-yung THAM
Address 105128 0
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong
4/F, Hong Kong Eye Hospital,
147K Argyle Street, Kowloon
Country 105128 0
Hong Kong
Phone 105128 0
+85239435823
Fax 105128 0
+85227159490
Email 105128 0
clemtham@cuhk.edu.hk

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9056Study protocol    380517-(Uploaded-19-12-2023-17-13-26)-Study-related document.docx
9057Informed consent form    380517-(Uploaded-03-09-2020-19-15-32)-Study-related document.doc
9058Ethical approval    380517-(Uploaded-16-01-2023-13-37-19)-Study-related document.pdf



Results publications and other study-related documents

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