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Trial registered on ANZCTR


Registration number
ACTRN12618000453280
Ethics application status
Approved
Date submitted
10/08/2017
Date registered
28/03/2018
Date last updated
27/06/2019
Date data sharing statement initially provided
27/06/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Progressive retinal nerve fiber layer (RNFL) thinning as a biomarker to guide intraocular pressure (IOP) lowering treatment in ocular hypertensives (OHT)
Scientific title
Progressive retinal nerve fiber layer (RNFL) thinning as a biomarker to guide intraocular pressure (IOP) lowering treatment in ocular hypertensives (OHT)
Secondary ID [1] 292583 0
None
Universal Trial Number (UTN)
U1111-1200-2487
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Retinal Nerve Fiber Layer Thinning 304253 0
ocular hypertension 304254 0
Condition category
Condition code
Eye 303603 303603 0 0
Normal eye development and function
Eye 303604 303604 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigator will monitor the enrolled subjects and make the decision to see is treatment is needed. Treatment parameters would be at the clinical discretion of the treating opthalmologist, Study team will examine retinal nerve fiber layer(RNFL) thickness of paradigm I participants using optical coherence tomography (OCT).. Upon detection of progressive retinal nerve fiber layer(RNFL) thinning, paradigm I participants will start to receive drug(s) for IOP lowering treatment. In 4-month follow up visits, participants need to receive visual acuity (VA) measurement, slit-lamp biomicroscopy for anterior and posterior segments, vertical cup-to-disc ratio (VCDR) measurement, Goldmann applanation tonometry and perimetry and optical coherence tomography. Participants need to receive fundus examination and central corneal thickness (CCT) with ultrasound pachymetry yearly

Period of intervention is 5-year.

Drugs:
prostaglandin analogue, 1 drop once daily, topical
brimonidine, 1 drop, 2-3 times daily, topical
carbonic anhydrase inhibitor, 1 drop, 2-3 times daily, topical

In paradigm I, study team will examine RNFL thickness of paradigm I participants using OCT.. Upon detection of progressive RNFL thinning, paradigm I participants will start to receive drug(s) for IOP lowering treatment. In 4-month follow up visits, participants need to receive visual acuity (VA) measurement, slit-lamp biomicroscopy for anterior and posterior segments, vertical cup-to-disc ratio (VCDR) measurement, Goldmann applanation tonometry and perimetry and optical coherence tomography. Participants need to receive fundus examination and central corneal thickness (CCT) with ultrasound pachymetry yearly

In Paradigm II, study team will examine according to OHTS-EPGS risk prediction model five risk factors including higher IOP, older age, thinner central corneal thickness, VCDR and greater Visual Field (VF) pattern standard deviation (PSD) to examine participants’ risk to glaucoma. Upon detection of a 5-year glaucoma conversion risk >15% calculated, participants will start to receive drug(s) for IOP lowering treatment. Participants need to receive fundus examination and central corneal thickness (CCT) with ultrasound pachymetry yearly.

All participants are taking all the listed drugs at the same dose in Paradigm I. And for those participants in Paradigm II, they are taking all the listed drugs at the same dose.Participants in Paradigm I and II will have different dosage.

Frequency of follow up visit: every 4 months for 5 years
Intervention code [1] 298796 0
Treatment: Drugs
Comparator / control treatment
OHTS-EPGS is referred as "Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS)"
study team will examine according to OHTS-EPGS risk prediction model five risk factors including higher IOP, older age, thinner central corneal thickness, VCDR and greater Visual Field (VF) pattern standard deviation (PSD) to examine participants’ risk to glaucoma. Upon detection of a 5-year glaucoma conversion risk >15% calculated, participants will start to receive drug(s) for IOP lowering treatment. Participants need to receive fundus examination and central corneal thickness (CCT) with ultrasound pachymetry yearly

Drugs:
prostaglandin analogue, 1 drop once daily, topical
brimonidine, 1 drop, 2-3 times daily, topical
carbonic anhydrase inhibitor, 1 drop, 2-3 times daily, topical

Treatment for IOP lowering treatment is 5 years
Control group
Active

Outcomes
Primary outcome [1] 302963 0
Primary outcome measures the proportion of patients requiring IOP-lowering treatment in 5 years., Using Optical Coherence Tomography to assess if patients require IOP-lowering treatment. The outcome can be assessed by review of study records,
Timepoint [1] 302963 0
every 4 months in 5-year
Secondary outcome [1] 337577 0
the proportion of patients with Visual Field (VF) progression

Using visual field to access. The outcome can be assessed by review of study records,
Timepoint [1] 337577 0
every 4 months in 5-year
Secondary outcome [2] 338055 0
the total treatment costs in 5 years

Looking at how much drug cost patients need to pay off. We will review the drug cost
Timepoint [2] 338055 0
every 4 months in 5-year

Eligibility
Key inclusion criteria
1) age more than or equal to 18 years;
2) best corrected VA is greater than or equal to 20/40
3) an average IOP is more than or equal to 23mmHg but less than 32mmHg in at least 1 eye an more than or equal to 21mmHg but less than 32mmHg in the fellow eye measured from 3 separate baseline visits within 6 months
4) gonioscopically open anterior chamber angles
5) 3 reliable VF results without VF defects, normal optic disc and RNFL configuration in clinical examination
6) no RNFL abnormalities(i.e. within the 95% normal ranges) in the OCT RNFL thickness deviation map
7) no prior history of surgical/laser procedure for IOP lowering and receiving no topical IOP-lowering medication.
8) IOP measurements for eligibility assessment are obtained after washout of prestudy topical IOP
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) secondary causes of elevated IOP;
2) ocular or systemic diseases that may cause VF loss or optic disc abnormalities
3) high myopia (spherical error<-6.0D)
4) inability to perform reliable VF; suboptimal quality of SDOCT images
5) previous intraocular surgery other than uncomplicated cataract extraction
6) diabetic retinopathy/maculopathy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analysis (1) The primary analysis is to compare the proportions of patients requiring
IOP-lowering treatment (in one or both eyes) between management paradigms I and II at 5 years with a two-tailed z-test. The difference in time from baseline to treatment initiation between the 2
treatment paradigms will be compared with Kaplan-Meier survival analysis and log-rank test. (2) The secondary outcome measure, the proportions of patients with VF progression, are compared using similar statistical methods. The total medication costs and the average treatment cost per subject required throughout the 5-year study period will be calculated and compared with independent t-test between the two management paradigms. (3) Risk factors for development of VF progression are analyzed with Cox proportional hazard models with correlation between fellow eyes in the same individual adjusted with shared frailty models. Sample size calculation In a previous study investigating the safety and potential savings of decreasing IOP-lowering medication in OHT patients recruited from Hong Kong Eye Hospital, we observed 26% of OHT patients had a 5-year risk of glaucoma conversion >15% (after medication washout) at baseline and an additional 6.2% of the untreated patients developed a 5-year risk >15% at 1 year of follow-up. Assuming the same proportion of patients (i.e. 6.2%) develop a 5-year risk >15% in each year of follow-up, 50.8% (26%+6.2%*4) of OHT patients would have a 5-year risk >15% and require IOP-lowering treatment throughout the 5-year study period. In a pilot study following 38 OHT eyes for at least 5 years, we observed 30.0% of eyes having progressive RNFL thinning detected by TPA in 5 years. We therefore estimated that at least 248 subjects (124 subjects per randomization arm) are needed to detect a difference of 20% in the proportions of patients requiring IOP-lowering treatment in 5 years with a power of 90% and an alpha of 5%. Taking 20% attrition over the study period, 310 patients will be recruited and each study site will enroll approximately 62 patients.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
1/09/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
310
Accrual to date
280
Final
Recruitment outside Australia
Country [1] 9125 0
Hong Kong
State/province [1] 9125 0

Funding & Sponsors
Funding source category [1] 297159 0
Government body
Name [1] 297159 0
General Research Fund - University Grants Committee
Country [1] 297159 0
Hong Kong
Primary sponsor type
Individual
Name
Prof Leung Kai Shun Christopher
Address
Department of Ophthalmology & Visual Sciences
The Chinese University of Hong Kong
4/F Hong Kong Eye Hospital
147K Argyle Street, Mongkok,
Hong Kong SAR
Country
Hong Kong
Secondary sponsor category [1] 296177 0
None
Name [1] 296177 0
Address [1] 296177 0
Country [1] 296177 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298327 0
Research Ethics Committee (Kowloon Central / Kowloon East)
Ethics committee address [1] 298327 0
Room 414, Nurse Quarters, Queen Elizabeth Hospital,
30 Gascoigne Road, Kowloon
Ethics committee country [1] 298327 0
Hong Kong
Date submitted for ethics approval [1] 298327 0
14/12/2015
Approval date [1] 298327 0
23/03/2016
Ethics approval number [1] 298327 0
KC/KE-15-0232/ER-1
Ethics committee name [2] 298344 0
Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee
Ethics committee address [2] 298344 0
8/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin
Ethics committee country [2] 298344 0
Hong Kong
Date submitted for ethics approval [2] 298344 0
16/12/2015
Approval date [2] 298344 0
09/03/2016
Ethics approval number [2] 298344 0
CRE-2015.723
Ethics committee name [3] 303712 0
New Territories West Cluster Research Ethics Committee (NTWC REC)
Ethics committee address [3] 303712 0
5/F, Rehabilitation Block, Tuen Mun Hospital
Ethics committee country [3] 303712 0
Hong Kong
Date submitted for ethics approval [3] 303712 0
28/08/2017
Approval date [3] 303712 0
21/09/2017
Ethics approval number [3] 303712 0
NTWC/CREC/17087

Summary
Brief summary
Glaucoma is a leading cause of irreversible blindness, afflicting 21.8 million patients in China by 2020. While the Ocular Hypertension Treatment Study (OHTS) established the effectiveness of lowering the IOP in decreasing the risk of glaucoma development, <10% of the untreated patients worsened and developed glaucoma in 5 years. Treating non- progressing patients not only incurs unnecessary costs to patients and health-care providers, but also induces adverse effects that can compromise visual function and quality of life. Risk stratification using the OHTS-EGPS (European Glaucoma Prevention Study) prediction model has been proposed to identify high risk OHT (5-year risk >15%) for IOP-lowering treatment to prevent glaucoma development. Notably, the risk calculated by the OHTS-EGPS model relies on five biometric parameters measured cross sectionally, which can be highly variable during follow-up. The ability to distinguish high-risk from low-risk OHT remains imprecise and it is largely unclear when to initiate IOP-lowering treatment. Identifying biomarkers indicative of disease deterioration behavior to guide IOP-lowering
treatment for prevention of visual impairment is an unmet need in the management of
OHT. We hypothesize progressive RNFL thinning to be a biomarker predictive of subsequent visual field (VF) progression and that IOP-lowering treatment initiated upon detection of progressive RNFL thinning is an effective approach to direct OHT at risk of VF progression for treatment. We propose a 5-year prospective study, randomizing 310 OHT patients into two management paradigms with IOP-lowering treatment initiated upon detection of (I) progressive RNFL thinning, as determined by spectral-domain optical coherence tomography Trend-based Progression Analysis of serial RNFL thickness maps; or (II) a 5-year glaucoma conversion risk >15% calculated from the OHTS-EGPS model. All patients will undergo clinical examination, RNFL imaging and perimetry 4-monthly for 5 years. The objectives are to compare the proportion of patients requiring IOP-lowering treatment and the proportion of patients developing VF progression within the two management paradigms. We expect that the proportion of patients requiring treatment is smaller for patients randomized to management paradigm I with a comparable/smaller proportion of patients developing VF progression compared with those randomized to management paradigm II. The finding of the study will transform the management of OHT. Specifically, we would be able to target treatment to OHT at risk of VF progression based on a biomarker indicative of disease deterioration behavior. It also would minimize both costs and adverse effects, and enhance the rational re-allocation of resources within the healthcare system to those at most need.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76730 0
Prof Leung Kai Shun Christopher
Address 76730 0
Department of Ophthalmology & Visual Sciences,
3/F, Hong Kong Eye Hospital
147K Argyle Street
KOWLOON
Country 76730 0
Hong Kong
Phone 76730 0
+85239435818
Fax 76730 0
Email 76730 0
[email protected]
Contact person for public queries
Name 76731 0
Jennifer Tsoi
Address 76731 0
Department of Ophthalmology & Visual Sciences,
3/F, Hong Kong Eye Hospital
147K Argyle Street
KOWLOON
Country 76731 0
Hong Kong
Phone 76731 0
+85239435818
Fax 76731 0
Email 76731 0
[email protected]
Contact person for scientific queries
Name 76732 0
Leung Kai Shun Christopher
Address 76732 0
Department of Ophthalmology & Visual Sciences,
3/F, Hong Kong Eye Hospital
147K Argyle Street
KOWLOON
Country 76732 0
Hong Kong
Phone 76732 0
+85239435818
Fax 76732 0
Email 76732 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be shared due to privacy concerns.


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

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