Award Title: Treatment of Advanced Glaucoma Study (TAGS): A multicentre randomised controlled trial comparing primary medical treatment with primary trabeculectomy for people with newly diagnosed advanced glaucoma
Funder: Department of Health and Social Care

Abstract: Glaucoma is a common potentially blinding disease.  It occurs when the intraocular pressure (eye pressure) in the eye is too high.  Patients presenting with advanced disease (severe visual field loss on visual field examination) are at high risk of becoming blind despite treatment.  It is the second commonest cause for blind registration in the UK. Blindness places a burden on society, patients and their family._x000D_
Glaucoma is treated by using eye drops (medical) or by an operation (surgery) to lower eye pressure. NICE recommends surgery in patients presenting with advanced glaucoma. The operation is called a trabeculectomy, this creates a small hole in the eye which lowers the eye pressure.  Medical care starts with eye drops and may require up to 4 different drops. If this fails to control the eye pressure, surgery (trabeculectomy) is required.  Surgery is good at lowering eye pressure but there can occasionally be severe side effects. _x000D_
Low eye pressure is the best way to prevent further visual loss and is very important in patients with advanced disease.  Surgery is better at lowering eye pressure than drops, but in the short-term it requires intensive post-operative follow-up with frequent hospital visits, adjustments to the surgery and has an increased risk of cataract development and vision threatening complications requiring further surgery.  Using drops to lower eye pressure as the first treatment may delay or prevent surgery altogether and maintain a better quality of life for patients. Uncertainty exists as to whether modern medical treatments lower eye pressure sufficiently to reduce the risk of blindness in the future._x000D_
Modern glaucoma drops are better at lowering IOP and have fewer side effects than those available in the past.  In addition many of these drops are now available as generic drops and so are much less expensive than in the past.  It is possible therefore that using drops will be less expensive than undertaking surgery for this group of patients._x000D_
We want to determine whether medication (drops) or surgery produces better patient health, quality of life, reduced risk of sight loss, and represents a better use of NHS and society resources in people presenting with advanced glaucoma.  Our proposed study involves giving either medication (drops) or surgery to 440 people who agree to take part.  They will be randomly allocated to have either eye drops or surgery.  The study will include a network of hospitals over 73 months with each participant being studied for 2 years. We will measure the impact of the treatments on the health of the participants, their vision and eye pressure and determine which treatment represents best value for money.  This information will be collected by asking the participants to complete a series of questionnaires over the 2 years and by staff at the study hospitals completing case report forms._x000D_
Our research team is made up of surgeons (ophthalmologists), lay experts and experts in the design, performance and analysis of clinical trials.  The study will be managed by a Clinical Trials Unit which is very experienced at running large multicentre randomised controlled trials within the NHS.  We also have the support of the patient organisation, The International Glaucoma Association.  We will convene a Trial Steering Committee and Data Monitoring Committee which will meet annually to over see the trial progress and ensure that there are no safety concerns with regards to the treatments being investigated._x000D_
The study will last 73 months.  This includes 5 months to set up the study; 36 months to set up centres, recruit participants, a further 26 months to complete the follow up on all participants and 6 months to analyse, write up and close down the study._x000D_
The study will take into account the NHS, patient and society perspectives so that our finding will provide further information for all stakeholders on how best to manage patients presenting with advanced glaucoma. The study will assess relative effectiveness, safety and costs in routine everyday NHS practice to ensure that the results are representative of NHS practice._x000D_
Our proposal specifically fulfils the requirement of the HTA surgery research call.  Our study will determine whether there is a need for initial surgery (as recommended by NICE) in patients presenting with advanced glaucoma when alternative effective modern glaucoma medications with fewer side effects have become available.  Patient views and experience are an important outcome in our proposal as we use a visual quality of life measure as our main outcome, To further clarify the patients treatment pathways we measure the patients visual health and general health status at frequent intervals to allow “profiling” of the patient experience during their follow-up on._x000D_
ADDENDUM (02-11-2018) - As a result of being given extra funding and ethical and regulatory approval, the study team will ask TAGS participants who consented to longer term follow-up to complete participant questionnaires 3, 4 and 5 years after they joined the study. We will also collect more clinical data at participants’ regular NHS clinical follow-up around 5 years after they joined the study. This is good news for people living with advanced glaucoma. The planned 2-year results will assist clinical and patient decision-making about which treatment has better outcomes. But additional 5-year data will afford more certainty that any differences are consistent in the longer term. This data will more accurately reflect the lifetime outcomes for patients with advanced glaucoma, and that will allow patients newly diagnosed with advanced glaucoma, and their clinicians, to make more informed choices regarding the treatment options.

Lay Abstract: Design:_x000D_
A pragmatic multicentre randomised controlled trial comparing primary medical treatment with primary trabeculectomy (standard care).  Participants will be randomised to medical treatment or trabeculectomy (1:1 allocation minimised by centre and bilateral disease). We will include an internal pilot to confirm the feasibility of recruitment and retention targets._x000D_
Setting:_x000D_
Secondary care (20 centres within the UK; Nottingham; London (x3); Leicester; Sheffield;, Portsmouth; Hinchingbrooke; Huddersfield; Cheltenham; Norwich; Belfast; Edinburgh; Glasgow; Birmingham; Bristol; Manchester; Maidstone; Warrington; Sunderland)_x000D_
Target population:_x000D_
Adults presenting with advanced glaucoma in at least one eye. Advanced disease will be classified as severe glaucoma by the Hodapp classification of glaucoma severity_x000D_
Health technologies being assessed:_x000D_
Primary medication: refers to initial treatment with step wise escalation of medical care (escalating glaucoma drops) to lower intraocular pressure (IOP) according to the following specifications: initially the patient will start on one or more glaucoma drops, if the clinician judges IOP control is inadequate an escalation of medical therapy follows (following NICE guidelines). _x000D_
Primary surgery: Trabeculectomy with mitomycin C (augmented trabeculectomy) is the recommended operation for advanced glaucoma._x000D_
Measurement of Costs and Outcomes:_x000D_
Patient centred outcomes: Vision specific health (NEI VFQ-25) at baseline, 4, 12 and 24 months via participant completed questionnaire. Generic (EQ5D, HUI-3), glaucoma specific (GUI) health status and patient experience questions measured at; baseline, 1, 3, 6, 12, 18 and 24 months post randomisation and immediately prior to trabeculectomy._x000D_
Clinical outcomes: Humphrey visual fields Mean Defect; Intraocular pressure; LogMAR visual acuity, measured at; baseline, 4, 12 and 24 months post randomisation and recorded on a case report form (CRF).  Complications of surgery and medical treatments and therapy changes will be recorded, also need for cataract surgery by 24 months, eligibility for registration as visually impaired and evaluation of legal driving status at 24 months._x000D_
Economic outcomes: Costs of initial treatments including time in hospital and secondary care use will be based on data collected in CRFs. Primary care, personal social service use and patient costs will be collected via questionnaire at 4, 12 and 24 months post randomisation. These data will be combined with both standard (NHS reference costs) and study specific unit costs.  Responses to the EQ5D; HUI-3 and GUI will be combined with relevant tariffs to produce QALYs. Costs and QALYs will be combined in a within trial cost-utility analysis, incorporating deterministic and stochastic sensitivity analysis. _x000D_
The cost-utility will also be modelled over the patient’s lifetime._x000D_
The scoring system for the GUI was developed from a sample of glaucoma sufferers, a comparatively small number of whom had advanced glaucoma.  In order to tailor this tool for the trial population a discrete choice experiment whose responses formed the basis of the GUI scoring system will be administered to trial participants.  This questionnaire has already undergone extensive piloting.   _x000D_
Sample size: _x000D_
The primary patient reported outcome is the health status measured by the NEI-VFQ-25 assessment at 24 months. A study with 190 participants in each group will have 90% power at 5% significance level to detect a difference in means of 0.33 of a standard deviation (SD), this translates to 6 points on the NEI-VFQ-25 assuming a common SD of 18 points observed in previous work which is a clinically relevant effect size in patients with advanced glaucoma.  Assuming a drop-out rate of 13.5% due to declining further follow-up and death, a total of 440 participants will need to be randomised to be able to detect this difference.  The primary outcome will be analysed using linear regression correcting for baseline VFQ-25, EQ5D, HUI-3 and MD. _x000D_
Project timetable including recruitment rates:_x000D_
The projected start date for the study is 1 January 2014: the study duration will be 73 months. Milestones are: prefunding: protocol development; multicentre research ethics, central R&D approvals; Months: 1-5 Study initiation; set up office, assemble team NHS approvals, start site set up Months 6 -17: establish study in all 20 centres; months 6-41: identify and recruit 440 participants; months; Months 42-67: complete 24 month follow up; Months 68-73: complete DCE, close down, analysis, report writing._x000D_
All participating centres have indicated a throughput of at least 20 eligible patients annually. The recruitment projection is based on 20 sites recruiting approximately 9-11 patients per year, with a staggered start of recruiting sites, allowing 440 participants to be recruited over 3 years._x000D_
Expertise: _x000D_
The applicants comprise a strong multidisciplinary research team of ophthalmologists, patient representatives and methodologists.  The study will be co-ordinated by the Centre for Health and Randomised Trials (CHaRT) an established clinical trials unit with expertise in running surgical randomised trials and specifically glaucoma studies._x000D_
ADDENDUM (02-11-2018) - Funding has been secured and regulatory approval given to follow TAGS participants who consented to longer term follow-up for up to 5 years post-randomisation. This includes a participant questionnaire at 3, 4 and 5 years as well as a clinic visit at 5 years. This visit should coincide with participants’ regular NHS clinical follow-up.

Research Activity Codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health Categories: EYE