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

Design: 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. Setting: 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) Target population: 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 Health technologies being assessed: 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). Primary surgery: Trabeculectomy with mitomycin C (augmented trabeculectomy) is the recommended operation for advanced glaucoma. Measurement of Costs and Outcomes: 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. 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. 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. The cost-utility will also be modelled over the patient’s lifetime. 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. Sample size: 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. Project timetable including recruitment rates: 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. 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. Expertise: 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. 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.