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Abstract
Purpose The Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial aims to establish whether initial treatment with selective laser trabeculoplasty (SLT) is superior to initial treatment with topical medication for primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
Design The LiGHT Trial is a prospective, unmasked, multicentre, pragmatic, randomised controlled trial. 718 previously untreated patients with POAG or OHT were recruited at six collaborating centres in the UK between 2012 and 2014. The trial comprises two treatment arms: initial SLT followed by conventional medical therapy as required, and medical therapy without laser therapy. Randomisation was provided online by a web-based randomisation service. Participants will be monitored for 3 years, according to routine clinical practice. The target intraocular pressure (IOP) was set at baseline according to an algorithm, based on disease severity and lifetime risk of loss of vision at recruitment, and subsequently adjusted on the basis of IOP control, optic disc and visual field. The primary outcome measure is health-related quality of life (HRQL) (EQ-5D five-level). Secondary outcomes are treatment pathway cost and cost-effectiveness, Glaucoma Utility Index, Glaucoma Symptom Scale, Glaucoma Quality of Life, objective measures of pathway effectiveness, visual function and safety profiles and concordance. A single main analysis will be performed at the end of the trial on an intention-to-treat basis.
Conclusions The LiGHT Trial is a multicentre, pragmatic, randomised clinical trial that will provide valuable data on the relative HRQL, clinical effectiveness and cost-effectiveness of SLT and topical IOP-lowering medication.
Trial registration number ISRCTN32038223, Pre-results.
- glaucoma
- treatment lasers
- intraocular pressure
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Introduction
Primary open-angle glaucoma (POAG) is an irreversible optic neuropathy affecting up to 4% of white and 15% of black populations by the age of 80,1 and a leading cause of blind registrations, falls and loss of independence,2 significantly affecting quality of life (QoL).3 Intraocular pressure (IOP) is the only modifiable risk factor, the reduction of which is proven to slow down the progression of the disease.4 Although the effectiveness of hypotensive drops is irrefutable, they come with a number of potential aesthetic, sight-threatening and serious systemic side effects,5 6 and may have a negative impact on the success of subsequent surgical intervention.7 Medical management of POAG and ocular hypertension (OHT) requires regular monitoring, as well as multiple hospital visits.
Selective laser trabeculoplasty (SLT) involves a painless outpatient application of laser to the trabecular meshwork. Economic modelling has predicted that using SLT as a first-line treatment compared with topical medication will significantly reduce healthcare costs,8 although this has been refuted by others.9 Research recommendations by National Institute for Health and Care Excellence (NICE) and Cochrane have identified the need for robust randomised clinical trials (RCT) investigating the efficacy and cost-effectiveness of SLT as a first-line treatment.10 11
This paper describes the design of the Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial, which compares health-related quality of life (HRQL), cost-effectiveness and clinical outcomes of patients who start treatment with topical IOP-lowering medication (‘Medicine-1st’ pathway) with that of patients who are first treated with SLT (‘Laser-1st’ pathway).
Methods
Study design
LiGHT is a multicentre RCT unmasked to treatment allocation. The study adheres to the tenets of the Declaration of Helsinki and is registered at www.controlled-trials.com (trial registration number: ISRCTN32038223). Ethical approval was granted by the City Road and Hampstead Research and Ethics Committee. The trial is monitored by a Trial Management Group, a Trial Steering Committee and a Data and Safety Monitoring Committee.
Eligible patients are randomised on a 1:1 ratio to receive either medical therapy or SLT as first-line treatment for POAG or OHT. All measurements influencing treatment escalation decisions, that is, IOP, Heidelberg retina tomography (HRT) and visual field (VF), are made by masked observers (optometrists and/or technicians). Patients are monitored for 3 years. Monitoring intervals and treatment escalation decisions are guided by clinical decision support software (DSS) implementing a defined protocol based on published evidence-based guidelines, while also attempting to capture the complexities of clinical practice. Although this is not used in usual National Health Service practice, it was designed to mirror normal UK clinical practice and, where it diverged from the treating clinician’s normal clinical practice, deviations were permitted with explanatory reasons given. Inclusion and exclusion criteria are shown in table 1.
Inclusion and exclusion criteria to the LiGHT Trial
Recruitment
Consecutive eligible patients were identified at six participating centres from October 2012 until October 2014 (online supplementary appendix 1). Patients who decided to participate were given a baseline assessment on a different day and those who declined were asked for a reason for their refusal.
Supplementary file 1
Baseline assessment
At the baseline assessment, participants underwent visual acuity testing (ETDRS logMAR), slit lamp examination, automated VF testing (Humphrey field analyser (HFA) Mark II SITA standard 24–2), HRT optic disc imaging, IOP measurement, gonioscopy, central corneal thickness (CCT) measurement, and assessment of the optic discs, maculae and fundi. The schedule of examinations is given in online supplementary appendix 2. The patients also filled in the following questionnaires: EQ-5D five-level (EQ-5D-5L),12 Glaucoma Utility Index (GUI),13 Glaucoma Symptom Scale (GSS),14 Glaucoma Quality of Life-15 (GQL-15; a visual function, rather than QoL, measure)14 and a modified version of the ‘Client Service Receipt Inventory’ (CSRI) questionnaire to collect health-related cost data.15
Supplementary file 2
Standardisation of disease stratification and individual patient treatment IOP targets using a web-based real-time decision support algorithm
The NICE-recommended thresholds were used for defining disease (POAG or OHT) for entry into the study, as well as initiating treatment.11 A real-time, web-based, clinical DSS, based on the analysis of HRT, VF and IOP measurements, avoids bias from unmasked clinicians. A disease category and stage were defined, using preset objective severity criteria from the Canadian Target IOP Workshop16 with additional central VF loss criteria according to Mills et al.17 Severity stratification (mild, moderate or severe) then determined the follow-up intervals and an eye-specific ‘Treatment Target IOP’. Target IOP was objectively defined based on both percentage reduction from untreated IOP and an absolute value, and then adjusted during the study according to the presence or absence of disease progression (figure 1). The lowest permitted target was 8 mm Hg for POAG and 18 mm Hg for OHT.i Not all permutations of clinical behaviour could be captured within the DSS, therefore deviation by the treating consultant from DSS advice was permitted; the reason was recorded for comparison between treatment arms, for example, if poor concordance contributed to a failure to meet Target IOP rather than drug effectiveness.
Process for Target IOP setting. *Disease stratification according to Mills et al. 17 IOP, intraocular pressure; GON, glaucoma optic neuropathy; OHT, ocular hypertension; POAG, primary open-angle glaucoma; VF, visual field.
Randomisation and allocation of participants to treatment groups
Randomisation was undertaken online using a web-based randomisation service, achieving full allocation concealment (www.sealedenvelope.co.uk). Stratified randomisation with random block sizes was used to randomise in a 1:1 ratio at the level of the patient, with the stratification factors of diagnosis and treatment centre. Patients with one or both eyes eligible were treated identically.
Trial arm 1: Laser-1st pathway
Standardisation of SLT delivery was achieved by protocol-defined settings and clinical endpoint of fine bubble formation at the trabecular meshwork at least 50% of the time (online supplementary appendix 3). One SLT retreatment was allowed, provided there was an initial response to the treatment. After two SLT treatments the next escalation was medical treatment. Significant complications of laser treatment (eg, severe uveitis, IOP spike greater than 15 mm Hg) or other new medical conditions prevented repetition of SLT.
Supplementary file 3
Trial arm 2: Medicine-1st pathway
Patients on the Medicine-1st pathway or patients who remained uncontrolled on Laser-1st pathway were started on single drugs at initiation and with each treatment switch or escalation. Drug classes for first-line, second-line or third-line treatment were defined as per NICE11 and the European Glaucoma Society (EGS) guidance18 (first line: prostaglandin analogues; second line: beta blockers; third or fourth line: topical carbonic anhydrase inhibitors or alpha-agonists). Fixed combination drops were allowed. Systemic carbonic anhydrase inhibitors were only permitted as a temporary measure while awaiting surgery and did not influence treatment escalation. Maximum medical therapy (MMT) is defined as the most intensive combination of drops an individual can reasonably, reliably and safely use and varied between patients. MMT is defined as a maximum of three drugs and five dosages per day for triggering the offer of surgery, although MMT may be less for certain patients; more agents could be used for patients who decline trabeculectomy. Criteria for failure to meet and to reassess Target IOP are shown in online supplementary appendix 4.
Supplementary file 4
Treatment escalation
To minimise bias for escalating treatment, standardised criteria were used according to a protocol following the international guidelines by the EGS, American Academy of Ophthalmology Preferred Practice Pattern and the South East Asia Glaucoma Interest Group. Treatment was escalated under the following circumstances:
‘Strong Evidence’ of progression irrespective of IOP
IOP above Target by more than 4 mm Hg at a single visit
IOP above Target by less than 4 mm Hg and ‘Less Strong Evidence’ for progression; if the IOP is above Target by less than 4 mm Hg with no evidence for progression, then the ‘Treatment Target IOP’ is re-evaluated.
The process for escalating treatment is shown in figure 2.
Process for escalating treatment in POAG. *On two consecutive visits. **As per protocol. ^Until progression confirmed/refuted. VF progression required three follow-up VF assessments. Maximal IOP, IOP above which surgery was offered even without progression or 35 mm Hg for OHT (see text). IOP, intraocular pressure; MMT, maximum medical therapy; POAG, primary open-angle glaucoma; VF, visual field.
Defining disease progression by HRT and VF
A minimum of two reliable baseline VF measurements (based on reliability indices and clinician judgement) and three follow-up VF were required. ‘Possible VF Progression’ was defined as deterioration of ≥3 locations on the HFA glaucoma progression analysis (GPA) with probability of <0.05 on three consecutive occasions. ‘Possible VF Progression’ was defined as deterioration of ≥3 locations on the HFA GPA with probablility of <0.05 on two consecutive tests. Any treatment escalation triggered by worsening VF loss required senior clinician verification.
Progression of optic disc damage was defined as a statistically significant rate of neuroretinal rim loss exceeding 1% of baseline rim area/year on a minimum of five repeat HRT images.
Progression of glaucoma was defined as ‘Strong evidence’=GPA ‘Likely progression’ and/or HRT rim area >1% per year (p<0.001); ‘Less strong evidence’=GPA ‘Possible progression’ and/or HRT rim area >1% per year (p<0.01).
Follow-up procedure and timing
Follow-up intervals were initially set at entry to the study according to NICE guidance11 and subsequently adjusted on the basis of IOP control, glaucoma progression or adverse reactions. The routine schedule of appointments and assessments for patients is shown in online supplementary appendices 2 and 5, respectively.
Adverse events
Adverse events were reported according to standard operating procedures to achieve standardisation across sites and between treatment allocation, with an annual safety report to the Research and Ethics Committee.
Outcome measures
The primary outcome measure is HRQL using EQ-5D-5L utility scores at 3 years, calculated using the EQ-5D-5L descriptive system and value set for England (Office of Health Economics).19 Quality-adjusted life years (QALYs) will also be calculated over the 36-month period using the baseline and six-monthly follow-up questionnaires, and calculating the area under the curve. There is a risk that the EQ-5D-5L might prove insensitive to QoL in glaucoma; if this is the case, then a difference in cost or treatment intensity outcome will also be of value.
The following are the secondary outcomes:
Treatment pathway healthcare resource use, cost and cost-effectiveness. Healthcare resource use will be ascertained from the record of treatment episodes and additional healthcare contacts from a modified CSRI.15 The cost components will include the cost of SLT, number of visits, number and type of medications and glaucoma surgeries and clinical tests.
Glaucoma-specific treatment-related QoL will be measured using the GUI, from which QALYs can also be derived.
Patient-reported disease and treatment-related symptoms using the GSS.
Patient-reported visual function using the GQL-15.
Objective measurements of pathway effectiveness for IOP-lowering and visual function preservation (eg, treatment intensity and time taken to achieve Target IOP, the number of Target IOP revisions, proportion of patients achieving Target after each year of treatment, number of patients with confirmed disease deterioration and rates of ocular surgery).
Objective safety measures for each pathway.
Concordance was assessed by two questions shown to predict the probability of non-concordance.20
Sample size calculation
A difference in EQ-5D-5L utility scores of 0.05 has been considered to be clinically meaningful in an Medical Research Council (MRC)-funded trial of glaucoma surgery,21 less than the difference between mild (0.84±0.17) and moderate (0.68±0.26) VF loss.22 A study with 305 participants in each group would have 90% power to detect, at 5% significance level, a difference in means of 0.05, assuming a common SD of 0.19 and using a two-sided test. Allowing for 15% loss to follow-up at 36 months, the total number required for the study is 718 (359 in each group). The sample size was calculated using Stata V.12.
Statistical analysis plan
The statistical analysis has been published elsewhere.23 The analysis will be based on all participants as randomised, irrespective of subsequent concordance with allocated treatment. The primary outcome will be compared between treatment arms using regression methods that adjust for baseline EQ-5D-5L score, IOP and disease laterality. Statistical significance will be at 5%. Mixed models will be used to investigate how primary and secondary outcomes change over time.
Discussion
LiGHT is a multicentre RCT, unmasked to treatment allocation, designed to compare HRQL, clinical effectiveness and cost-effectiveness, and clinical safety of SLT versus topical IOP-lowering medication in treatment-naïve patients with newly diagnosed POAG or OHT. This study addresses well one of the James Lind Alliance glaucoma research priorities.24
In the LiGHT Trial, concern about possible confounding effects of placebo treatment and altered compliance from sham laser require patients to be aware of their treatment allocation. Patients’ knowledge of prior medical treatment and/or initial treatment with laser may influence subsequent medication-taking behaviour and compliance. Although the patients and clinicians are unmasked to the treatment arm, all clinical measures (IOP, VF, HRT) are made by masked observers. Moreover, treatment decisions are masked by the use of a computerised evidence-based DSS. The potential for bias arising from lack of masking patients to treatment allocation will be investigated by comparison of EQ-5D and GUI in patients who use eye-drops after laser alone with those patients who never received laser and with the prior period when laser alone was sufficient.
Very few controlled trials have compared medical with laser treatment in patients with POAG or OHT. The LiGHT Trial compares the two treatment pathways in previously untreated patients, unlike previously conducted trials.25 26 The non-randomised trial by Katz et al 26 is the only trial to have set a personalised IOP Target. The Target IOP for LiGHT is eye-specific, objectively defined and adjusted by the DSS to avoid bias from unmasked clinicians.
The LiGHT Trial will provide valuable data on the HRQL, clinical effectiveness and cost-effectiveness of SLT and topical IOP-lowering medication, with the potential to define the choice of first-line treatment.
Supplementary file 5
Acknowledgments
We are grateful to Emily Dowse, Karine Girard-Claudon, Seetal Savania-Dholakia, Gurveen Panesar, Ayse Barnes, Dominic Carrington, Emerson Tingco, Charles Amoa Kanom Bibi.
References
Footnotes
↵i Although CCT has an effect on IOP measurement and risk of progression, the true magnitude of this interaction is unknown because of complex non-linear interactions between CCT, ‘true’ IOP and corneal material properties; CCT is, therefore, not used in the algorithm for setting Target IOP. Myopia and family history are also not included in this algorithm, as data on the effect size of these risk factors on progression rates are weak.
Contributors GG led the initial conception and design of the trial and writing the protocol, acquired funding and ethics approval, is the chief investigator of the trial, and was a major contributor in writing the manuscript. DG-H was a major contributor to the design of the trial and the trial protocol, and was involved in the drafting of the manuscript and critical revision of the study design. EK wrote the manuscript together with GG and is involved in the acquisition of the data. KB was involved in the drafting of the protocol and critical revision of the study design. RW was involved in the drafting of the manuscript and critical revision of the study design and protocol. SM and RH contributed to the design of the outcome measures and the data to be collected, and was involved in the drafting of the manuscript. GR was involved in the drafting of the manuscript and critical revision of the study design. MB contributed in overlooking the conduct of the trial and was involved in the drafting of the manuscript. GA contributed in the design of the outcome measures and the data to be collected, and was involved in the drafting of the manuscript. CB contributed in the design of the outcome measures and the data to be collected, and was involved in the drafting of the manuscript. All authors read and approved the final manuscript.
Funding The trial was funded by the National Institute of Health Research Health Technology Assessment Panel (Project reference number 09/104/40) and was sponsored by Moorfields Eye Hospital NHS Foundation Trust. The sponsor or funding organisation had no role in the design or conduct of this research. This report presents independent research commissioned by the NIHR; the views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, CCF, NETSCC, the HTA programme or the Department of Health.
Competing interests GG, DG-H, KB, RW, SM, RH, GR, MB, GA and CB have received a grant from the National Institute for Health Research for the submitted work. DG-H and RW have received financial support through the Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. GG received a research grant from Lumenis prior to the submitted work. GG, DG-H and KB have conflicts of interest outside the submitted work.
Ethics approval The City Road and Hampstead Research and Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional data at the moment.
Collaborators The LiGHT Trial Study Group: Gareth Ambler, Keith Barton, Rupert Bourne, David Broadway, Catey Bunce, Marta Buszewicz, Amanda Davis, Anurag Garg, David Garway-Heath, Gus Gazzard, Rachael Hunter, Yuzhen Jiang, Evgenia Konstantakopoulou, Sheng Lim, Joanna Liput, Timothy Manners, Stephen Morris, Neil Nathwani, Gary Rubin, Nicholas Strouthidis, Victoria Vickerstaff, Sarah Wilson, Richard Wormald, Haogang Zhu.