Intravitreal aflibercept compared with panretinal photocoagulation for proliferative diabetic retinopathy: the CLARITY non-inferiority RCT

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 12/66/15. The contractual start date was in July 2014. The final report began editorial review in July 2017 and was accepted for publication in March 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Sobha Sivaprasad reports grants and non-financial support from Bayer HealthCare, Bayer Plc (Reading, UK) during the conduct of the study and has received research grants, travel fees and advisory board honoraria from Bayer HealthCare, Novartis Pharmaceuticals UK Ltd (Frimley, UK), Allergan Ltd (Marlow, UK) and Roche Holding AG (Basel, Switzerland); grants and advisory board honoraria from Boehringer Ingelheim (Ingelheim am Rhein, Germany); and advisory board honoraria from Heidelberg Engineering GmbH (Heidelberg, Germany), outside the submitted work. Philip Hykin reports grants, personal fees and non-financial support from Bayer HealthCare during the conduct of the study.

Copyright statement

© Queen’s Printer and Controller of HMSO 2018. This work was produced by Sivaprasad et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2018 Queen’s Printer and Controller of HMSO

Background

Diabetes mellitus is a major public health problem that affects 415 million people worldwide. 1 Diabetic retinopathy is the most common complication of diabetes mellitus. With the increasing prevalence of diabetes mellitus globally, diabetic retinopathy is emerging as the leading cause of avoidable blindness worldwide. The progression and severity of diabetic retinopathy can be delayed by optimal control of medical risk factors such as hyperglycaemia, hypertension and hyperlipidaemia. 2 However, despite better control of these well-established risk factors, good uptake of established national diabetic retinopathy screening programmes in many countries and improved patient awareness, diabetic retinopathy remains a significant morbidity, indicating the need for alternative management options for this condition. 3–5 The two vision-threatening complications of diabetic retinopathy are diabetic macular oedema (DMO) and proliferative diabetic retinopathy (PDR). DMO is caused by accumulation of excess extracellular fluid in the macula. PDR is characterised by growth of new blood vessels on the retina and, if left untreated, these blood vessels can bleed and scar the retina, causing severe visual loss because of vitreous haemorrhage, retinal detachment and neovascular glaucoma (NVG). Approximately 110,000 people in the UK have PDR and, of these, 14,000 have severe visual loss in both eyes, highlighting the need to address this prevalent public health problem. 5,6

Objectives

To compare the efficacy, safety and cost-effectiveness of intravitreal aflibercept with standard of care, PRP for PDR for 52 weeks, in a Phase IIb randomised active-controlled clinical trial.

Study design

This is a multicentre, prospective, individually randomised, single-masked, active-controlled non-inferiority trial with concurrent economic evaluation that compared the clinical efficacy and cost-effectiveness of intravitreal aflibercept versus PRP in patients with treatment-naive PDR or post-PRP active retinal NV at 52 weeks. A subset of the participants also took part in a mechanistic evaluation substudy.

The study was registered on 10 July 2014 (as ISRCTN 32207582). Clinical trial authorisation was given by the Medicines and Healthcare products Regulatory Agency (MHRA): European Clinical Trials Database (EudraCT) 2013-003272-12. Ethics approval was granted by the National Research Ethics Service Committee London – South East; 14/LO/0203. Recruitment commenced in August 2014 and was completed to time and target in November 2015.

The trial protocol is available at www.journalslibrary.nihr.ac.uk/programmes/eme/126615. The trial steering and data monitoring committees provided independent oversight.

Setting and locations

The study was conducted at the 22 NHS clinical sites listed below. The sites were chosen based on previous clinical trial experience or by the estimated volume of potentially eligible patients. Interested sites completed a site feasibility questionnaire.

• Birmingham and Midland Eye Centre, Sandwell and West Birmingham NHS Foundation Trust, Birmingham.

• Brighton and Sussex University Hospitals NHS Trust, Brighton.

• Bristol Eye Hospital, Bristol.

• Essex County Hospital, Colchester.

• Frimley Park Hospital NHS Foundation Trust, Surrey.

• Hillingdon Hospitals NHS Foundation Trust, London.

• James Paget University Hospital, Great Yarmouth.

• King’s College Hospital, London.

• Leicester Royal Infirmary, Leicester.

• Maidstone & Tunbridge Wells NHS Trust, Kent.

• Moorfields Eye Hospital NHS Foundation Trust, London.

• Princess Alexandra Hospital, Harlow.

• Royal Bolton Hospital NHS Trust, Greater Manchester.

• Royal Liverpool & Broadgreen University Hospitals NHS Trust, Liverpool.

• Royal Victoria Hospital and Queen’s University, Belfast.

• Royal Victoria Infirmary, Newcastle upon Tyne.

• St James’s University Hospital, Leeds.

• Sunderland Eye Infirmary, Sunderland.

• Torbay Hospital, South Devon.

• University Hospital Southampton NHS Foundation Trust, Southampton.

• Wolverhampton & Midland Counties Eye Infirmary, Wolverhampton.

• York Hospital NHS Trust, York.

Participants

Randomisation

Randomisation was completed via a bespoke web-based randomisation system hosted at the King’s Clinical Trials Unit (KCTU) on a secure server (www.ctu.co.uk). Patients were randomised 1 : 1 at the level of the individual using the method of minimisation incorporating a random element. The minimisation factors were PDR status (naive PDR and non-naive PDR), HbA_1c level (< 8%, 8–10%, > 10%), diastolic BP (> 90 vs. ≤ 90 mmHg), BCVA (54–69 vs. ≥ 70 letters) and trial site. After informed consent was signed, a patient identification number (PIN) was generated by registering the patient on the MACRO electronic case report form (eCRF) system (InferMed Elsevier Macro v4.0, London, UK) and this PIN was used in the randomisation system. This unique PIN was also recorded on all source data worksheets and used to identify the patient throughout the study. Only authorised staff were allowed to log in to the randomisation system. Once a patient was randomised, the system automatically generated e-mails to key staff within the study. E-mails were also sent to site pharmacies to alert them to a patient’s treatment group – aflibercept or PRP therapy. The pharmacy department used this alert to cross-check the trial prescription to ensure that aflibercept was being dispensed for the correct patient. Additional e-mails were also generated from the randomisation system and sent to key trials staff, with or without treatment allocation information, depending on their role in the study.

Masking

The research optometrists were the primary outcome assessors and they conducted the visual acuity tests at screening, 12 and 52 weeks. They were masked to treatment allocation throughout the study. The optometrists received the participants into the visual acuity lanes with a visual acuity-specific source data worksheet that included the PIN and details of the study eye and non-study eye to be refracted, but with no previous records or case report forms by which the patient’s treatment arm could be identified. The optometrists also assessed the secondary outcome measure of contrast sensitivity and low-luminance visual acuity using the same technique of masking as above. At all other visits, visual acuity examiners were provided with a copy of the refraction log to conduct an open aperture visual acuity test in both eyes with the previous refraction. At these time points, visual acuity tests were also conducted by unmasked professionals and these data were not used for the primary outcome analysis. The other tests of secondary outcome measures, including visual fields and OCT scans, were performed by masked technicians. The technicians received the patients into the visual field and OCT room using the specific source data worksheet that provided details of the patient’s PIN and eye to be examined. After every visit, the completed source data worksheets were kept with the principal investigator’s team. The participants were also advised at enrolment that they must not discuss the study arm they were in with these assessors. The retinal photographs at screening, and at 12 and 52 weeks and FFA at screening and 52 weeks were graded by masked graders in the independent reading centres within the Network of Ophthalmic Reading Centres UK (NetwORC UK). The photographers were trained to take the photographs as per the standard operating procedures (SOPs) for this study. The graders in the Reading Centre were trained and quality assured to grade diabetic retinopathy based on the ETDRS grading system as required for this study. These masking procedures avoided both performance and detection bias.

Intervention

Intravitreal aflibercept (Bayer plc, Reading, UK) dosed at 2 mg/0.05 ml is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for wet age-related macular degeneration, DMO, retinal vein occlusion related macular oedema and myopic choroidal NV. Study eyes assigned to the aflibercept arm received an intravitreal injection of aflibercept 2 mg/0.05 ml at baseline, 4- and 8-week visits.

Patterns of regression

The treatment response was defined by degree of regression of retinal NV as assessed by colour photographs as per predefined SOP. The categories of regression patterns are summarised in Figure 1.

FIGURE 1.

Classification of patterns of regression. NVD, neovascularisation of the disc; NVE, neovascularisation elsewhere.

Week-12 retreatment

At 12 weeks, the patients were reviewed and categorised into three groups depending on treatment response to the first three injections. Figure 2 shows the retreatment plan at week 12 following first review of regression pattern.

FIGURE 2.

Retreatment plan at week 12 following the first review of regression pattern. NR, no regression; PR, partial regression; TR, total regression. Reproduced from Sivaprasad et al. 33 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

If an eye had experienced adverse effects from prior intravitreal injection, retreatment with intravitreal aflibercept was at the discretion of the investigator. In addition, if any future treatment with aflibercept was contraindicated based on a previous adverse reaction, treatment with PRP for PDR was at the investigator’s discretion after discussion with the chief investigator or his/her designee.

Week-16 to week-48 retreatment

All patients in the aflibercept arm were reviewed on a 4-weekly basis. From week 16, further treatment was determined by both regression and reactivation of NV on clinical examination with adequate visualisation of the entire retina and by comparing the four-field colour photographs or wide-field imaging carried out in the previous visit. The treatment responses were categorised into four groups (no regression, partial regression, reactivation and total regression) and the retreatment was based on the protocols shown in Figure 3.

FIGURE 3.

Summary of retreatment plan from week 16 to 48. NR, no regression; PR, partial regression; RAc, reactivation; RP, regression pattern; TR, total regression. Reproduced from Sivaprasad et al. 33 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

Reproduced from Sivaprasad et al. 33 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

Further fields of colour retinal photographs or FFA could be performed at any visit if there was any doubt that a clinical feature represented retinal NV.

Aflibercept injections were deferred if an eye had experienced adverse effects from prior intravitreal injection. In this circumstance retreatment with intravitreal aflibercept was at the discretion of the investigator. In addition, if any future treatment with aflibercept was contraindicated based on a previous adverse reaction, treatment with PRP for PDR was also at the investigator’s discretion. Treatment with aflibercept or PRP could also be deferred in cases of total vitreous haemorrhage with no clear view of the fundus until the fundus was sufficiently well visualised to permit subsequent intraocular injection, in an eye that developed a rhegmatogenous retinal detachment or required surgical intervention for tractional retinal detachment threatening the fovea. Aflibercept injections could be resumed following surgical repair. Aflibercept injections could also be deferred if the interval between visits was < 4 weeks or if the intraocular pressure remained > 30 mmHg despite apraclonidine (Iopidine 1%) eye drops. In such scenarios, the participant could be prescribed Iopidine eye drops for a week and rescheduled for aflibercept injection within 1 week if the intraocular pressure was < 30 mmHg. PRP was deferred in the aflibercept arm in the ‘no regression’ category if the medium was too hazy to allow PRP or if, in the opinion of the investigator, PRP was not deemed necessary at that visit.

Comparator

The comparator was PRP, the current standard of care. Patients in the PRP group were initiated on PRP, which was completed in fractionated 2-weekly sessions. From week 12, all patients in the PRP arm were assessed for treatment response every 8 weeks and categorised using exactly the same categories as the intervention arm (as shown in Figure 1). Figures 2 and 3 give the summary of further treatment in the PRP arm. PRP treatment could be carried out using any PRP delivery system including indirect PRP. If PRP had to be performed as a day-case it was not recorded as a serious adverse event (SAE) despite hospitalisation of the patient. PRP was deferred in the PRP arm if the medium was too hazy to perform the procedure or if, in the opinion of the investigator, the eye had received adequate PRP and there was insufficient space for further fill-in PRP.

Assessments

The study assessments for the aflibercept arm of the study are shown in Table 1 and for the PRP arm in Table 2.

The flow of patients in both arms of the study at the initiation of the trial are shown in Figure 4.

FIGURE 4.

Summary of flow of patients at screening/baseline. a, The number of sites was increased to 22 from 17 during the conduct of the trial as shown in the list of protocol amendments (see Table 4). CLARITY, clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy.

Data collection and management

It was the responsibility of the principal investigator at each site to identify the personnel responsible for data collection and handling, including those who had access to the trial database, and to ensure the completeness of the delegation log. All source documents were prepared in advance by the trial team and these forms were signed by the researcher who completed the assessments. The principal investigator at each site was also responsible for the accuracy of all data entered in the worksheets in accordance with good clinical practice and the Data Protection Act 199843, ensuring that the source data worksheets were filed in a suitably secure location to ensure that source data verification could be undertaken throughout the study. Source data worksheets were reconciled at the end of the trial with the patients’ NHS medical notes in the recruiting centres. During the trial, critical clinical information was written into patients’ medical notes to ensure that informed medical decisions could be made in the absence of the study team. Trial-related clinical letters were copied to the medical notes during the trial.

Randomisation and collection of data on completion at each visit were performed by the unmasked research staff. The randomisation details were e-mailed to the pharmacy, the delegated unmasked researcher, the principal investigator at that site and the UK trial manager. The study data were entered into a study-specific eCRF created in collaboration with the trial statistician and the chief investigator, and maintained by the KCTU using the InferMed MACRO database system hosted on a dedicated secure server within King’s College London [MACRO electronic data capture (EDC) V4 at www.ctu.co.uk]. This system was regulatory compliant, supported real-time data cleaning and reporting, and had data discrepancy functionality and database lock functionality. A series of logic and range checks were built into the system to reduce the possibility of erroneous data being entered. The system also contained an audit trail of all notable events associated with the trial (including inserts, updates and deletions) and this provided a clear and complete audit trail throughout the trial. The trial manager was responsible for providing usernames and passwords to permitted local study personnel. Only those authorised by the trial manager were able to use the system.

Monitoring and site visits

The first site visit was a prerecruitment visit for training of the protocol, adverse event reporting, MACRO and randomisation and data entry training and outline of good clinical practice. The optometrists were certified at Moorfields Eye Hospital. The trial photographers were certified by the Central Angiographic Resource Facility (CARF) or by Optos. The trial manager ensured that all relevant documentation and certifications were complete before a greenlight letter was sent to each site to initiate the study. All procedures were detailed in an operation manual. On-site monitoring visits were conducted routinely; more monitoring visits were arranged if problems were identified (e.g. poor data collection or under-reporting of primary end point data) or when a site requested a visit to discuss specific issues (including data collection, screening patients, recruitment and staff training). The main areas of focus included consent, SAEs, essential documents in study site files, and source data verification on selected outcomes including the primary outcome measure. A monitoring report was prepared after each monitoring visit and the points raised in the monitoring report were then addressed with sites remotely or at the next onsite monitoring visit. A data management plan and a monitoring plan were designed to ensure that the relevant data were monitored methodologically. In addition, the unblinded statisticians performed central statistical monitoring by reviewing event rates, unusual trends and data anomalies.

In addition, all adverse events and SAEs were monitored at each data monitoring committee meeting. All SAEs were also sent to the drug manufacturer (Bayer Plc, Reading, UK) and to the sponsor. The SAE data were collected on paper SAE report forms and faxed to the KCTU. Summary details of SAEs were also transcribed to the adverse event section of the eCRF.

The principal investigator provided an electronic signature for each patient case report form once all queries were resolved and immediately prior to database lock.

Multiple systematic approaches were therefore instituted to ensure that all outcome data were as accurate and complete as possible.

Outcomes

Mechanistic evaluation

1. To explore whether intravitreal aflibercept, compared with PRP, causes measurable regression of retinal NV at 12 and 52 weeks in terms of decimal disc area units in 4-field colour photographs and FFA: difference in means.

2. To explore differences in the mean change in retinal vessel calibre and oxygen saturation in eyes treated with intravitreal aflibercept compared with PRP at 12 and 52 weeks: difference in means.

3. To explore whether intravitreal aflibercept reduces angiographically quantifiable areas of retinal non-perfusion compared with PRP through 52 weeks: means and proportions.

Sample size calculation

The sample size calculation was performed using nQuery Advisor v4.0 software (Statistical Solutions, Saugus, MA, USA). The primary outcome is the change in BCVA ETDRS letter score from baseline to 52 weeks. Based on the objectives of this study and the potential deleterious effects on visual function of PRP, a non-inferiority margin of 5 letters was judged to be clinically acceptable. 17,33,34,51–53 In addition, this margin is less than the lower limit of the 95% confidence interval (CI) for the comparison of PRP with observation. This helped to ensure that aflibercept is superior to observation alone in the event that it was found to be non-inferior to PRP. In the wider patient population, if aflibercept was no more than 5 letters worse than PRP, it would therefore be defined as being non-inferior. The sample size was based on providing a 95% CI for the between-arm difference in mean change in visual acuity that would be sufficiently narrow to detect non-inferiority (by the CI lying entirely above the margin) with high power, while keeping a false declaration of non-inferiority to 5% through use of a statistical test applied at the two-sided 5% level of significance.

The standard deviation (SD) of the change in visual acuity, after adjustment for baseline, was estimated to be 10.3, based on a relevant trial. 54 There was no issue of clustering of outcomes from eyes within subject effects because only one eye per subject was selected for the study.

With 110 patients (one eye per subject) randomised per group (total 220 patients), 182 had to be followed up to 52-week outcome [allowing for 17% dropout or per protocol (PP) exclusion]. This provided 90% power to detect non-inferiority using a two-sided 95% CI from an analysis of covariance (ANCOVA) test with adjustment for baseline visual acuity.

For a continuous secondary outcome, with 182 subjects followed up, we can detect effects of size 0.42 SDs difference between means with 80% power using a two-sided t-test at the 5% significance level. For binary outcomes, we had at least 77% power to detect a difference in proportions of 0.2 using a chi-squared test at the 5% significance level.

Collection and analysis of outcome data

Analysis covariates

Stratifiers

Covariates were predefined according to the International Conference on Harmonisation (ICH) E9 guideline, which recommends considering factors on which randomisation has been stratified as these factors tend to be predictive of outcome, and therefore the need for adjustment of the minimisation stratifiers. 55 Randomisation stratifiers as shown in Figure 5, as covariates were planned to improve the precision of the estimated treatment effects.

FIGURE 5.

Randomisation stratifiers.

Primary outcome analysis

Intention-to-treat strategy

Outcome data were valid and included if the BCVA measure was refracted. All randomised subjects who provide at least one post-baseline valid measurement were included.

The achieved trial sample comprised those study participants who consented to participate and were actually randomised into this trial. This randomised trial sample was also the trial intention-to-treat (ITT) population. The ITT principle states that every subject will be analysed according to the treatment group to which they were randomised. In this trial, subjects’ data were analysed in accordance with Intention to Treat Strategy,58 under which at least one analysis is recommended to be based on the ITT population.

The trial ITT population comprised all randomised participants, regardless of eligibility (inclusion/exclusion) error, post-randomisation withdrawal, and whether the correct study treatments or other interventions were received. On 20 November 2015, The Data Monitoring and Ethics Committee (DMEC) discussed the circumstances under which the BCVA score at either 12 or 52 weeks would not reflect the underlying visual status of a participant. In particular, recent vitreous haemorrhages that might cause low BCVA scores which would then return to normal for the patient, either spontaneously or through appropriate clinical management (vitrectomy), were discussed. The challenge was that any such measurements occurring at week 12 or 52 could artificially induce very large negative changes in BCVA which would have enormous influence in statistical analysis – specifically by leading to very large inflations in the standard deviation for the change from baseline. This could have profound implications for the ability of this non-inferiority trial to achieve its objectives, which rely on the 95% CI for the difference between randomised groups in the change from baseline falling within prespecified bounds (the non-inferiority margin). As such values do not intrinsically reflect the underlying visual status of the patient, the DMEC proposed that the trial steering committee (TSC) consider amending the primary analysis population to exclude from analysis any BCVA measurement at 12 or 52 weeks, that is both > 3SD below the mean at that timepoint (including all measurements) and taken within 3 months of occurrence of a vitreous haemorrhage. Endophthalmitis was also considered as a comparable cause (to vitreous haemorrhage), but, as this is rare and unlikely to occur in a trial of this size, the definition of primary outcome analysis measurements had not encompassed this. The absolute number of measurements excluded was expected to be small.

Per-protocol analysis

For the analysis of the primary outcome, the mixed-effects models were refitted in a reduced PP population, excluding patients found to be ineligible at entry, those patients who received the alternative treatment to that allocated up to the end point, and those not receiving at least the minimal randomised treatment up to and including the 8-week visit (whether because of discontinuation, exclusion or another reason for missing a randomised treatment in this period). This was prior to the point of treatment stratification from the 12-week visit, which included a stratum for patients who required no further treatment.

Superiority

If non-inferiority was concluded, superiority was planned to be assessed from the ITT LME model by reporting the p-value from the two-sided test of the hypothesis of a zero difference in population means using a 5% significance level without need for correction for multiple testing.

Subgroup analysis

Subgroup analysis was performed by baseline retinopathy status (naive and non-naive PDR), HbA_1c (< 8%, ≥ 8% to ≤ 10% and > 10%), diastolic BP (≤ 90 mmHg vs. > 90 mmHg) and BCVA (54–69 vs. ≥ 70 letters). The p-value for the between-subgroup comparison of effectiveness was obtained from the ITT LME model from the interaction between arm and the subgroup variable at 52 weeks. The treatment effect and associated 95% CI were reported within each of the categories of the subgroup variable.

Sensitivity to missing data

An expert missing-data group concluded that, rather than statisticians reacting to missing data at the end of a trial, there should be comprehensive, proactive planning for handling missing data at the stage of designing trials. 63 The group recommended that there should be consideration of missing data mechanisms (e.g. missing at random) and, if the missing data may be informative, that appropriate sensitivity analyses should be undertaken to investigate the robustness of the inferences to the different assumptions made by the main analysis. It has also been recommended that analyses allowing for non-response and low intervention uptake (or compliance) are best specified in advance and included in the analysis plan. 64 As it was expected that compliance would be high from the fear of loss of sight, and as non-inferiority is concluded only when declared in both a compliant PP population and a less compliant ITT population, the focus was on the handling of missing data.

The main reasons for dropout in this study were thought to be related to patients’ comorbidities, such as hypertension and hyperlipidaemia, and less connected with underlying visual acuity. Such reasons mean that dropout may not depend on visual acuity and, as data on BP and HbA_1c were collected, it was possible to explore the association between these data and dropout to improve the interpretation of the sensitivity analysis results. The primary outcome of refracted BCVA was collected only at two post-baseline measurement points, and there were limited serial data. Nevertheless, as described in Sensitivity analysis to use of concomitant treatments, a sensitivity analysis was undertaken to assess the possibility of alternative plausible values of treatment effect arising from potential mishandling of missing data in the primary analysis model.

The LME model for the primary outcome analysis described above was the first of a two-part approach called the intention-to-treat strategy,64 in which a second analysis examined the sensitivity of the results to missing data in the full randomised ITT population. This met the ideal objectives of ITT. The approach to missing data taken for this study followed the recently published implementation paper of the ITT strategy. 62 The few cases with values that were affected substantially to become unrepresentative temporarily because of vitreous haemorrhage were included among the measurements with missing visual acuity data. This approach was then also applied again to the PP population so that the non-inferiority conclusion could be reassessed under the sensitivity analysis.

For the sensitivity analysis, we prespecified a range for BCVA from –20 to +20 letters over which the mean of the ‘unobserved outcome data’ might depart (or be different) from the mean of the ‘observed outcome data’. 62 In other words, this range can be thought of as how much a typical subject with missing data may on average have had a different estimated treatment effect from the corresponding subject with the outcome data observed (given the same baseline covariates and follow-up data in the LME model). The range (–20 to +20) was chosen to represent both negative and positive departures that could potentially arise as the ‘net effect’ of alternative reasons that may be unknown, such as dropout because of no anticipated further improvement or dropout because of no improvement so far together with no anticipated achievable improvement.

This range of 40 letters (from –20 to +20) was generously wide for exploring sensitivity of the main results to departures from the missing at random (MAR) assumption because 20 letters (as the maximum departure in either direction) is larger than the detectable between-arm treatment effect of 3 lines (15 letters) seen in superiority trials (difference in means), a sizeable shift in the mean of the distribution for dropouts than completers.

At the end of the trial, the fractions of individuals with missing data for visual acuity at 52 weeks were available in each arm: f_i (for intervention) and f_c (for control). The parameter representing excess visual acuity in those missing compared with those observed, δ, took values by passing across the range –20 to +20. Three scenarios were undertaken within the sensitivity analysis. 61,62 These reflected whether departures from the MAR assumption applied within the intervention arm only (aflibercept), within the comparator arm only (PRP) or within both arms equally and in the same direction (thereby potentially cancelling out across the sensitivity range, if the dropout rate were to be the same in both arms).

Scenario 1: the treatment effect from the LME model will be increased by f_iδ.

Scenario 2: the treatment effect from the LME model will be increased by –f_cδ.

Scenario 3: the treatment effect from the LME model will be increased by (f_i – f_c)δ.

Sensitivity analysis to use of concomitant treatments

The use of concomitant treatments was monitored by the DMEC. A sensitivity analysis was not undertaken to examine the robustness of the 52-week PP analysis to the use of concomitant treatments as there were none.

Secondary outcome analysis

Missing items in scale and subscales

The number (%) of patients with complete data for each scale was reported. If scales provide, missing value guidance was used.

Use of data transformation

It was not anticipated that any continuous outcomes would need to be considered for transformation, because the sample size was reasonably large for group comparisons in the main trial analyses. Assumptions of normality and constant variance required by the models were examined using residual and other diagnostic plots. If relevant, and necessary (e.g. in the mechanistic evaluation where sample size is reduced) a log-transformation could be considered, because this retains a sensible interpretation for inferences in relative terms between arms. If an absolute interpretation was needed then data transformation would not be undertaken; instead, a non-parametric bootstrap method for obtaining CIs was considered. 65 For the mechanistic evaluation, non-parametric methods were also considered.

Defining outliers

Outliers are observations that have extreme values relative to other observations detected under the same conditions. An outlier was defined here as a data point at least 4 SDs from the mean of its distribution of values observed across other patients. This definition was applied to the transformed scale for those outcomes that were log-transformed.

A ‘bivariate outlier’ was defined here as the difference between successive serial data points of the same measure being at least 4 SDs from the mean of these differences. Simple plots of successive pairs of serial measures were used through the 24-month period to assist in identifying outliers.

Handling outliers

Outliers were identified for further investigation by looking at the distributions of the data through histograms, scatterplots or box plots. Univariate tests for the compatibility of the distribution with a normal distribution were not undertaken since they can be too sensitive to departures that are often not relevant for the comparison of means (the central limit theorem).

Once an outlier was found, a blinded member of the team with sufficient clinical experience was involved in the decision as to whether a data value was impossible versus implausible versus plausible. If the outlier was impossible it would be set to missing and a list of these occurrences then appended to the statistical analysis plan. If an outlier was clinically plausible, the outlier remained. If an outlier was clinically implausible (but possible), it was not ignored or deleted and was retained for ITT analysis.

If outliers remained in the distribution of a variable then data transformations or non-parametric methods of analysis were considered.

Sensitivity analyses were undertaken to check whether the outlier was influential by obtaining results with and then without the inclusion of the outlier. If the conclusions were changed, these were documented.

Analysis methods for secondary outcomes

All study analyses were based on tests that are two-sided, including the two-sided 95% CIs assessed at the 5% significance level. Table 3 shows the method of analysis chosen for each secondary measure.

Handling multiple comparisons

Significance tests were used sparingly and were restricted, where possible, to addressing stated hypotheses. Secondary outcomes, as well as the primary outcome, were summarised using an effect size with a 95% CI. Interpretation for those secondary outcomes that did not directly address the stated study hypotheses was more cautious.

Ethics approval and monitoring

The study was granted approval by the National Research Ethics Committee Service London – South East (14/LO/0203). Clinical Trials Authorisation was given by the MHRA (11518/0013/001-0001) and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) number was 2013-003272-12. The trial was run using the SOPs of the sponsor, Moorfields Eye Hospital NHS Foundation Trust. The sponsor provided the oversight of the study and the KCTU collaborated with the sponsor to ensure efficient delivery of the study. The trial had two committees overseeing its conduct: the TSC and the Trial Management Group (TMG). In addition, there was an independent DMEC to ensure the safety of patients in the trial and review operational issues such as recruitment. The membership of the DMEC is provided in the Acknowledgements.

The DMEC was the only group to review interim analyses broken down by treatment groups during recruitment and follow-up of patients in the trial. The DMEC performed interim safety analyses. The interim reports contained details of patient recruitment, demographic and baseline characteristics, the intervention, primary safety end points, the primary efficacy end point and other end points identified by the DMEC including adverse events and SAEs.

The TSC consisted of four independent members, two lay members and key members of the TMG, in addition to clinical and methodological experts. The membership of the TSC is provided in the Acknowledgements. The TSC had overall responsibility for the scientific integrity and quality of the trial. This involved conducting the trial to the standards set out in the guidelines for good clinical practice, adhering to the protocol as far as possible and holding responsibility for overall patient safety, as well as considering new relevant information as it arose throughout the duration of the trial. The TSC was also responsible for considering any recommendations made by the DMEC. The TSC met throughout the trial to monitor the progress and qualities of the trial (review the recruitment rate and consider protocol amendments). The TMG was responsible for the day-to-day running of the trial, meeting fortnightly during the setting up of the clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (CLARITY) trial and the early stages of recruitment and then approximately monthly for the remainder of the trial. This group consisted of the chief investigator, co-lead, trial manager, research fellow, statisticians, sponsor representative, data manager and the KCTU operations manager. The role of the TMG was to monitor the conduct and ensure progress of the trial according to the study protocol and to take appropriate action to safeguard participants and the trial itself.

Patient and public involvement

The study design, patient information sheets and consent forms for the main trial and mechanistic substudy were discussed with the North East London Diabetes Research Network patient and public involvement group, who provided feedback and support for the study. A user representative was a grant co-applicant and two other user representatives were members of the TSC and as part of this role made suggestions for the use of laser instead of PRP to describe the comparator.

Reporting

The trial was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement.

Summary of changes made to protocol

Table 4 summarises the changes made to the protocol. In addition, the statistical analysis plan was amended after publication of the protocol. Version 5.0 was amended to version 5.1 as a result of the DMEC meeting held on 3 November 2015, in open session, and the DMEC recommendation to the TSC, accepted at the TSC meeting on 20 November 2015.

The TSC requested confirmation that vitreous haemorrhage will be reported as an outcome by arm, and this has been confirmed to be present in Table 3; the number of measurements excluded from the analysis, by arm, will be reported.

Version 5.1 of the protocol was amended to version 5.2 as a result of the DMEC meeting held on 4 October 2016.

It was decided that study site should be taken out of the primary and secondary outcome LME and ANCOVA models as a covariate since the models would be parameter-heavy with as many as 22 sites having recruited, and where some sites have only included one or a few patients who, at follow-up, could contribute to estimating site rather than to treatment effect. For transparency, sites will then be added as a covariate in a sensitivity analysis. In response to a query by the principal investigator, it was clarified, in the open session of the DMEC meeting, that the actual categorised baseline values of stratifying covariates, rather than those used in the randomisation, which included errors, will be used in the outcome models, so that any baseline confounding by these is more fully adjusted for, and analyses are consistent with subgroup analyses using the same categorisations of these covariates. There was agreement for this approach as the trial employs minimisation. The outcome ‘A small number of summary measures will be calculated and reported to represent the pattern and frequency of randomised treatment received over time’ was added as a process outcome.

Trial milestones

Study start date was August 2014 and was planned to involve 17 recruiting sites around the UK. The sample size was 220 participants. The eligible patients were identified from the medical retina clinics. New patients were also referred in from the diabetic retinopathy screening programmes. As these patients had to be seen in retinal clinics within 2 weeks of referral and treated within 4 weeks, it was necessary for the trial team to communicate well with the referral team to ensure that these patients were identified before they were treated with PRP in the clinic.

Success in trial recruitment and management

The National Institute for Health Research (NIHR) recognises the need for good trial management and recommends that a clinical trials unit collaborate in the conduct of the study. A multidisciplinary team at the KCTU was funded for the study. As a collaborator on the CLARITY study, the unit ensured the appointment of a dedicated trial manager – a crucial step for the success of this study. The KCTU also has a trial methodologist, data manager, operations manager and statisticians who met with the chief investigator, co-lead and the trial manager for initial brainstorming sessions and then on a regular basis to ensure the smooth running of the study. This group approach and shared ownership were very useful in the successful delivery of the study. During the early part of the set-up phase of the study, the team met often to develop the protocol, obtain all the regulatory approvals and prepare the IMP delivery system. The study source documents and case report forms were user-friendly and we paid significant attention to detail in order to capture all of the required outcome measures. Following the approvals, meetings focused on targeting and solving barriers to site set-up, identifying and managing recruitment hurdles and monitoring recruitment. During these meetings, we evaluated the reasons for initial delay in recruitment.

The start-up delays at some sites were associated with the following:

• delay in completion of training and certification of the staff for the study

• IT system delay

• lack of approved devices to do the study assessments

• delay in site approval process

• patients being treated with PRP at first attendance itself to maintain national time to treatment target

• patients referred from diabetic retinopathy screening programmes not being targeted

• other retinal consultants preferred standard of care to intervention

• research team and clinical team were not at the same area and so patients were being missed.

Recruitment strategies used

The target recruitment rate for the study was one to two patients per month per centre, based on the original 17 centres recruiting and a target recruitment figure of 220. We decided to open five further recruiting centres to counteract initial slow recruitment. We made no changes to the inclusion criteria and the recruitment time was not extended.

The trial management meetings enabled us to pay attention to the trial pathway and ensured that all barriers were tackled in time as we progressed. The trial manager and the chief investigator were always available to provide guidance and support to the clinical sites. The sites were chosen based on previous clinical trial experience or by the estimated volume of potentially eligible patients. Interested sites completed a site feasibility questionnaire. Some sites required support from the UK Clinical Research Network to be able to recruit patients for the study.

Recruitment was monitored closely. We sent out a recruitment league table in a newsletter to all sites every month initially so that the sites were aware of the progress of the study. The chief investigator also e-mailed or telephoned the principal investigators of clinical sites that were recruiting below target. The trial manager had to travel to all sites to monitor the study at the sites.

Screening and eligibility

A total of 290 patients were assessed for eligibility. Of these, 58 were excluded either because they did not meet the inclusion/exclusion criteria (n =  51) or because they were not eligible or not keen (n =  7). The remaining eligible patients (n = 232) were randomised into the trial.

Randomisation

A summary of the recruitment and randomisation across the 22 sites has already been detailed in Table 5. Randomisation was balanced across the treatment groups and hospital sites, and within strata.

Withdrawals

Table 6 shows the numbers of participants who did not complete week 52 in both arms. In total, 21 out of 232 (9.1%) did not complete week 52: 9 from the aflibercept arm and 12 from the PRP arm. Table 7 shows the time to withdrawal and reason for withdrawal, for all patients. The withdrawals were requested by the participants themselves. The withdrawals were balanced between arms.

Baseline characteristics

Baseline characteristics were well balanced between treatment groups, as shown in Table 8. A total of 123 (53%) treatment-naive and 109 (47%) non-naive patients were recruited. Mean baseline BCVA was 81.4 (SD 8.1) ETDRS letters. The proportion of patients with baseline BCVA 54–69 and ≥ 70 ETDRS letters was 9% and 91%, respectively. Table 9 shows the baseline BCVA.

The trial flow

The CONSORT flow diagram (Figure 7) shows the participant flow through the study period.

FIGURE 7.

Participant flow through the study period. 66 a, ITT population included in the sensitivity analysis. Reprinted from The Lancet, Vol. 389, Sivaprasad S et al. ,66 Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial, pp. 2193–203, © 2017, with permission from Elsevier.

Reprinted from The Lancet, Vol. 389, Sivaprasad S et al. ,66 Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial, pp. 2193–203, © 2017, with permission from Elsevier.

Derivation of the intention-to-treat model and per-protocol populations

Patients included in the prespecified ITT LME model were derived as follows:

1. The BCVA data were available for 211 patients of 232 randomly assigned patients (n = 107 in the aflibercept arm and n = 104 in the PRP arm) at 52 weeks and for 214 patients at 12 weeks (n = 109 in the aflibercept arm and n = 105 in the PRP arm).

2. A total of four patients in the PRP arm at 12 weeks and two patients in the aflibercept arm at 52 weeks were excluded because of the presence of vitreous haemorrhage within 3 months of BCVA recordings and BCVA was more than 3 SD below the mean at that time point (including all measurements).

3. There were 198 patients with BCVA available at both 12 and 52 weeks. A total of 11 patients had BCVA recorded at 52 weeks and not 12 weeks (n = 8 in the PRP arm and n = 3 in the aflibercept arm). In addition, there were 12 patients who had BCVA recorded at 12 weeks but not at 52 weeks (n = 5 in the PRP arm and n = 7 in the aflibercept arm).

4. There were therefore 221 patients who contributed to the analysis in the LME model for the ITT strategy (n = 109 in the PRP arm and n = 112 in the aflibercept arm).

5. A total of 18 patients did not meet the PP definition and were not included in the PP population (n = 214). This included 11 (9.5%) patients in the aflibercept arm and 7 (6.0%) in the PRP arm, with 4 patients in the aflibercept arm and 4 in the PRP arm not being compliant with the eligibility criteria and a further 7 patients in the aflibercept arm and 3 in the PRP arm not receiving initial mandatory treatment requirements. There were therefore 210 patients who contributed to the PP analysis in the LME model (n = 106 in the PRP arm and n = 104 in the aflibercept arm).

Primary outcome

The primary outcome at 52 weeks showed that aflibercept was both non-inferior and superior to PRP in terms of BCVA in both ITT and PP populations (Table 10 and Figure 8). The 95% CI for the adjusted difference between arms fell both above the prespecified acceptable non-inferiority margin of –5 letters and above the superiority margin of 0 letters, at both 12 and 52 weeks.

FIGURE 8.

Primary outcome at 52 weeks (ITT and PP).

Three sensitivity analyses on the population with completed follow-up at 52 weeks were carried out, adjusting for sites, outliers and missing data. No patients were offered anti-VEGF treatment for macular oedema in the PRP arm so sensitivity analysis for concomitant treatments was not required. When sites were considered, the adjusted difference in BCVA between arms remained significant at 4.1 letters (95% CI 2.4 to 5.7 letters; p < 0.0001) and 4.1 letters (95% CI 2.4 to 5.7 letters; p < 0.0001) in the ITT and PP populations, respectively. A total of 207 and 198 patients remained after outliers in the ITT and PP populations, defined as less than or more than 4 SDs, were removed. This sensitivity analysis showed the adjusted difference in BCVA between arms as significant at 4.0 letters (95% CI 2.7 to 5.4 letters; p < 0.0001) in the ITT and 4.1 letters (95% CI 2.7 to 5.5 letters; p < 0.0001) in the PP population. The sensitivity analysis for missing data also confirmed a superiority effect in both ITT (n = 232) and PP populations (n = 214) for three prespecified alternative scenarios.

The primary outcome was also analysed at 12 weeks and the superiority of aflibercept was noted as early as 12 weeks in both the ITT and PP population (Figure 9).

FIGURE 9.

Visual outcome at 12 weeks in the (a) ITT population; and (b) PP population.

Subgroup analysis of BCVA in both the ITT and PP populations at 52 weeks was carried out based on the baseline PDR status and HbA_1c categories (Table 11).

Table 12 shows the change in BCVA in patients categorised into diastolic BP > 90 mmHg versus those ≤ 90 mmHg. There was no significant difference in BCVA outcome between patients who presented with BCVA 54–69 letters than those who presented with 70 letters or better.

Secondary outcomes

The proportion of patients with a ≥ 10-letter improvement and able to do so with a baseline BCVA of ≤ 90 was 5% (5/101) in the aflibercept arm compared with 2% (2/95) in the PRP arm (difference between arms was 2.8%, 95% CI –3.1% to 9.1%; p = 0.45). The proportion of patients with a ≥ 10-letter worsening was 5% (5/107) in the aflibercept arm compared with 15% (16/104) in the PRP arm (difference between arms was 10.7%, 95% CI 2.6% to 19.3%; p = 0.009). There were 5% (5/107) of patients with a ≥ 15-letter worsening in the aflibercept arm and 6% (6/104) in the laser arm (difference between arms was 1.1%, 95% CI –5.5% to 7.9%; p = 0.72) (Figure 10).

FIGURE 10.

Best corrected visual acuity (≥ 10 letters) improvement and worsening at week 52.

Binocular Esterman scores showed significant worsening in the PRP arm. This was also reflected in lower binocular visual acuity scores in the PRP arm. Other visual function tests did not vary between arms. Table 13 shows changes in visual function between baseline and week 52.

The NEI-VFQ-25 scores did not show significant differences between arms (Table 14).

The RetTSQ scores showed that patient satisfaction scores were significantly better in the aflibercept arm and the adjusted mean difference was 3.0 (95% CI 0.4 to 5.5; p = 0.022). There are no thresholds for clinically meaningful change for the RetTSQ. 67 However, in the validation of the RetTSQ a three-point difference was observed between those with very good visual acuity and those in the category below (five-category visual acuity variable). 38 The quality-of-life change assessed using RetDQoL did not show any difference between arms (Table 15).

Anatomical outcomes

Macular thickness and volume (Table 16) significantly increased in the PRP arm compared with the aflibercept arm. The proportion of patients with new-onset centre-involving macular oedema also increased significantly in the PRP arm.

The proportion of patients with macular oedema at 52 weeks assessed by the clinical investigator was significantly higher in the PRP arm than in the aflibercept arm (Table 17).

Treating investigators determined regression and reactivation patterns of retinal new vessels to decide retreatment based on predefined criteria. Table 18 shows the proportion of patients with each regression pattern in each arm.

A significant proportion of eyes showed total regression of retinal new vessels in the aflibercept arm compared with the PRP arm. The difference in proportions of total regression favouring the aflibercept arm was 30% (95% CI 16% to 42%; p < 0.0001) at 52 weeks.

NetwORK UK, masked to treatment allocation, graded ETDRS diabetic retinopathy severity scores from colour fundus photographs obtained at baseline, 12 weeks and 52 weeks. 14 Of patients with gradable photographs (n = 227), 175 (77%) were graded low-risk PDR (levels 61 and 65) and 52 (23%) high-risk PDR (levels 71 and 75). Three eyes were graded below level 61. Improvement from diabetic retinopathy severity score is difficult to assess in lasered eyes and so the improvement of the level of remaining retinopathy was graded. A significantly higher proportion of patients in the PRP arm remained at PDR (level 61 or above) than in the aflibercept arm at both 12 and 52 weeks.

Treatment outcomes

The proportion of patients who received treatment in accordance with protocol was 94% (109/116) in the aflibercept arm and 97% (113/116) in the PRP arm. The treatment allocation guess form, which measures the success of masking of primary assessors to treatment allocation, was reported for 210 participants. Assessors guessed correctly for 15% (32/210), incorrectly for 10% (20/210), and were unable to tell for 75% (158/210) of participants.

By 52 weeks, aflibercept arm patients received a mean (SD) of 4.4 (1.7) injections (95% CI 4.1 to 4.7) [median (IQR) 4.0 (3.0 to 5.0)] including the three mandated loading doses. The mean number of aflibercept injections in treatment-naive patients was 4.6 (1.6) [median (IQR) 4 (3.0 to 6.0)] while non-naive patients received a mean number of injections of 4.1 (1.8), [median (IQR) 4.0 (3.0 to 4.8)]. A total of two (1.6%) patients required supplemental PRP in the aflibercept arm.

In the PRP arm, 78 (69%) received multispot laser and the remaining received single-spot laser. The type of laser delivery was not recorded for three patients. From week 12, 75 patients (65%) in the PRP arm required supplemental PRP.

Safety outcomes

A breakdown of the ocular adverse events reported is shown in Table 19. Trials such as CLARITY are not designed to detect reasonably small effects in secondary safety outcomes because adverse events are typically sparsely categorically distributed and sample size is set to provide power instead for the primary outcome. The ratio of false-positive significant findings to genuine significant findings is consequently larger than for primary outcomes. We therefore use p-values as a guide only, with caution, and we use 95% CIs whose width demonstrate the extent of the lack of information around the effects between arms in adverse event rates. Twice as many patients in the PRP arm (18%) developed vitreous haemorrhage as patients in the aflibercept arm (9%; p = 0.034). This 9% higher PRP rate had a wide 95% CI from 1% to 18%. The percentage of patients requiring vitrectomy was 6% in the PRP arm compared with 1% in the aflibercept arm (p = 0.066). This 5% higher PRP rate had a 95% CI from –0% to 11%. Later phase trials may be helpful to validate these results and to add to the body of safety evidence around these and other preliminary safety event results. There were no cases of NVI, NVA or NVG in either eye observed in a study of this size, where absence of evidence (low rates) means that there is low precision in estimated rate differences; this would be ameliorated for study treatments taken forwards in larger and longer later phase trials. There were no cases of endophthalmitis in the study. Table 20 shows the frequency of non-ocular adverse events in both groups. Twice as many patients in the aflibercept arm (n = 8) had APTC-defined events than in the PRP arm (n = 4), representing a 3% excess (Table 21). This was not statistically significant (p = 0.25) and the 95% CI for the between-arm difference was –3% to 10%. Three patients died during the trial (two in the aflibercept arm and one in the PRP arm).

Pregnancy

Two trial participants in the aflibercept arm and three in the PRP arm became pregnant despite being advised on double contraception. One patient’s partner became pregnant in the aflibercept arm (Table 22). Aflibercept was stopped in both the patients who were randomised to aflibercept, but none of them required supplemental PRP during the trial. The patient whose partner became pregnant did not need further treatment as per retreatment guidelines. All pregnancies were followed up after the trial and there were no adverse events reported among the mothers or babies.

Background

In this project, aflibercept was evaluated as an alternative treatment to PRP in PDR without macular oedema. The clinical efficacy results showed that aflibercept is superior to PRP in terms of visual acuity change at 52 weeks. In this chapter, we report the economic evaluation of aflibercept as a treatment option for PDR.

Objective

Drawing on the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist,68 we report cost-effectiveness of intravitreal aflibercept compared with PRP.

Methods

Results

Cost-effectiveness analysis

In our primary cost-effectiveness analysis using BCVA as our measure of outcome, we divided the difference in mean adjusted total cost between arms by the difference in mean adjusted change in BCVA between arms to gain an ICER of £1392.99 for aflibercept as compared with PRP laser treatment. Figure 11 is a cost-effectiveness plane, a scatterplot of the joint distribution of incremental cost and effect (BCVA) between the two arms. Figure 11 shows the 5000 bootstrapped replications used to generate a 95% CI around our mean point estimate ICER. All bootstrapped points appear in the north-east quadrant (more effective but more costly) of our cost-effectiveness plane. Accompanying this plane is a CEAC (Figure 12) that shows that at the threshold of £1400, our hypothetical societal willingness to pay, there is a probability of 56.60% of aflibercept being cost-effective at its list price of £816.

FIGURE 11.

Cost-effectiveness plane: using BCVA as the measure of effectiveness.

FIGURE 12.

Cost-effectiveness acceptability curve.

Objectives

1. To explore whether intravitreal aflibercept compared with PRP causes measurable regression of retinal NV at 12 and 52 weeks in terms of decimal disc area units in 4-field colour photographs and FFA: difference in means.

2. To explore differences in the mean change in retinal vessel calibre and oxygen saturation in eyes treated with intravitreal aflibercept compared with PRP at 12 and 52 weeks: difference in means.

3. To explore whether intravitreal aflibercept reduces angiographically quantifiable areas of retinal non-perfusion compared with panretinal photocoagulation through 52 weeks: means and proportions.

Participants for the mechanistic study

The mechanistic substudy was carried out on 40 patients recruited at Moorfields Eye Hospital. These patients also underwent retinal oximetry in addition to the other study assessments carried out at baseline, 12 and 52 weeks. A total of 20 patients were in the aflibercept arm and 20 were in the PRP arm. A total of 20 patients were treatment-naive and 20 patients had been previously treated with PRP but had persistent new vessels at baseline.

Retinal oximetry

Retinal oximetry was performed using the retinal oximeter (Oxymap T1 device connected to Topcon TRC50-DX fundus camera; Oxymap ehf., Reykjavik, Iceland). 78

The retinal oximeter consists of a fundus camera with an attached image splitter as well as a digital camera that captures images at two wavelengths, 605 nm and 586 nm. Optical density is sensitive to oxygen saturation at 605 nm but not at the reference wavelength of 586 nm. The oxyhaemoglobin saturation (SO₂) of a vessel can therefore be calculated because the optical density ratio at these wavelengths has been shown to have an approximately inverse linear relationship with SO₂. Although the saturation data are not absolute, the oximeter has been shown to give reproducible results and to be sensitive to changes in oxygen saturation. The comparison of data in the same eye before and after treatment is therefore valid. 79

Optic disc-centred images were captured through dilated pupils. The images obtained were 1200 × 1600 pixels and covered a 50° field of central retina. The images were captured for both eyes but only the study eye was used in this analysis. Images were analysed by two independent observers (Luke Nicholson and Roxanne Crosby-Nwaobi) using the Oxymap Analyser software (Oxymap ehf., Reykjavik, Iceland) version 2.5, which automatically detects vessels > 8 pixels in diameter. The area analysed was selected by centring quadrant lines on the optic disc. An initial central circle was used to delineate the optic disc. Two additional measurement circles, an inner and outer circle, two and four times the diameter of the central circle, respectively, were then demarcated. The area between the circles centred on the optic disc was analysed. The width of this ring was two disc diameters (DDs). Vessels beyond the area of analysis, certain areas where vessel detection would prove inaccurate (branching, overlapping or intersecting) and segments of vessels < 19 pixels in length were excluded. Vessels to be measured were selected manually. Measurements were first taken to yield arteriolar SO₂ (SaO₂) by quadrant. This was repeated for venules to yield venular SO₂ (SvO₂) by quadrant. Overall saturation was computed by averaging saturation values of each quadrant. Because Oxymap software measurements are calibrated to non-diabetic young individuals, results are relative to that calibration, occasionally resulting in SO₂ measurements > 100%. These values were not truncated to 100%, per established oximetry protocol. The retinal oximetry data streams were extracted from the source data file. The data streams underwent multistep preprocessing to eliminate missing or invalid data. The data were inspected for (1) interrupted regions of the recording (as noted in the research record) and (2) regions where it was not able to properly measure saturations. The entire data epoch was rejected if the data stream failed one or more of these checks or if continuous measurements were not available. Data collected from the Oxymap software included the mean oxygen saturation in the identified segments of first and second branch retinal arterioles (SaO₂) and venules (SvO₂) within 0.5–1.0 optic DDs from the disc margin, and their difference, the Sa – vO₂. The mean arterial and venous diameters were also recorded.

Ultrawide field colour fundus photography

All 40 patients underwent CFP and fluorescein angiography using the Optos 200TX (Optos Plc, Dumfermline, UK) ultrawide field system.

The 200° images were captured with steering, that is aligning images with three axes, eyes looking at centre, superiorly and inferiorly. The pattern of vessel regression was assessed by one investigator (JR) and confirmed by a second investigator (SS or LN) (Table 32).

Ultrawide field fundus fluorescein angiography

The FFA images were acquired after intravenous bolus infusion of 5 ml of 20% fluorescein sodium. The images were acquired at transit phase (up to 45 seconds), arteriovenous phases (3–4 minutes) and late frames at 5–7 minutes. A single investigator (LN) identified the best macular-centred fluorescein angiography (FA) image in the arteriovenous phase from the FA series of each eligible eye. A correction factor was applied for the flattening of the three-dimensional image to a two-dimensional image using the Optos V2 Vantage Pro software (Dunfermline, Scotland). Capillary non-perfusion was defined as an area of the capillary network that failed to fill with fluorescein by the late arteriovenous phase, with minimum linear dimension of at least 63 µm (width of a retinal venule at the disc margin).

In order to assess spatial location and quantity of non-perfusion and area of new vessels, a concentric rings template was applied to each image in accordance with previously described methods. 80 In brief, this validated method incorporates a macular ring with a radius of 2.5 DDs and five additional concentric rings (rings 1–5), each with a 2.5-DD increment in radius. Each of the six rings (ring M and rings 1–5) was divided into 12 segments. Each segment is graded as ungradeable, not perfused or perfused (if ≥ 50% of the segment is involved). In addition to quantifying non-perfusion, the concentric rings method allows documentation of location of non-perfusion. The area of each cell in each concentric ring was modified based on the enlargement factor identified using 3D printed model eyes. 81 The enlargement factors for rings M, 1, 2, 3, 4 and 5 were 1.08, 1.20, 1.34, 1.54, 1.81 and 1.97, respectively. The modified area of each segment in each ring is represented in Table 32.

Statistical analysis

The oximetry measurements, new vessel area and area of retinal non-perfusion were described using means and SD at cross-sectional time points within each arm, and the change from baseline to follow-up time points in each arm was estimated by the mean change and its standard error (SE). The outcomes were compared between aflibercept and PRP arms at both 12 and 52 weeks for oximetry and area of new vessels and at 52 weeks for area of retinal non-perfusion using ANCOVA. If the data contained highly skewed outcomes, the Mann–Whitney U-test was used instead and data were also described using medians and interquartile ranges (IQRs). The statistical significance was set at 0.05.

Mechanistic results

The baseline characteristics of the 40 patients were evenly matched. Retinal oximetry measurements reveal fairly similar SaO₂ and SvO₂ saturations in both arms at every visit. The mean Sa – vO₂ at baseline was 36.7% in the PRP group and 33.4% in the aflibercept group. At week 12, the Sa – vO₂ was 36.1% and 35.5% for the PRP and aflibercept group, respectively. At week 52, the Sa – vO₂ increased in the PRP arm to 39.7% and minimally decreased in the aflibercept arm to 32.5%. However, the –4.0% (95% CI –8.8% to 0.8%) adjusted difference in the change from baseline between the two groups was not found to be statistically significant (p = 0.10). Mean arterial and venous diameter decreased in both groups at week 52, again with no significant difference between groups. Table 33 shows the detailed retinal oximetry values in the whole cohort and Tables 34 and 35 show the oximetry values in the treatment-naive and non-naive groups, respectively.

The mean total area of retinal non-perfusion increased in both PRP and aflibercept groups with no statistically significant difference between groups. At baseline, the total area of retinal non-perfusion was 125.1 disc areas in the PRP group and 131.2 disc areas in the aflibercept group. At week 52, this increased to 156.1 disc areas and 158.4 disc areas in the PRP and aflibercept groups, respectively. The proportion of eyes that experienced an increase in retinal non-perfusion of more than 20 disc areas was 51.6%, while 22.6% had an increase in retinal non-perfusion of 5–20 disc areas and 25.8% did not experience a significant increase (< 5 disc area change). This is further detailed in Table 36.

The total area of new vessels was reduced from baseline with treatment in both arms with more rapid and significant regression in the aflibercept arm at 12 weeks (p = 0.019). By 52 weeks, the PRP arm also showed similar regression of new vessel area (p = 0.45). This is further detailed in Table 37.

Summary of findings

The CLARITY study showed that intravitreal aflibercept monotherapy was superior to standard PRP treatment for PDR through 52 weeks; the effect was achieved with a median of one aflibercept injection only in the 40 week post-loading phase, indicating that aflibercept is a feasible new approach for compliant patients. The superior BCVA findings were supported by significantly better binocular visual acuity and binocular Esterman scores in the aflibercept arm. These observations have significant impact on eligibility to retain a driving licence. In the UK, the Driver and Vehicle Licensing Agency has designated both a minimum visual acuity and Esterman visual field standard to maintain a valid driving licence. 83 With advances in laser technology and techniques, there are reports with short follow-up suggesting that modern-day laser techniques and technology, such as multispot laser, have reduced the prevalence of visual field loss with PRP. 84,85 However, our study shows that, despite 69% of the study cohort being treated with multispot laser, aflibercept is associated with a lower risk of visual field loss than modern-day laser at 52 weeks, in keeping with findings noted in the recent ranibizumab trial in PDR at 2 years. 53 Other visual outcomes that measured adverse effects of PRP, such as contrast sensitivity and low-luminance visual acuity, were not significantly different between arms, although removing outliers suggested greater preservation of low-luminance visual acuity letter score by 52 weeks in the aflibercept arm.

Panretinal photocoagulation remains an effective treatment in preventing severe visual loss. 52 On average, the visual acuity remained very stable over 52 weeks but twice as many people lost 10 or more letters when treated with PRP. In contrast, the proportion of patients who lost visual acuity was minimal in the aflibercept arm. However, the study reiterates the Protocol S study in that PRP is not a one-off procedure: 65% of patients require supplemental therapy despite advances in laser technology.

Aflibercept also improved the level of diabetic retinopathy severity, which resulted in a higher proportion of eyes with total regression of new vessels than PRP. This anatomical effect should also be considered when choosing between anti-VEGF and PRP as a first-line option in PDR. As aflibercept is licensed for DMO, the findings of this study indicate that aflibercept is also effective in the management of PDR in the first year, allowing the use of a single agent to address both of these sight-threatening complications of diabetes mellitus.

These data are likely to promote a paradigm shift in the treatment of PDR.

Economic evaluation

Our objective was to evaluate the cost-effectiveness of intravitreal aflibercept therapy for PDR versus standard care, PRP.

Economic evaluation was undertaken on 202 participants (101 per arm) with complete cost and outcome data. This represents 96.7% of the clinical sample included in primary outcome ITT analysis. From a public sector multiagency perspective that covers health and social care services, treatment with aflibercept costs more in terms of total resource use (mean adjusted total additional cost per patient = £5475, bootstrapped 95% CI £5210.79 to £5749.82) than PRP laser treatment over the 52-week follow-up period. Sensitivity analysis in which we varied the costs of aflibercept from the list price to reflect possible NHS PAS showed this to be the case at any price because of the additional cost of administering aflibercept. Participants who received aflibercept gained some benefit in BCVA (mean = 3.93, bootstrapped 95% CI 3.84 to 4.02) but at an increased cost. No statistically significant difference was found in self-reported generic HRQoL (EQ-5D-3L) or in terms of capability (ICECAP-A). It may be that these measures were not sufficiently sensitive to pick up any changes over the 52-week follow-up period between arms. We have undertaken a secondary exploratory cost–utility analysis (i.e. cost-per-QALY analysis). Evidence is mixed, but points to the EQ-5D-3L not being sufficiently sensitive to be useful in studies of visual impairment. 44,45 The results of our study speak for themselves: a mean adjusted cost difference of £5475 is divided by an extremely small and not statistically significant mean adjusted QALY difference of –0.022. This yields a cost per QALY of –£252,827, in which we do not have much confidence. Given that a positive significant difference was observed in the BCVA for the intervention group, we interpreted this as the EQ-5D-3L not being sufficiently sensitive in this context. Interestingly, the vision-specific self-reported health-related QoL measures (RetDQoL and NEI-VFQ-25, non-preference-based) also showed no statistically significant difference over the study period between arms. If society is willing to pay £1400 for an additional 1-point improvement in BCVA, then aflibercept has a 56.60% probability of being cost-effective at the list price of £816.

Mechanistic evaluation

This section is adapted from Nicholson et al. 82 ©The Authors, 2018. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

Our study on 40 patients (20 in each arm) did not reveal any significant change in retinal oximetry between arms. This may be because of the small sample size. The study was not powered to detect important clinically significant differences between arm. The study was exploratory and hypothesis driven to decide on sample size of future studies in this area if changes observed were worth pursuing. The SaO₂ and SvO₂ at baseline were both high compared with the normative data on retinal oximetry, in keeping with reports on retinal oximetry in PDR. In addition, the standard deviations of the values for both SaO₂ and SvO₂ are similar to reports on PDR, suggesting that the non-significant changes are unlikely to be errors in measurement. After accounting for test–retest variability, we would require a mean of 5% change in SO₂ in the arteries and veins to confidently report a treatment effect. 78 This was not achieved in either the treatment-naive group or the post-PRP-treated non-naive group in either arm. Therefore, although there may be an overall change in the distribution of oxygen supply and consumption with either treatment, our study results show that these treatments do not affect the overall oxygen exchange in the retina. Guduru et al. 86 reported a correlation between retinal capillary non-perfusion and retinal arterial SaO₂. Our study participants in the mechanistic study did show significant areas of capillary non-perfusion but both aflibercept and PRP failed to show any difference in change in capillary non-perfusion at 52 weeks, with patients in both arms showing a continuing increase in area of total non-perfusion. This increase in non-perfusion was not associated with a corresponding change in retinal oximetry values, emphasising that retinal oximetry represents only global change in oxygen and may not be accurate enough to measure local changes in redistribution of oxygen demand and supply. 87

Strengths and limitations

This study included patients presenting prospectively to the medical retina clinics where patients are managed in a real-life setting so the study allowed accurate testing of the hypothesis. The study also included both treatment-naive eyes and eyes with persistent NV post-initial PRP and was therefore representative of the UK population who would benefit from an alternative treatment to PRP. Patients who have been previously treated are often excluded from ophthalmology trials and, therefore, this is the first study that demonstrated the impact of anti-VEGF in this indication. We excluded eyes with macular oedema to avoid any confounding effect on the primary outcome analysis. Therefore, the study provided the true benefit of anti-VEGF agent in PDR. Participants underwent thorough phenotyping including clinical, qualitative and objective assessment and an independent Reading Centre also further graded the retinal images to ensure a robust validation of the study anatomical outcomes.

The study was slow to recruit initially but we successfully met the target by increasing recruitment of five clinical trial sites in time. The main reason for the slow recruitment in the initial phase was the additional burden on busy clinics, the provision of PRP being available on the same day as the retinal consultation, and the perception that anti-VEGF therapy is short-acting. The increase in performance across the sites in the later half of the study may be because of the availability of new data on the effectiveness of anti-VEGF on diabetic retinopathy and so the research team became more reassured that anti-VEGF agents may indeed be a useful treatment for PDR too.

The robust randomised controlled trial (RCT) design, high statistical power and excellent retention rates are particular strengths of this study. The study patients are representative of the PDR population and, therefore, these findings can be generalised to clinical practice for the first year of therapy. Retreatment criteria used in CLARITY were very similar to those followed in the ranibizumab trial17 and were determined by treating investigators at each study visit. Compliance with treatment (94% aflibercept arm and 97% PRP arm) was very good in CLARITY, indicating that these retreatment criteria can be easily applied to routine clinical practice.

The safety evaluation of aflibercept in CLARITY revealed no new concerns on this drug. There were no statistically significant differences in APTC events or other systemic adverse events between arms at 52 weeks, substantiating the reports of previous intravitreal aflibercept studies in diabetic patients. Long-term studies on anti-VEGF in PDR patients are required for meta-analysis of the safety of these agents in PDR.

The limitation of this study is that it was a Phase IIb study with follow-up for only 52 weeks. To date, the only other well-designed study on anti-VEGF for PDR included patients with DMO and so the treatment regimen was preplanned to be more intense than this study. 11 However, as a 5-year study, it will provide long-term outcomes of ranibizumab in PDR, information on the disease-modifying effect of anti-VEGF and the long-term compliance of patients. The study also excluded patients with significant fibrovascular proliferation or tractional retinal detachment in the posterior pole and eyes with prior vitrectomy. We have limited experience of treating severe retinopathy at the posterior pole with anti-VEGF therapy and so we decided that this group is best avoided as risks may outweigh benefits.

Approximately 75% of the PDR patients included in this study had low-risk PDR. This mirrors the study population in Protocol S suggesting that PRP is now initiated in patients with low-risk PDR.

We did not collect information on ADL that would have told us something about how treatment of this condition with aflibercept versus PRP affects home and work life.

This study used a 12-month recall period for contacts with health and social care services, which is considered reasonable but towards the boundary of recall for patients. 88

For the economic evaluation, we were primarily interested in our health economic analysis on how the cost per change in BCVA compared with the cost per QALY and hence decided to use complete-case analysis where full data were available for these outcome measures. We do not impute costs and, therefore, this left us with 202 participants (this represents 96.7% of the clinical sample included in primary outcome ITT analysis).

Comparison with existing literature

The DRCR.net performed a multicentre (55 sites), randomised clinical trial comparing panretinal photocoagulation with 0.5 mg of intravitreal ranibizumab in 305 patients with PDR. 52,53 PRP was performed at baseline and ranibizumab was given at baseline and week 4 pro re nata. Eyes with DMO in both groups were eligible to receive ranibizumab. The primary outcome was change in BCVA and the secondary outcomes included area under the visual acuity curve, peripheral visual field loss (as measured on Humphrey automated visual field testing), incidence of vitrectomy, development of DMO, and persistent or new neovascularisation. Improvements in BCVA for the ranibizumab and PRP groups were +2.2 and +0.2 letters, respectively (95% CI –0.5 to + 5.0). The group receiving ranibizumab experienced less peripheral visual field sensitivity loss (–23 dB vs. –422 dB, 95% CI 213 dB to 531 dB; p < 0.001), fewer vitrectomies (4% vs. 15%, 95% CI 4% to 15%; p < 0.001), and a lower incidence of DMO (9% vs. 28%). Ranibizumab-treated eyes required a median of seven injections through year 1 and 10 injections through year 2. Forty-five per cent of eyes in the PRP group required additional laser and 53% of eyes required ranibizumab for DMO. The authors concluded that ranibizumab may be a reasonable alternative to PRP through 2 years. The decreasing number of injections in year 2 suggests that some disease modulation occurs after 1 year of ranibizumab therapy.

Comparison with other economic evaluation studies

A US study exploring the cost-effectiveness of intravitreal ranibizumab compared with PRP for PDR found that over 2 years, compared with PRP, 0.5 mg of ranibizumab was within the US$50,000 to US$150,000 per QALY range frequently cited as cost-effective in the USA for eyes presenting with PDR and vision-impairing DMO, but not for those with PDR without vision-impairing DMO. 88 The US study measured costs associated with ocular treatments and potential complications only, and based quality-of-life adjustments in QALY calculations on utility weights by mapping from Brown et al. 89 for a 2-year period. Sensitivity analysis explored the effect on the ICER of time trade-off responses from trial participants. Brown et al. 89 did not collect preference-based utility data directly from patients.

Implications for practice and research recommendations

In addition to improving the visual acuity, intravitreal aflibercept also reduced the level of diabetic retinopathy severity and resulted in a higher proportion of eyes with total regression of new vessels than PRP, fewer visually disabling vitreous haemorrhages and fewer cases of incident macular oedema. These anatomical effects should be considered when choosing between anti-VEGF and PRP as a first-line option in PDR. As aflibercept is licensed for DMO, the findings of this study indicate that aflibercept is also effective in the management of PDR in the first year, allowing the use of a single agent to address both of these sight-threatening complications of diabetes mellitus in patients presenting with both PDR and DMO.

We recommend a longer study investigating the efficacy and effects of this treatment, including safety events over a duration of up to 5 years to inform future treatment guidelines for this indication.

Future health economics studies in this area should ensure the inclusion of a range of outcome measures (vision specific and generic, as we did in this study) and should model costs and benefits over a longer period. Although the CLARITY study was limited to 1 year, the rate of complications was significantly higher in the PRP arm in terms of new-onset macular oedema and vitreous haemorrhage by 52 weeks. A similar study, Protocol S,53 showed that, over 2 years, significantly more vitrectomies were performed in the PRP arm. Cataract surgery is also frequently needed after vitrectomy. Similarly, more patients in the PRP arm need to be treated with anti-VEGF therapy for macular oedema. The costs of these complications have to be taken into account when modelling costs over a 5-year period or longer.

Some physicians who prefer anti-VEGF therapy over laser will probably use bevacizumab although data for these drugs are not yet available. Confirmatory studies have to be done before translating the effect of ranibizumab and aflibercept studies to bevacizumab as the number of injections varied between Protocol S and CLARITY and the study designs of these two studies were not identical. Therefore, the CLARITY study results should be used cautiously if other anti-VEGF agents are used to treat PDR.

If there is an intention in a future economic evaluation study to use QALYs as an outcome measure to allow comparison with, for example, the NICE payer threshold of £20,000 per QALY, then feasibility work is necessary to identify ways of measuring utility relating to visual impairment that make the QALY a meaningful outcome measure in this context.

Support

The study was sponsored by NIHR Moorfields Biomedical Research Centre and supported by the UK Clinical Research Network. The research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, the NIHR Moorfields Clinical Research Facility and the UK Clinical Research Collaboration-registered KCTU at King’s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. We would also like to thank Maggie Shergill, the Research Manager (Monitoring) and the other team members of the NIHR Evaluation Trials and Studies Coordinating Centre (NETSCC).

Contributions of authors

All authors reviewed, revised and approved the final version of the manuscript.

Sobha Sivaprasad (Professor, Consultant Ophthalmologist) was the chief investigator and co-authored the first draft.

Philip Hykin (Consultant Ophthalmic Surgeon) was a co-applicant, was involved in the design and recruitment of the study and co-authored the first draft.

A Toby Prevost (Professor, Medical Statistics) was a co-applicant, was involved in the design and statistical analysis of the study and co-authored the first draft.

Joana Vasconcelos (Research Fellow, Medical Statistics) was involved in the design and statistical analysis of the study and co-authored the first draft.

Amy Riddell (Trial Manager) was involved in all aspects of the study’s management and monitoring and co-authored the first draft.

Jayashree Ramu (Research Fellow, Moorfields Eye Hospital) was involved in the design and recruitment of the study and co-authored the first draft.

Caroline Murphy (King’s Clinical Trial Unit) was a co-applicant and was involved in the design and trial management and co-authored the first draft.

Joanna Kelly (King’s Clinical Trial Unit) was a co-applicant, was involved in the design and data management and co-authored the first draft.

Rhiannon Tudor Edwards (Professor, Health Economics) was a co-applicant and was involved in the design, management, analysis and interpretation of the health economics part of the study, the co-authoring of the first draft and the writing up of the report.

Seow Tien Yeo (Research Fellow, Health Economics) was involved in the management, analysis and interpretation of the health economics part of the study, the co-authoring of the first draft and the writing up of the report.

James Bainbridge (Professor, Consultant Ophthalmic Surgeon) was a co-applicant and was involved in the design of the study.

David Hopkins (Diabetologist) was a co-applicant and was involved in the design of the study.

Beverley White-Alao (King’s Clinical Trial Unit) was involved in the protocol development and study management and co-authored the first draft.

Publications

Sivaprasad S, Prevost AT, Bainbridge J, Edwards RT, Hopkins D, Kelly J, et al. Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial. BMJ Open 2015;5:e008405.

Sivaprasad S, Prevost AT, Vasconcelos JC, Riddell A, Murphy C, Kelly J, et al. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet 2017;389:2193–203.

Nicholson L, Crosby-Nwaobi R, Vasconcelos JC, Prevost AT, Ramu J, Riddell A, et al. Mechanistic evaluation of panretinal photocoagulation versus aflibercept in proliferative diabetic retinopathy: CLARITY substudy. Invest Ophthalmol Vis Sci 2018;59:4277–84.

Data-sharing statement

Data are archived at Moorfields Eye Hospital. All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslifes You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research. 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, the MRC, NETSCC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the EME programme or the Department of Health and Social Care.

Resource centres

We would also like to thank the following resource centres for their support of the trial:

King’s College Clinical Trial team: Gill Lambert, Beverley White-Alao, Oliver Pressey, Negin Sarafraz-Shekary, Evangelos Georgiou and Janice Jimenez.

The Royal Free London NHS Foundation Trust Pharmacists team: Nicky Heath and Sabina Melander.

The North East Diabetes Research Network’s lay panel.

Patient-reported outcomes consultant to the study: Professor Clare Bradley, Royal Holloway, University of London.

Mechanistic Evaluation team: Luke Nicholson, Roxanne Crosby-Nwaobi, Lauren Leitch-Devlin at the NIHR Moorfields Clinical Research Facility.

Certifications for visual acuity and contrast sensitivity: Catherine Grigg and Katherine Binsted at Moorfields Eye Hospital, London.

Members of the NetwORC UK: Professor Usha Chakravarthy, Professor Tunde Peto, Professor Simon Harding, Dr Pauline Lenfestey, Ms Savitha Madhusudhan, Clare Newell, Michelle McGaughey, Vittorio Silvestri, Karleigh Kelso, Barbra Hamill, Graham Young, Irene Leung, Peter Blows, Frank Picton, David Parry and Sophie Leach.

Trial steering committee

Independent chairperson: Mr Alistair Laidlaw (Guy’s and St Thomas’ NHS Foundation Trust, London); independent members: Graham A Hitman (Blizard Institute, Barts and The London School of Medicine and Dentistry, London), Winfried Amoaku (University Hospital, Queen’s Medical Centre, University of Nottingham), Gillian Hood (NIHR Clinical Research Network, North West London); and lay representatives: Daniel Preece and Paul Burns.

Data monitoring and ethics committee

Sarah Walker (Oxford University, Oxford, UK; Chairperson), Niral Karia (Southend NHS Trust) and Evelyn Mensah (Central Middlesex NHS Trust, UK).

Trial management group members

Sobha Sivaprasad, Philip Hykin, A Toby Prevost, Joana Vasconselos, Amy Riddell, Beverley White-Alao, Caroline Murphy, Joanna Kelly and the sponsor representative (Moorfields Eye Hospital).