TERRA is a phase 4, multicentre, observational, non-interventional study conducted at 13 sites in England and Wales, with both retrospective and prospective components. The study protocol (MREC: 16/YH/0336; IRAS ID: 205633) was approved by the Multicentre Research Ethics Committee and written consent was obtained from all patients prior to enrolment and data collection.
The study enrolled two cohorts of patients with nAMD that were being treated with ranibizumab: a cohort that switched from a PRN to a T&E regimen (‘prior PRN cohort’) and a cohort that received no prior anti-VEGF therapy before initiating ranibizumab according to the T&E regimen (‘anti-VEGF-naïve cohort’) (Fig. 1).
Eligibility criteria included: (1) adult patients ≥50 years of age with active choroidal neovascularisation secondary to AMD in one or both eyes at the time of diagnosis; (2) medical records providing at least 12 months of retrospective data on either the ranibizumab PRN regimen prior to switching to T&E (prior PRN cohort), or the T&E regimen (anti-VEGF-naïve cohort) immediately prior to enrolment; and (3) no prior treatment with an anti-VEGF agent (i.e., bevacizumab or aflibercept) other than ranibizumab in the study eye (defined as the eye first treated with a T&E regimen). Patients were able to withdraw consent and discontinue from the study at any time without affecting their medical care.
In the prior PRN cohort, the primary endpoint of the study was change in VA [in Early Treatment Diabetic Retinopathy Study (ETDRS) letters] from regimen switch to 12 months of treatment on the T&E regimen. In the anti-VEGF-naïve cohort, the primary endpoint of the study was change in VA from initiation of ranibizumab treatment on the T&E regimen to 12 and 24 months of treatment. The endpoints will be evaluated separately in their respective cohorts. The period required to achieve 24 months’ follow-up data from all patients was estimated to be from 31 August 2016 to 28 February 2018. It should be noted that the definition of baseline was different for the two cohorts; for the prior PRN cohort, baseline was defined as the date of switch from a PRN to a T&E regimen (i.e., the date of the first ranibizumab injection under the T&E schedule), whereas baseline for the anti-VEGF-naïve cohort was defined as the initiation date (and first ranibizumab injection) on the T&E regimen. Thus, these two baseline definitions represent different time points in the patient cohorts’ respective treatment pathways.
The results of both the pre-specified and non-pre-specified interim analyses (with a data cut-off date of 15 November 2016) from the retrospective component of the study are presented here. Full efficacy and safety results from both cohorts will be presented in a future publication following completion of the prospective observational component of the study. The results of the interim analyses reported here will not impact the conduct of the ongoing study. Final study conclusions will be drawn from the primary analyses performed on the full data set following completion of the prospective phase of the study.
For each patient in both cohorts, the date of study enrolment was defined as the time point at which the consent form was signed. In the anti-VEGF-naïve cohort, data [e.g., patient demographics, medical history, VA, central subfield retinal thickness (CSRT)] were collected from patients’ case notes retrospectively for all visits that occurred, beginning from the first ranibizumab injection administered. For the prior PRN cohort, these data (e.g., patient demographics, medical history, VA, CSRT) were collected retrospectively for 12 months of PRN treatment prior to study enrolment. For visits after the date of study enrolment, i.e., during the prospective part of the study, data for both cohorts were collected from patients’ case notes after each completed visit in an ongoing, observational manner.
The study protocol did not influence the way that patients were treated in terms of any re-treatment criteria. Therefore, the frequencies of clinic visits, ranibizumab injections, and clinical assessments (i.e., VA and CSRT) were also not pre-specified by the study protocol. It was assumed that the patients were treated according to routine medical practice and local prescribing information based on the licensed ranibizumab posology, which for the T&E regimen is a monthly injection until maximum VA is achieved and/or there are no signs of disease activity (i.e., no change in VA, optical coherence tomography, and other signs and symptoms of the disease) . Therefore, patients on the T&E regimen had their treatment intervals and monitoring determined by their physician accordingly. To accurately capture real-world evidence, only data that were available in the case notes documented as part of patients’ routine standard care were collected to avoid any influence from data collection on clinical decision-making.
Handling of Missing Data
If the data from the baseline visit were incomplete or there was no visit on the recorded baseline date, data from no more than 30 days earlier were considered valid. In the prior PRN cohort, the date of the 12-month pre-baseline time point was defined as baseline (switch date) minus 365 days. If there was no visit exactly on this date, the nearest data from a visit plus or minus 30 days were considered valid. In the event of two equidistant visits from minus 365 days, data from the earlier visit were prioritised. In the anti-VEGF-naïve cohort, the date of the 12-month post-baseline time point was defined as baseline plus 365 days. If there was no visit exactly on this date, the nearest data from a visit plus or minus 90 days were considered valid. In the event of two equidistant visits from plus 365 days, data from the later visit were prioritised. Missing data outside of these criteria were not imputed.
Assessment of Healthcare Resource Use
Resource use was assessed through an operating cost questionnaire (Supplementary Table 1) , which was completed by the principal investigator or a member of their study team once at each study site on initiation of the study (enrolment of the first patient). The questionnaire collected information on healthcare staff resource use required to administer ranibizumab and monitor outcomes, such as clinic type (e.g., one-stop and separate monitoring and injection clinics, defined as a two-stop clinic service), the length of time to deliver each clinic, the estimated time patients spent in clinic at each visit, and the staff resource use [including type (e.g., clinicians, administrative coordinators, healthcare assistants, etc.), post, NHS grade/band, roles in clinic, and time spent by staff in a clinic session] required to run the clinics. For the purposes of the questionnaire, a one-stop clinic service was defined as a service in which monitoring and investigations were conducted on the same day as ranibizumab was administered. A two-stop clinic service was defined as a visit where the monitoring and investigations occurred on separate days to the administration of ranibizumab.
Assessment of Clinical Outcomes
Clinical outcomes were measured using VA and CSRT. VA was assessed and manually converted on-site to ETDRS letters via a standard conversion chart , where applicable (VA data not provided in ETDRS letters were excluded from analyses). CSRT was measured by spectral domain optical coherence tomography.
The overall target sample size for this study was set at 300 patients. The cut-off for the interim analyses was defined as 15 November 2016 or when 150 patients were enrolled, whichever occurred first. Assuming a standard deviation (SD) of 12.9 letters for the change in VA from baseline to 24 months , and conservatively assuming the same SD for the change in VA from baseline to 12 months, the expected width of a two-sided 95% confidence interval (CI) for 100 prior PRN and 50 anti-VEGF-naïve patients was calculated to be 5.0 and 7.2 letters, respectively.
There were no adjustments made for multiple analyses, due to the descriptive nature of this study. All statistical analyses were performed in SAS software, Version 9.4 (SAS Institute, Cary, NC, USA). For patients with missing values or who withdrew from the study, no imputation was used. The p values and 95% CIs were calculated using a paired t test.
The full analysis set for the interim analysis consisted of all patients who were enrolled in the study and received at least one dose of ranibizumab treatment as part of a PRN or T&E regimen.