Discussion
DMO
DISEASE, RETINAL DISEASES
In this post hoc analysis, we examined the novel concept of time in range, a potentially clinically relevant functional endpoint designed to examine response to treatment over time. This measure reflects the fluctuations in BCVA over time and, by incorporating a VA threshold that coincides with a patient’s ability to perform certain tasks such as driving, can be considered to indirectly reflect the impact of the disease on daily activities.Using data from Protocol T to evaluate time in range in patients with DMO, we assessed the duration of time that a patient had BCVA letter scores of ≥69 (approximate Snellen equivalent 20/40 or better), chosen to align with the majority of global vision requirements for driving [Although the use of time in range to monitor treatment efficacy has been used previously to assess blood glucose control in diabetic patients [Traditional clinical endpoints are often measured at a single point in time (for example, change in BCVA from baseline to Month 12; ETDRS letter score improvement ≥15 by Month 12). These methods do not, however, capture the variability in response to therapy that patients may have over the course of their treatment and consequently do not reflect potential impact on activities of daily living. In one example (Fig. The Protocol T data used in exploring the time-in-range concept serve as a conduit for describing the application of the technique and demonstrate how this analysis assesses the consistency of treatment efficacy above a predefined threshold over time, rather than a static measurement at the end of the trial. This approach could be applied to either a treatment cohort to assess mean time in range or to an individual patient to monitor their treatment response. Time in range could also provide an additional or alternative approach for physicians when discussing clinical trial results with patients, by describing the number of weeks that an individual given a specific treatment might expect to experience VA above a certain threshold.This time-in-range analysis shows similar trends in efficacy of the studied anti-VEGFs with respect to letter gains in BCVA over the course of the trial that reflect the prespecified primary outcome results reported for Protocol T. Also consistent with the findings from the Protocol T study, which showed that baseline BCVA was associated with BCVA gains at Month 12 [The US Food and Drug Administration recognises the value of a patient-focused approach in drug development and is supportive of the development of novel, patient-focused endpoints [The concept of time in range is not limited to BCVA or patients with DMO; possible applications of the approach could be developed for OCT measurements, patient-reported outcomes, or for patients with other retinal diseases. Indeed, analyses from patients with DMO, including those in Protocol T, have shown that eyes with larger fluctuations in CST have worse VA compared with eyes with more stable anatomical outcomes [The approach used here to calculate time in range has certain limitations, especially when applied to a progressive disease and continuous endpoints. Although all available data were utilised for the time-in-range calculations, BCVA was not assessed daily and assumes patients to have the same BCVA value until a newer measurement was performed. It is, therefore, not 100% accurate and, as such, the data and interpretation should be treated with caution. In addition, as this method is reliant on repeat measurements, the frequency of these measurements may impact time-in-range results; increasing the number of measurements within a given timeframe results in a more sensitive time-in-range calculation. In this time-in-range analysis of Protocol T, a cut-off of ≥7 VA measurements was required within the first year, given that this corresponds with the dosing regimens of anti-VEGF agents and excluded 22/660 (3.3%) eyes with fewer measurements. As noted in our methodology, 2-year outcomes are provided as supplemental analyses, as more limitations must be considered for the data between 1 and 2 years given the variable follow-up schedule. For sensitivity analysis, we have shown stable results when considering different cut-off values from 0 to 100 letter scores other than 70. In addition, we have included the “Responder-type” analysis showing the percentage of responders when considering 0–100% time in range as a response. Additional sensitivity analysis for cut-offs of ≥6 or ≥8 measurements were not performed because similar numbers of eyes would have been excluded (17 [2.6%]) and 30 [4.5%]) as with the ≥7 cut-off, and any potential impact would have been minimal. When using time in range to compare IVT-AFL, IVT-BEV, and IVT-RAN, consistent results were obtained across BCVA letter score thresholds from ≥30 to <90; this observation minimises the possibility that the focus on the ≥69-letter score cut-off in the primary analysis produced anomalous findings.In summary, time in range is a potentially clinically relevant visual endpoint to assess functional treatment outcomes over time beyond AUC outcomes presented previously in trials evaluating DMO.