Outcome measures
The primary outcome measures were the occurrence of serious AEs, adverse events of special interest (AESIs), AEs, and adverse drug reactions (ADRs). A serious AE was considered any AE that occurred at any dose that resulted in death, a life-threatening AE, inpatient hospitalization or prolongation of an existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect. The AESIs were glaucoma or increased intraocular pressure (IOP). An AE was considered any untoward medical occurrence in a patient who was administered the pharmaceutical product and did not necessarily have a causal relationship with the treatment. The severity of an AE was established by clinical determination as follows: mild (awareness of sign or symptom, but easily tolerated), moderate (discomfort enough to cause interference with usual acuity), or severe (incapacitating with inability to work or do usual activity). An ADR was considered a response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of diseases, or for modification of physiological function. AEs were determined and reported as such by the investigator and categorized based on clinical judgement.
Assessments
At the enrollment visit (visit 1), a pre-designed clinical report form was used to collect patient demographics, relevant medical and ophthalmic history, concomitant medications, date of the last DEX injection, if applicable, date of the present DEX injection, and detailed information about SAEs, AESIs, AEs, and ADRs following DEX treatment. AEs were collected once informed consent was obtained, regardless of whether the patient had been administered study drug.
Post-injection evaluations were not mandated. All follow-ups (clinic visits/telephone contact) were scheduled at the discretion of the physician/investigator, and similarly, results of follow-up evaluations were reported at the physician’s/investigator’s discretion only if they deemed them as AEs. During the follow-up visits (or telephone contact), the physician/investigator collected information about SAEs, AESIs, AEs, and ADRs (including dates, if available) on the form, and recorded newly prescribed/administered medications (regardless of their association with an AE). Each patient interview started with simple open-ended questions and questions designed to collect information regarding the specific outcomes. If the patient was seen by a non-study physician, the study physician made every effort to follow-up to facilitate accurate reporting.
Data collected for AEs consisted of the term used to describe the event, onset and resolution dates, seriousness, severity (mild, moderate, or severe), outcome, treatment, relationship of the event to intravitreal DEX injection as determined by the study physician, the action taken in terms of DEX, and the concomitant medications administered for the AE (start date, stop date, dose, unit, and frequency). Medical records were used to collect data to determine exposure, effects, and outcomes. Other variables such as potential confounding variables and effect modifiers were also collected.
Upon the occurrence of an SAE, the site informed the governing IEC of the SAE as required by the IEC. Furthermore, as this was a postmarketing surveillance study, reporting of an AE or SAE to the governing health authority followed the applicable regulations for a marketed product (ie, all cases involving serious unexpected AEs were reported to the licensing authority by the study sponsor within 15 days of initial receipt of the information, and other non-serious AEs were reported through a Periodic Safety Update Report that followed the prescribed periodicity).
All events were recorded and sent to the sponsor’s global safety team using the designated postmarketing form: SAEs within 24 h of awareness of the event and AEs within 10 calendar days. SAEs were also reported to the governing IEC.
Statistical methods
The analysis population included all enrolled patients who met eligibility criteria and were administered at least one DEX injection. All data collected on the clinical report form were transferred to a clinical database and then imported into SAS (Cary, NC, USA) for further analysis. Medical history, current medical conditions, and SAEs, AEs, and ADRs were coded using the Medical Dictionary for Regulatory Activities version 20.1 nomenclature and presented by primary system organ class and preferred term. The frequency of treatment-emergent SAEs, AESIs, SAEs, and ADRs during the study period was summarized in one of two ways: (1) the number and percentage of patients reporting each event, counting those who reported multiple episodes of the same event only once, divided by the number of patients who were treated with DEX during the study period; and (2) the number and percentage of each event, counting multiple episodes of the same event separately, divided by the number of patients who were treated with DEX during the study period. The safety profile was further evaluated by patients with and without prior DEX treatment.
Continuous data are presented as the mean (95% confidence interval [CI] or standard deviation [SD]) and median (minimum and maximum). Categorical data are presented as percentages. The number of non-missing records was determined. Missing values as a consequence of patients who did not return to follow-up visits were not replaced and were treated as censored. Thus, no imputation for missing data was performed.
Because this was an observational, prospective, non-interventional study without a comparison group, no formal sample-size calculation was performed. However, based on the enrollment potential, approximately 250 patients from 20 sites across India were planned to be enrolled as a representative sample.