Ranibizumab (Lucentis, Novartis Pharma AG, Basel, Switzerland, and Genentech Inc., South San Francisco, CA, USA) is a humanised monoclonal antibody Fab fragment, specifically designed for ocular use, that binds with high affinity to and inhibits multiple biologically active isoforms of vascular endothelial growth factor A (VEGF-A; [
RCTs are by nature conducted in a controlled setting, have stringent inclusion and exclusion criteria, and mostly include treatment-naïve patients. Consequently, it is of interest to translate RCT results into real-world clinical practice. Therefore, there is a need for observational studies conducted on a large and diverse patient population to further evaluate the potential risks of serious but infrequent adverse events (AEs) and the efficacy of ranibizumab in a real-world setting. Evidence to establish the safety profile of ranibizumab in routine clinical practice is growing with small clinical studies as well as with the large on-going LUMINOUS study [
The EPICOHORT study was designed, as part of the on-going postmarketing commitment of Novartis Pharma AG (Basel, Switzerland) to the European Medicines Agency (EMA). The EPICOHORT was a postapproval study designed to assess the safety profile, treatment patterns, and efficacy of ranibizumab in real-life clinical setting/routine clinical practice. This 2-year study was conducted between September 30, 2008, and November 15, 2011, in a cohort of European ophthalmology clinics that had, by EMA request, not previously participated in clinical studies with ranibizumab. Ranibizumab treatment was based on investigator’s judgment and guided by EU SmPC in effect during the time of study limited by their daily practice. More specifically, up until September 19, 2011, the EU SmPC retreatment criteria were based on a loss of visual acuity (VA). All clinical assessments were performed at the discretion of the study investigator as part of his/her current practice to reflect the real-life practice in EU ophthalmology clinics. This paper reports the findings from this 2-year, phase IV, multicentre, observational study conducted in a real-world setting.
This was a 2-year, multicentre, phase IV, open-label, observational, noncomparative cohort study on patients with nAMD from 54 European clinical centres that had not participated in clinical studies with ranibizumab. The study was conducted in accordance with the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice, with applicable local regulations and ethical principles laid down in the Declaration of Helsinki. The study protocol was reviewed and approved by the Independent Ethics Committee or Institutional Review Board of each centre. Written informed consent was obtained from each participating patient before enrolment.
The outpatient study population consisted of patients diagnosed with choroidal neovascularisation (CNV) secondary to AMD. The patients were to be treated with ranibizumab at study entry.
Due to the observational nature of the study, the study protocol did not impose diagnostic/therapeutic interventions like optical coherence tomography (OCT) assessments or a visit schedule. Patients were treated with the commercially available intravitreal injections of ranibizumab 0.5 mg (Lucentis) as per the investigators’ judgement and guided by the current EU SmPC in effect during the time of the study, During the study period (September 30, 2008, to November 15, 2011), the SmPC was updated nine times and all SmPC versions before September 2011 had the same retreatment criteria. The treatment criteria were to treat with ranibizumab 0.5 mg when patients experienced a loss of
The key objectives of the study were to describe the characteristics of nAMD patients treated with ranibizumab in European clinics; incidence of bilateral use of ranibizumab; compliance to the EU SmPC in effect during the time of the study; incidence of the following selected adverse events (AEs): endophthalmitis, retinal detachment, vitreous haemorrhage, retinal tear, traumatic cataract, uveitis, and elevated intraocular pressure (IOP); and best-corrected visual acuity (BCVA) as a clinical efficacy measure in the study population.
Demographic patient data including age, gender, race, and ethnicity were collected at the study entry. Details on medical history and current medical conditions (including ocular-related history/conditions), on-going medications, and significant nondrug therapies were also recorded, if provided by the patient. BCVA was assessed at study entry or if not done a prior VA value closest to the study entry was recorded. However, during the analysis, patients who did not have the baseline VA were excluded from the analyses.
The number of ranibizumab injections and the bilateral use of ranibizumab were recorded over the 2-year treatment period. Bilateral use of ranibizumab was assessed by (i) proportion of patients receiving ranibizumab treatment in both eyes at any time during the study and (ii) proportion of patients with bilateral treatment within 28 days and on the same day.
Data on compliance to the EU SmPC in terms of treatment dose, use of antimicrobial eye drops, treatment despite contraindications, interval between two treatments, and compliance to retreatment criteria, as well as reported reasons for noncompliance, were collected at every patient visit.
Safety profile was assessed by recording the incidence of AEs and serious adverse events (SAEs) over the 2-year assessment period. AEs were assessed by the investigator by nondirective questioning of patients at each visit (i.e., asking questions without including symptoms, so as not to influence the outcomes), voluntary reports by the patients during or between visits or through physical examination. Incidence of the selected AEs (endophthalmitis, retinal detachment, vitreous haemorrhage, retinal tear, traumatic cataract, uveitis, and elevated IOP) was assessed based on the records provided by the study investigator. The incidence was calculated on a per-patient basis over 2 years. In addition, the incidence of the selected AEs was also calculated on per-injection and per-patient-year basis for a period of 2 years.
BCVA was assessed using either the Snellen or ETDRS charts. For the analysis, the Snellen equivalent was converted to an ETDRS score. The efficacy end point was mean change in BCVA letter score from baseline to Month 24. Other efficacy end points included proportion of patients with BCVA letter score gain of ≥15 ETDRS letters and loss of
The EPICOHORT study focused primarily on the safety profile of ranibizumab and no statistical hypothesis testing was intended. All analyses were performed on the safety set, which included patients treated with at least one dose of ranibizumab and who had at least one safety assessment after the first treatment. All analyses were conducted on the safety set except for patient disposition, which was based on the enrolled set (patients who entered into the study and for whom data were recorded). Patient characteristics were summarised using descriptive statistics. All AEs were reported based on the Medical Dictionary for Regulatory Activities (MedDRA) system organ classes and preferred terms. The incidence of AEs (ocular/nonocular) was listed based on the seriousness and relationship to the study drug/procedure. The incidence of selected AEs was calculated based on the proportion of patients with at least one AE over 2 years. The corresponding 95% (Clopper-Pearson) confidence intervals for the incidence rate were presented on a per-patient basis. Ocular and nonocular safety assessments were carried out including assessments of the second-treated eye (as applicable). The first-treated eye was the eye that received the first dose of treatment according to the date and time of treatment during the study. The other eye was considered as a fellow eye (nontreated) until the date it was treated during the study, at which it became the second-treated eye. In this paper, we mainly report the results for the first-treated eye. Compliance to the EU SmPC was summarised using descriptive statistics. All efficacy analyses were performed on the observed data of the safety set. In addition, the analysis was repeated using the last observation carried forward (LOCF) results (i.e., carrying forward the last nonmissing postbaseline results).
A total of 770 patients were enrolled in this study and the gross enrolment happened within 4 months of the study. Out of 770 enrolled patients, 755 patients received treatment. Fifteen patients did not receive any ranibizumab treatment and therefore were not included in the safety analysis. Overall, 695 (90.3%) patients and 545 (70.8%) patients completed the study in years 1 and 2, respectively. The premature study discontinuation was mainly due to “administrative reasons” (58 [7.5%]) or patients “lost to follow-up” (75 [9.7%]). Two patients (0.3%) discontinued the study due to an AE and 11 patients (1.4%) discontinued because of unsatisfactory therapeutic effect. The proportion of patients who discontinued the study and the reasons for discontinuation are shown in Figure
Patient disposition (all enrolled patients). *Except for one, none of the deaths were suspected to be related to the study treatment.
A mean of 6.2 ranibizumab injections was administered during the study (first year: 4.4; second year: 1.8) over 2 years (Table
Treatment exposure and the incidence of bilateral treatment (safety set).
Ranibizumab 0.5 mg |
|
---|---|
Number of injections in the first-treated eye | |
Year 1 | 3306 |
Mean (SD) | 4.4 (2.3) |
Overall (24 months) | 4711 |
Mean (SD) | 6.2 (4.3) |
Patients with bilateral treatment over 24 months, |
133 (17.6) |
Patients with bilateral treatment within 28 days, |
87 (11.5) |
Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion.
The total number of injections is number of injections received since the start of the study in the specific eye.
Patients with bilateral treatment represent the patients who received treatment in both eyes.
SD: standard deviation.
A mean (±SD) of 4.9 (±3.5) injections was administered in the second-treated eye over 2 years. Overall, 133 (17.6%) patients received bilateral treatment during the study, of which 87 (11.5%) patients received bilateral treatment within 28 days and 19 (2.5%) patients received bilateral treatment on the same day (Table
Patients with at least one protocol deviation were recorded during the study. The majority of protocol deviations were related either to patients not self-administering antimicrobial eye drops before or after the injection (360 [47.7%]) or to minor procedural deviations (379 [50.2%]). These procedural deviations were mainly related to the patient reconsent process after the informed consent amendment and to the delay of SAE reporting (Table
Protocol deviations with respect to treatment compliance over 2 years.
Protocol deviation | Ranibizumab 0.5 mg |
---|---|
At least one protocol deviation*, |
|
Injection of more than 0.5 mg (overdose) | 1 (0.1) |
Minor procedural deviations without obvious impact on the safety of the patient | 379 (50.2) |
No single use of vial (multiple injections) | 40 (5.3) |
Patient did not self-administer antimicrobial drops (4 times daily for 3 days) before or after the injection | 360 (47.7) |
Patient has no CNV secondary to AMD | 2 (0.3) |
Overall instances of each protocol deviation |
|
Injection of more than 0.5 mg (overdose) | 1/1 |
Minor procedural deviations without obvious impact on the safety of the patient | 575/379 |
No single use of vial (multiple injections) | 40/40 |
Patient did not self-administer antimicrobial drops (4 times daily for 3 days) before or after the injection | 2242/360 |
Patient has no CNV secondary to AMD | 2/2 |
AMD: age-related macular degeneration; CNV: choroidal neovascularisation.
The overall incidence of the selected AEs in the first-treated eye is shown in Table
Incidence of selected AEs over 2 years (safety set, first-treated eye).
Preferred term | Ranibizumab 0.5 mg |
95% CI* |
---|---|---|
Total | 21 (2.8) | (1.7, 4.2) |
Intraocular pressure |
14 (1.9) | (1.0, 3.1) |
Vitreous haemorrhage | 3 (0.4) | (0.1, 1.2) |
Retinal tears | 2 (0.3) | (0.0, 1.0) |
Endophthalmitis | 1 (0.1) | (0.0, 0.7) |
Uveitis | 1 (0.1) | (0.0, 0.7) |
Cataract traumatic | 0 | (0.0, 0.5) |
Retinal detachment | 0 | (0.0, 0.5) |
Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion.
Special event-preferred terms are presented in the descending order of frequency.
AEs occurring only during the safety observation period are included.
A patient with multiple occurrences of an AE is counted only once in the preferred term category.
AE: adverse event; CI: confidence interval; LL: lower limit; UL: upper limit.
Selected AEs over 2 years: per injection, per patient-year (first-treated eye), and per treated eye (safety set).
Preferred term | Ranibizumab 0.5 mg |
---|---|
AEs per injection* | |
Total number of injections | 4711 |
Intraocular pressure increased | 40 (0.0085) |
Vitreous haemorrhage | 3 (0.0006) |
Retinal tear(s) | 2 (0.0004) |
Endophthalmitis | 1 (0.0002) |
Uveitis | 1 (0.0002) |
Cataract traumatic | 0 |
Retinal detachment | 0 |
AEs per patient-year |
|
Total number of years | 1361 |
Intraocular pressure increased | 40 (0.0294) |
Vitreous haemorrhage | 3 (0.0022) |
Retinal tear(s) | 2 (0.0015) |
Endophthalmitis | 1 (0.0007) |
Uveitis | 1 (0.0007) |
Cataract traumatic | 0 |
Retinal detachment | 0 |
AEs per treated eye |
|
Total number of treated eyes | 888 |
Intraocular pressure increased | 41 (0.0462) |
Vitreous haemorrhage | 5 (0.0056) |
Retinal tear(s) | 2 (0.0023) |
Endophthalmitis | 1 (0.0011) |
Uveitis | 1 (0.0011) |
Cataract traumatic | 0 |
Retinal detachment | 0 |
Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion.
*Number of AEs (rate per injection), where rate per injection is calculated as the number of events/total number of injections.
Preferred terms are presented in the descending order of frequency.
All occurrences of the AE during the safety observation period are included in the AE category (including multiple occurrences per patient).
AE: adverse event.
Overall, ocular SAEs (first-treated eye) were reported in 12 (1.6%) patients (Table
Patients with ocular SAEs and frequent nonocular SAEs (≥3 patients) over 2 years (safety set, first-treated eye).
Preferred term | Ranibizumab 0.5 mg |
95% CI* |
---|---|---|
Ocular SAEs | ||
Total | 12 (1.6) | (0.8, 2.8) |
Retinal haemorrhage | 4 (0.5) | (0.1, 1.4) |
Retinal pigment |
2 (0.3) | (0.0, 1.0) |
Angle closure |
1 (0.1) | (0.0, 0.7) |
Endophthalmitis | 1 (0.1) | (0.0, 0.7) |
Glaucoma | 1 (0.1) | (0.0, 0.7) |
Intraocular pressure |
1 (0.1) | (0.0, 0.7) |
Macular hole | 1 (0.1) | (0.0, 0.7) |
Open angle glaucoma | 1 (0.1) | (0.0, 0.7) |
Optic neuritis | 1 (0.1) | (0.0, 0.7) |
Visual acuity reduced | 1 (0.1) | (0.0, 0.7) |
Vitreous haemorrhage | 1 (0.1) |
(0.0, 0.7) |
Nonocular SAEs | ||
Total | 89 (11.8) |
(9.6, 14.3) |
Cerebrovascular |
5 (0.7) | (0.2, 1.5) |
Chronic obstructive |
5 (0.7) | (0.2, 1.5) |
Hypertension | 5 (0.7) | (0.2, 1.5) |
Pneumonia | 4 (0.5) | (0.1, 1.4) |
Cardiac failure | 3 (0.4) | (0.1, 1.2) |
Colon cancer | 3 (0.4) | (0.1, 1.2) |
Depression | 3 (0.4) | (0.1, 1.2) |
Femur fracture | 3 (0.4) | (0.1, 1.2) |
Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion.
*Exact Binomial (Clopper-Pearson).
SAEs occurring only during the safety observation period are included.
Preferred terms are presented in the descending order of frequency.
A patient with multiple occurrences of an AE is counted only once in the preferred term category.
A patient with multiple AEs is counted only once in the total row.
AE: adverse event; CI: confidence interval; LL: lower limit; SAE: serious adverse event; UL: upper limit.
Nonocular SAEs were reported in 89 (11.8%) patients. Most frequent nonocular SAEs were cerebrovascular accident, chronic obstructive pulmonary disease, and hypertension, each reported in 5 (0.7%) patients (Table
There were 23 (3%) deaths reported during the study. Except for one, none of the deaths were suspected to be related to the study treatment. For this one patient, who had a medical history of hypertension and myocardial ischaemia, the cause of death was stroke and the event was suspected to be related to the study drug and treatment procedure, by the investigator.
Ocular AEs (first-treated eye) were reported in 255 (33.8%) patients. The most frequently reported ocular AEs were conjunctival haemorrhage (58 [7.7%]), eye irritation (25 [3.3%]), and cataract (24 [3.2%]; Table
Patients with frequent (≥1%) ocular and nonocular AEs over 2 years (safety set, first-treated eye).
Preferred term | Ranibizumab 0.5 mg total, |
95% CI* |
---|---|---|
Ocular AEs | ||
Total | 255 (33.8) | (30.4, 37.3) |
Conjunctival |
58 (7.7) | (5.9, 9.8) |
Eye irritation | 25 (3.3) | (2.2, 4.8) |
Cataract | 24 (3.2) | (2.0, 4.7) |
Conjunctivitis | 22 (2.9) | (1.8, 4.4) |
Eye pain | 21 (2.8) | (1.7, 4.2) |
Vitreous floaters | 18 (2.4) | (1.4, 3.7) |
Retinal haemorrhage | 17 (2.3) | (1.3, 3.6) |
Intraocular pressure |
14 (1.9) | (1.0, 3.1) |
Ocular hypertension | 14 (1.9) | (1.0, 3.1) |
Conjunctivitis allergic | 10 (1.3) | (0.6, 2.4) |
Injection site discharge | 10 (1.3) | (0.6, 2.4) |
Retinal pigment |
10 (1.3) | (0.6, 2.4) |
Blepharitis | 9 (1.2) | (0.5, 2.3) |
Glaucoma | 8 (1.1) | (0.5, 2.1) |
Posterior capsule |
8 (1.1) | (0.5, 2.1) |
Nonocular AEs | ||
Total | 236 (31.3) | (28.0, 34.7) |
Hypertension | 19 (2.5) | (1.5, 3.9) |
Influenza | 17 (2.3) | (1.3, 3.6) |
Diabetes mellitus | 10 (1.3) | (0.6, 2.4) |
Nasopharyngitis | 10 (1.3) | (0.6, 2.4) |
Urinary tract infection | 10 (1.3) | (0.6, 2.4) |
Hypercholesterolemia | 9 (1.2) | (0.5, 2.3) |
Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion.
*Exact Binomial (Clopper-Pearson).
AEs occurring only during the safety observation period are included.
Preferred terms are presented in the descending order of frequency.
A patient with multiple occurrences of an AE is counted only once in the preferred term category.
A patient with multiple AEs is counted only once in the total row.
AE: adverse event; CI: confidence interval; LL: lower limit; UL: upper limit.
Ranibizumab treatment led to BCVA (mean [±SE]) improvements at Month 3 (+4.5 [0.52] letters) and then to a continuous decline in BCVA until Month 24. At Months 12 and 24, the mean change (
(a) Overall mean change in BCVA over time in the first-treated eye and (b) mean change in BCVA overtime based on the number of injections in the first-treated eye (safety set, LOCF). Safety set was defined as all those patients who were treated with at least one dose of ranibizumab and who had at least one safety assessment after study entry and no protocol deviations that warranted exclusion. Baseline VA results were recorded for 680 patients. Month 24 results were evaluated for 673 patients using the LOCF approach. BCVA: best-corrected visual acuity; LOCF: last observation carried forward.
The EPICOHORT study conducted in a routine clinical practice in Europe demonstrated that ranibizumab 0.5 mg therapy was well tolerated in patients with nAMD, with no new ocular or nonocular safety findings observed over the 2-year study period. The broad involvement of European clinics across 54 centres and an observational design of the study (i.e., no treatment protocol) reflect the real-life practice in European ophthalmology clinics.
In the EPICOHORT study, the incidence of selected AEs was low (0%–1.9%) and similar to that observed in RCTs with pro re nata (PRN) regimen in nAMD patients [
Of a total of 4711 ranibizumab injections administered during the study, only one case of endophthalmitis (0.0002/injection) was reported. In this case, the patient received 40 intravitreal ranibizumab injections prior to the event (20 in the first-treated eye and 20 in the second-treated eye); the first-treated eye with endophthalmitis responded to ranibizumab treatment and the patient completed the study with a gain of 3 letters in that eye. Although 19 patients received bilateral treatment on the same day, no cases of endophthalmitis were reported in these patients. In addition, there were no unexpected safety findings in both the bilateral treatment categories whether administered on the same day (
The incidence of ocular and nonocular AEs and SAEs over the 2-year study period was low and consistent with those observed in RCTs using PRN regimen in patients with nAMD [
Over the 2-year study period, at least one protocol deviation was reported in majority of the patients. It may be inferred that due to the observational nature of this study and especially since the clinics chosen were participating for the first time in a ranibizumab clinical trial, the standard procedure of ocular injections (as per the EU label) may not be consistently followed. This is supported by the observation that the majority of protocol deviations were due to omission of antimicrobial eye drops before or after injection (47.7%). Despite this noncompliance to the EU SmPC and protocol deviations, the overall incidence of endophthalmitis (0.1%; 0.0002/injection) was low and within the range as observed in RCTs with PRN regimen [
In the current study, a mean BCVA gain of +4.5 letters from baseline was observed at Month 3 followed by a decline over 24 months. A subgroup analysis of BCVA improvement based on the number of injections showed that more than 1/3 (
Overall, the mean number of injections was low (6.2) and potentially some patients may have been undertreated during the study. The possible undertreatment may be due to the observational nature of the study design (without a scope for specific retreatment criteria other than that in the product label, a standard diagnostic/therapeutic intervention or a visit schedule) and factors related to local practice (e.g., reimbursement issues, patient follow-up). Additionally, for a major part of the study period (i.e., until September 2011) the patients were treated only if they experienced a loss of ≥5 letters as per the current EU SmPC at the time of study. This may have led to retreatment decisions reactive to loss of VA rather than proactive that aim at detecting the early signs of disease activity before actual VA loss. In contrast to this study, a more recent study that has used PRN dosing regimen using both VA and OCT retreatment criteria with monthly monitoring showed VA outcomes comparable to that observed with monthly ranibizumab treatment [
In summary, ranibizumab treatment was generally well tolerated in patients with CNV secondary to AMD in routine clinical practice in European clinics that had not previously participated in clinical trials with ranibizumab. The incidence of selected AEs was low, and no new ocular or nonocular safety findings were observed in this study. Noncompliance to prior antibiotic application did not seem to have any effect on the incidence of endophthalmitis. The recommendation for the patient self-administering antimicrobial drops, four times daily for 3 days before and after injection, is now removed in the current EU label (January 2014). Further studies supporting ranibizumab use in clinical practice are on-going. The on-going LUMINOUS study (ClinicalTrials.gov [
The study was conducted in accordance with the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice, with applicable local regulations and ethical principles laid down in the Declaration of Helsinki. The study protocol was reviewed and approved by the Independent Ethics Committee or Institutional Review Board of each centre. Written informed consent was obtained from each participating patient before enrolment.
Sergio Pagliarini is a consultant for Bayer and Novartis and received grant support from Novartis and educational sponsorship to conferences from Allergan, Novartis, and Alcon. Stephen Beatty has received research grant support from Novartis. Margarita Gekkieva, Abdelkader Si Bouazza, and Stefan Pilz are employees of Novartis Pharma AG. A part of the data from this study was presented at the World Congress on Controversies in Ophthalmology (COPHy), 2013.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Usha Gutti from Medical Communications, Novartis Healthcare Private Ltd., Hyderabad, India, for her medical writing and editorial assistance towards the development of this paper.