- Email: [email protected]
safety of ranibizumab monotherapy or with laser versus laser monotherapy in DME
ORIGINAL ARTICLE
Efficacy/safety of ranibizumab monotherapy or with laser versus laser monotherpay in DME Alan Berger, MD,* Tom Sheidow, MD,† Alan F. Cruess, MD,‡ Jean Daniel Arbour, MD,§ Anne-Sophie Courseau, PharmD,║ Frederica de Takacsy, BSc║ ABSTRACT ● RÉSUMÉ Objective: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema. Design: Twelve-month, multicentre, open-label, parallel-group, randomized, active-control study. Participants: A total of 220 (ranibizumab monotherapy: n ¼ 75, ranibizumab þ laser: n ¼ 73, laser monotherapy: n ¼ 72) patients with a diagnosis of type I or II diabetes and visual impairment caused by macular edema were included in the efficacy analysis. Methods: Ranibizumab was initiated with a fixed loading phase of 3 monthly injections followed by as needed therapy until stable vision achievement. Efficacy end points were the change in best corrected visual acuity (BCVA), change in central retinal thickness (CRT) measured by optical coherence tomography, proportion achieving a 15-letter BCVA gain, and 12-month Visual Function Questionnaire-25 (VFQ-25) score. Safety was assessed with the incidence and severity of adverse events. Results: At 12 months, significant (p o 0.001) mean BCVA improvements were observed for both the ranibizumab monotherapy (þ8.9 [95% confidence interval (CI) 7.0–10.7] letters) and the ranibizumab þ laser (þ8.2 [95% CI 6.0–10.4] letters) groups compared with the laser monotherapy group (þ0.3 [95% CI –2.9 to 3.5] letters). Similarly, a better response in terms of CRT improvement, BCVA letter gain, and VFQ-25 was observed in both ranibizumab groups compared with laser monotherapy. The safety profile was comparable in the 2 ranibizumab groups. Conclusions: Ranibizumab as monotherapy or combined with laser resulted in significantly higher improvements in visual acuity and vision-related quality of life at month 12 as compared with laser monotherapy. Objet : Comparer l’efficacité et l’innocuité du ranibizumab (injections intravitréennes de 0,5 mg), en monothérapie et combiné au laser, avec celles de la monothérapie au laser chez des patients ayant une déficience visuelle due à un œdème maculaire diabétique. Nature : Étude à contrôle actif randomisée de douze mois, à groupes parallèles, ouverte et multicentres. Participants : 220 patients (ranibizumab en monothérapie : n = 75; ranibizumab + laser : n = 73; monothérapie au laser : n = 72) avec un diagnostic de diabète de type 1 ou 2 et une déficience visuelle due à un œdème maculaire ont été inclus dans l’analyse de l’efficacité. Méthodes : Le traitement au ranibizumab a commencé par une phase d’induction fixe de trois injections mensuelles, suivie d’un prolongement si nécessaire, jusqu’à l’obtention d’une vision stable. Les critères d’efficacité étaient : la variation de la meilleure acuité visuelle corrigée (MAVC); la variation de l’épaisseur centrale de la rétine mesurée par tomographie de cohérence optique; la proportion de patients présentant une amélioration de 15 lettres de la MAVC; et le score au questionnaire sur la fonction visuelle (VFQ-25) après 12 mois. L’innocuité était évaluée en fonction de l’incidence et de la gravité des événements indésirables. Résultats : À 12 mois, des améliorations moyennes (intervalles de confiance de 95 %) significatives (p o 0,001) de la MAVC ont été observées tant pour le groupe recevant le ranibizumab en monothérapie [+8,9 (7,0, 10,7) lettres] que pour le groupe traité avec le ranibizumab combiné au laser [+8,2 (6,0, 10,4) lettres], comparativement au groupe traité avec la monothérapie au laser [+0,3 (2,9, 3,5) lettre]. De la même manière, les deux groupes traités avec le ranibizumab ont affiché une meilleure réponse que le groupe traité avec la monothérapie au laser pour ce qui concerne l’amélioration de l’épaisseur centrale de la rétine, la proportion de patients présentant une amélioration de la MAVC ainsi que le score au questionnaire VFQ-25. Le profil d’innocuité était comparable dans les deux groupes traités avec le ranibizumab. Conclusions : Le ranibizumab, tant en monothérapie que combiné avec le laser, a produit des améliorations significativement plus prononcées de l’acuité visuelle et de la qualité de vie liée à la vision, à 12 mois, que la monothérapie au laser.
Diabetic macular edema (DME) is the most common microvascular retinal complication of diabetes and is a leading cause of visual impairment in the working-age population in developed countries.1,2 In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the point prevalence rate of DME in patients with type I
or II diabetes mellitus ranged from 2% to 6%, and the 10year incidence rate ranged from 13% to 25%.3 Moreover, the prevalence rate of DME increases from 0% to 3% in individuals with a recent diagnosis of diabetes to approximately 30% in those with diabetes for Z20 years.3 DME is closely associated to the type and duration of diabetes
From the *St. Michael’s Hospital, Toronto ; †Ivey Eye Institute, St. Joseph’s Hospital, London, Ont ; ‡Dalhousie University, Halifax, N.S; § CHUM, Notre-Dame Hospital & University of Montreal, Montreal ; and ║Novartis Pharmaceuticals, Dorval, Que
Correspondence to Tom Sheidow, MD, Ivey Eye Institute, 268 Grosvenor St., London ON N6A 4V2; [email protected]
Abstract presented at the Association for Research in Vision and Ophthalmology Meeting in Seattle, Wash., October 27, 2014.
Can J Ophthalmol 2015;50:209–216 0008-4182/15/$-see front matter & 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.12.014
Originally received Jul. 22, 2014. Final revision Nov. 3, 2014. Accepted Dec. 22, 2014 CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. and, if left untreated, may lead to vision loss and blindness. Currently, 382 million individuals worldwide are living with diabetes, and the prevalence rate is expected to increase by more than 55% by 2035, with the number of cases estimated to reach 592 million.4 With an aging population and an increasing prevalence of diabetes, the public health concern for DME is significant. Laser photocoagulation, the past standard of care in Canada for DME, has been demonstrated to stabilize central visual acuity (VA) and decrease vision loss but has limited effectiveness at improving VA in the majority of patients. Thus, there remains a clear unmet need for new therapies that are safe and can induce rapid and durable visual improvement. Ranibizumab is a recombinant humanized IgG1κ isotype monoclonal antibody fragment (Fab), designed for intraocular use, that selectively binds vascular endothelial growth factor and blocks its activity. Previous studies have reported that treatment with ranibizumab is well tolerated and effective in improving VA and reducing excess foveal thickness in patients with DME.5–9 In the pivotal phase III trials, RISE and RIDE, where patients were randomized to receive monthly injections of either 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham injection, with eligibility for rescue laser after month three of treatment, significant (p o 0.001) differences, in favour of ranibizumab, were observed in the proportion of patients gaining Z15 BCVA letters after 2 years of follow-up, compared with sham-treated patients (RISE: 18.1% sham vs 44.8% 0.3 mg vs 39.2% 0.5 mg; RIDE: 12.3% sham vs 33.6% 0.3 mg vs 45.7% 0.5 mg).9 Furthermore, the proportions of patients with resolution of macular edema and fluorescein leakage were also significantly greater among ranibizumab-treated patients. We are reporting the results of a Canadian phase IIIb trial, designed to evaluate the efficacy and safety of ranibizumab administered either as monotherapy or in combination with laser photocoagulation in comparison with current standard of care (laser photocoagulation monotherapy) in patients with visual impairment caused by DME (the RESPOND study).
METHODS Study design
This study is a 12-month, multicentre, open-label, 3-parallel-treatment arm, randomized study comparing the efficacy and safety of ranibizumab (Novartis Pharmaceuticals Canada Inc) 0.5 mg intravitreal injection as monotherapy or in combination with laser and active comparator treatment with laser monotherapy in Canadian patients with visual impairment caused by DME (RESPOND). The study was conducted according to the tenets of the Declaration of Helsinki and was approved by the Independent Ethics Committee or Institutional
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Review Board of each participating centre. The enrolment period was between July 7, 2010 and March 28, 2012. All participating patients provided written, informed consent before study entry. The study is registered at clinicaltrials. gov: NCT01135914. Patients
Patients enrolled in the study were males and females Z18 years of age with the following characteristics: (i) a diagnosis of type I or II diabetes mellitus as per the American Diabetes Association or World Health Organization (WHO) guidelines, considered to be stable and with glycosylated hemoglobin r 10%; and (ii) visual impairment caused by focal or diffuse DME with a best corrected visual acuity (BCVA) score between 78 and 39 letters, based on Early Treatment Diabetic Retinopathy Study (ETDRS)–like testing charts at a testing distance of 4 m. Key exclusion criteria were: (i) presence of a concomitant condition in the study eye that could, in the opinion of the investigator, prevent the improvement of VA while on study treatment; (ii) active intraocular inflammation or active infection in either eye; (iii) history of uveitis in either eye; (iv) uncontrolled glaucoma or neovascularization of the iris in either eye; (v) evidence of vitreomacular traction or active proliferative diabetic retinopathy in the study eye; (vi) panretinal laser photocoagulation (within 6 months) or focal/grid laser photocoagulation (within 3 months); (vii) history of vitrectomy or intraocular surgery (within 3 months) in the study eye; (viii) history of a stroke or renal failure; and (ix) blood pressure readings of systolic greater than 160 mm Hg or diastolic greater than 100 mm Hg, untreated hypertension, or change in antihypertensive treatment within 3 months before baseline. An exhaustive list of the inclusion/exclusion criteria is provided in Appendix 1 (available online). Treatment
Eligible patients were randomized at baseline in a 1:1:1 ratio to receive 0.5 mg ranibizumab intravitreal injections monotherapy, 0.5 mg ranibizumab intravitreal injections plus laser photocoagulation, or laser photocoagulation monotherapy. Randomization was stratified by centre and followed a permutated block size of 6. Laser photocoagulation was administered at day one in both the ranibizumab þ laser and laser monotherapy groups. Initial photocoagulation could be split into 2 sessions with 4 weeks in between. Subsequent laser treatments could be administered in accordance with the ETDRS guidelines10 at intervals no shorter than 3 months from the last treatment, and as per the discretion of the investigator. Ranibizumab treatment was initiated with a fixed loading phase of 3 monthly injections followed by as-needed therapy until achievement of stable vision. Stable vision was defined as: (i) stable BCVA scores (i.e., change in BCVA score of r2 letters) over the past 3 consecutive
Efficacy/safety of ranibizumab for DME—Berger et al. visits and no visible intraretinal fluid based on either spectral-domain or time-domain (TD) optical coherence tomography (OCT); or (ii) BCVA score of Z73 letters (approximate Snellen equivalent of 20/40) at the last 2 consecutive visits and no visible intraretinal fluid based on spectral-domain OCT or TD-OCT. Type of OCT technology used was not protocol mandated and was as per the routine clinical care of the site. If 1 of the earlier criteria was met, treatment was to be suspended and patients were followed monthly over a 10-month maintenance phase. After the suspension of treatment, intravitreal injections were to be reinitiated if at least 1 of the following criteria was met: (i) a decrease of BCVA of Z5 letters over the last 2 consecutive visits; (ii) a central retinal thickness (CRT) increase of Z10% by OCT over the last 2 consecutive visits, or (iii) visible intraretinal fluid or cysts by OCT. When treatment was reinitiated, the patient would be treated with at least 2 consecutive monthly injections until stable vision was reached again. Laser treatment in the ranibizumab combination therapy and laser photocoagulation monotherapy groups was administered on day one. If required, the initial photocoagulation could be split into 2 sessions, 4 weeks apart. Subsequent treatments could be readministered in accordance with the ETDRS guidelines at intervals no shorter than 3 months from the last treatment as per the judgement of the treating investigator. For combination therapy, laser treatment had to be administered before the intravitreal injections, allowing a minimum interval between these treatments of 30 minutes. This interval could be extended to a maximum of 48 hours, as judged required by the treating investigator. Patients in the ranibizumab combination group receiving re-treatment with active laser continued to be treated with monthly ranibizumab injections as long as the aforementioned treatment criterion for intravitreal injections was fulfilled. Decisions on re-treatment with laser and on administration of intravitreal injections were independent of one another.
Efficacy and safety assessments
Patients were followed for 12 months, and study visits were scheduled every 30 ⫾ 7 days. Efficacy assessments included BCVA, OCT, colour fundus photography, and fluorescein angiography. The primary outcome measure was the mean change in BCVA from baseline to 12 months. Secondary outcome measures were the mean change in BCVA at 3, 6, and 9 months, the change in CRT over time, the proportion of patients with a 15letter (3-line) gain in BCVA over time, and the mean health-related quality of life at 12 months (adjusted for baseline score) as measured with the Visual Function Questionnaire-25 (VFQ-25). Safety was assessed with the incidence and severity of adverse events (AEs) and serious AEs (SAEs), coded using MedDRA version 15.1.
Statistical analysis
Sample size estimations were based on the primary end point, namely, the change in BCVA between baseline and 12 months. Bonferroni correction was used to account for 2 pairwise comparisons (ranibizumab monotherapy vs laser monotherapy and ranibizumab combination therapy vs laser monotherapy). Based on 80% power and a 2.5% level of significance for a 2-sided unstratified Mann– Whitney test under the normal distribution, and assuming a 10% dropout rate, approximately 80 patients per arm for a total of 240 patients were to be recruited in the trial. The main efficacy analysis was conducted on the intentto-treat (ITT) population, consisting of all patients receiving at least 1 dose of either study treatment for monotherapy or 1 of the 2 study treatments for combination therapy, and had at least 1 postbaseline assessment. In addition, efficacy analyses were performed on the per-protocol (PP) population, which comprised all patients in the ITT population who adhered to the protocol without any major deviations and completed both baseline and the 12-month follow-up assessments, as well as all mandatory visits. Safety analyses were carried out on the safety population including all patients who received at least 1 dose of the study medication in any treatment group. Fifteen study patients from 1 participating centre were excluded from all efficacy analyses as a gesture of prospective due diligence because of concerns for the quality of the data. Therefore, 2 safety populations were defined: 1 excluding these patients (Safety, used for AEs) and another including them (Safety II, used for SAEs). Descriptive statistics (including number of observations, mean, standard deviation [SD], and confidence intervals [CIs]) were provided for continuous variables and frequency distributions for categorical variables. Primary efficacy analysis used t tests to compare treatment arms, focusing on ranibizumab monotherapy or ranibizumab þ laser versus laser monotherapy. The Hochberg step-up procedure was used to control family-wise type 1 error rate at alpha ¼ 0.05 due to multiple comparisons among the treatment groups. Within-group changes in BCVA over time were assessed for statistical significance with the paired t test, and estimates were presented with 95% CIs. Between-group differences in categorical variables were assessed with the χ2 test, whereas a generalized linear model, adjusting for baseline value, was used to compare the health-related quality of life at 12 months among the 3 groups. All analyses were conducted using SAS version 9.2 (SAS Institute Inc, Cary, N.C.).
RESULTS A total of 237 patients were randomized and received study treatment, of whom 220 comprised the ITT population (Fig. 1). Seventy-five (34.1%) ITT patients were treated with ranibizumab monotherapy, 73 (33.2%) CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. Safety Population II (N=237)
Excluded (n=15)
Safety Population (N=222)
Excluded (n=2)
ITT Population (N=220)
Ranibizumab 0.5 mg (n=75)
Laser (n=72)
Ranibizumab 0.5 mg + Laser (n=73)
Fig. 1 — Patient disposition. *Patients from 1 participating centre were excluded from all efficacy analyses as a gesture of prospective due diligence because of concerns for the quality of the data. †Patients did not have at least 1 postbaseline assessment.
with ranibizumab þ laser, and 72 (32.7%) with laser monotherapy. Overall, the mean (SD) age of the ITT population at baseline was 61.7 (9.8) years, with the majority being male (60.0%) and white (87.7%). Table 1 summarizes the baseline demographics and disease characteristics for the 3 treatment arms. Patient characteristics were comparable between groups; the only exceptions being the type of DME, which was focal in 42.7% of patients in the ranibizumab monotherapy group, 53.4% of patients in the ranibizumab þ laser group, and 36.1%
in the laser monotherapy group and CRT (448.5 vs 422.1 vs 458.0 μm, respectively). The mean (SD) time elapsed since diabetes diagnosis was 17.2 (10.4) years, and the mean (SD) duration of DME was 1.8 (2.8) without any remarkable differences between groups (Fig. 2). After 12 months of treatment, statistically significant (p o 0.001) improvements in the BCVA letter score were observed for both the ranibizumab monotherapy group (þ8.9 letters [95% CI 7.0–10.7]) and the ranibizumab þ
Table 1—Baseline demographics and disease characteristics: intent-to-treat population Parameter Mean age, y (SD) Race, n (%) White Asian Black Other Male sex, n (%) Type of diabetes, n (%) Type I Type II Other Mean years since diabetes diagnosis (SD) Mean years since DME diagnosis (SD) History of DME treatment, n (%) Study eye, n (%) Left eye Right eye Study eye DME type, n (%) Diffuse Focal BCVA study eye, letters, mean (SD) CRT study eye, μm, mean (SD) Mean HbA1c, % (SD)
Ranibizumab 0.5 mg (N ¼ 75)
Ranibizumab 0.5 mg þ Laser (N ¼ 73)
Laser (N ¼ 72)
61.5 (9.9)
60.8 (10.2)
62.8 (9.4)
65 4 2 4 42
(86.7) (5.3) (2.7) (5.3) (56.0)
64 3 2 4 47
(87.7) (4.1) (2.7) (5.5) (64.4)
64 3 0 5 43
(88.9) (4.2) (0.0) (6.9) (59.7)
9 66 0 16.5 1.6 46
(12.0) (88.0) (0.0) (9.0) (2.3) (61.3)
11 58 4 18.5 2.1 55
(15.1) (79.5) (5.5) (11.6) (3.1) (75.3)
8 63 1 16.6 1.7 48
(11.1) (87.5) (1.4) (10.7) (2.9) (66.7)
33 (44.0) 42 (56.0) 43 32 63.1 448.5 7.8
(57.3) (42.7) (10.6) (136.6) (1.3)
39 (53.4) 34 (46.6) 34 39 64.8 422.1 7.7
(46.6) (53.4) (9.3) (142.3) (1.1)
SD, standard deviation; DME, diabetic macular edema; BCVA, best corrected visual acuity; CRT, central retinal thickness; HbA1c, glycosylated hemoglobin.
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44 (61.1) 28 (38.9) 46 26 61.9 458.0 7.6
(63.9) (36.1) (10.6) (133.1) (1.3)
Efficacy/safety of ranibizumab for DME—Berger et al. A.
Change from Baseline to Month 12 in BCVA Letters
Mean (95% CI) BCVA Letters Gained
12 10 8
Ranibizumab 0.5mg
6
Ranibizumab 0.5mg + Laser 4
Laser
2 0 -2
B.
Change from Baseline to Month 12 in CRT (μm)
Mean Change (95% CI) in CRT (μm)
0 -20 -40 -60 -80
Ranibizumab 0.5mg
-100
Ranibizumab 0.5mg + Laser
-120
Laser
-140 -160 -180 -200
Fig. 2 — Change from baseline to month 12 in best corrected visual acuity (BCVA) and central retinal thickness (CRT).
laser group (þ8.2letters [95% CI 6.0–10.4]) compared with the laser monotherapy group (mean þ0.3 [95% CI – 2.9 to 3.5]; Table 2 and Fig. 2A.). PP analysis showed similar results (data not shown), with slightly higher within-group improvements in all treatment groups. Similar results were observed when looking at 3, 6, and 9 months of treatment with ranibizumab inducing statistically significant improvements in BCVA as early as 3 months and laser monotherapy being associated with modest nonsignificant changes in BCVA. With respect to CRT, rapid and sustained improvements were observed in both ranibizumab arms. The laser monotherapy arm showed a slower, although steady improvement. Change in CRT after 12 months was considerably better in the ranibizumab monotherapy (–143.5 mm (95% CI –177.5 to –109.4]) and ranibizumab þ laser (–152.2 mm [95% CI –185.5 to –119.0]) groups as compared with laser monotherapy (–107.1 mm [95% CI –143.9 to –70.2]; Table 2 and Fig. 2B). Furthermore, at month 12, 20.0% of patients in the ranibizumab monotherapy group and 23.3% of patients in the ranibizumab þ laser group had a gain of Z15 letters
from baseline, in comparison with 5.6% of patients in the laser monotherapy group. Similar results were observed when looking at the proportion of patients gaining Z5 letters (66.7% vs 58.9% vs 34.7% in the 3 groups, respectively) or Z10 letters (49.3% vs 32.9% vs 13.9%, respectively) at 12 months. Vision-related quality of life at 12 months was significantly higher in the 2 ranibizumab treatment groups as compared with laser monotherapy (p o 0.001). Upon adjusting for baseline values, the difference in mean composite VFQ-25 score between the ranibizumab monotherapy group and the laser monotherapy group was 6.0 (95% CI 2.7–9.4) and 6.3 (95% CI 2.9–9.6) for the ranibizumab þ laser group. Within the Safety population, treatment exposure was similar between the ranibizumab monotherapy group and the ranibizumab þ laser group, with patients receiving a mean (SD) of 9.2 (2.8) and 8.8 (2.9) injections in the 2 groups, respectively, during the trial. The mean (SD) number of laser treatments in the ranibizumab þ laser and laser monotherapy groups was 1.6 (1.0) and 2.6 (2.1), respectively. Although the safety profile was similar between groups, the incidence of AEs was slightly higher in the CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. Table 2—Efficacy outcomes: intent-to-treat population
Mean change from baseline in BCVA (letters) Month 12 (95% CI) Month 9 (95% CI) Month 6 (95% CI) Month 3 (95% CI) Mean change from baseline in CRT, μm Month 12 (95% CI) Month 9 (95% CI) Month 6 (95% CI) Month 3 (95% CI) Patients achieving a gain of Z15 letters† Month 12 Month 9 Month 6 Month 3 Patients achieving the following gain‡ at month 12 Z10 letters Z5 letters Mean baseline VFQ-25 (SD) Mean difference in VFQ-25 from laser monotherapy group at month 12‡ (95% CI)
Ranibizumab 0.5 mg (N ¼ 75)
Ranibizumab 0.5 mg þ Laser (N ¼ 73)
Laser (N ¼ 72)
p o 0.001* 8.9 (7.0, 10.7) 6.9 (4.0, 9.8) 7.1 (5.2, 8.9) 5.3 (3.5, 7.0)
p o 0.001* 8.2 (6.0, 10.4) 7.1 (5.2, 9.0) 5.6 (3.6, 7.6) 3.7 (1.1, 6.2)
— 0.3 (–2.9, 3.5) –0.2 (–3.0, 2.6) 0.9 (–0.9, 2.7) 1.4 (–0.1, 3.0)
–143.5 (–177.5, –109.4) –135.9 (–169.5, –102.3) –129.3 (–156.7, –102.0) –108.9 (–135.0, –82.9)
–152.2 (–185.5, –119.0) –138.1 (–168.3, –107.8) –114.2 (–140.7, –87.8) –105.7 (–135.9, –75.5)
–107.1 (–143.9, –70.2) –85.8 (–119.5, –52.2) –64.4 (–91.8, –36.9) –32.5 (–59.9, –5.1)
20.0% 20.0% 13.3% 9.3%
23.3% 12.3% 11.0% 8.2%
5.6% 0.0% 1.4% 2.8%
49.3% 66.7% 76.9 (15.4) 6.0 (2.7–9.4)
32.9% 58.9% 78.4 (16.0) 6.3 (2.9–9.6)
13.9% 34.7% 76.6 (16.2) —
BCVA, best corrected visual acuity; CI, confidence interval; CRT, central retinal thickness; SD, standard deviation; VFQ-25, Visual Function Questionnaire-25. *Between-group comparison with laser group. † Patients with missing information were considered as not achieving the target gain. ‡ Upon adjusting for baseline value.
2 ranibizumab groups compared with the laser monotherapy group (Table 3). Fifty-three (70.7%) patients in the ranibizumab monotherapy group experienced at least 1 AE, 49 (67.1%) in the ranibizumab þ laser group, and 44 (59.5%) in the laser monotherapy group. Intraocular pressure increase, conjunctival hemorrhage, vitreous hemorrhage, and nasopharyngitis were the most common AEs in patients who received active treatment. Overall, 26 (11.0%) patients in the Safety II population experienced 40 SAEs; 6 patients (7.6%) experienced at least 1 SAE in the laser monotherapy group, 11 patients (13.8%) in the ranibizumab monotherapy group, and 9 patients (11.5%) in the ranibizumab þ laser group. Vitreous hemorrhage (3.8% of patients in the laser monotherapy group vs 0% in the 2 ranibizumab groups), congestive cardiac failure (2.5% of patients in the laser monotherapy group vs 0% in the 2 ranibizumab groups), and cellulitis (2.5% of patients in the ranibizumab monotherapy group vs 0% in the other 2 groups) were the most common SAEs. One SAE (ischemic colitis) in the ranibizumab þ laser group was judged by the investigator to be related to the study treatment and none in the ranibizumab monotherapy and laser monotherapy groups. No fatal events were reported. The incidence of AEs leading to discontinuation in the Safety population was similar in the ranibizumab monotherapy (n ¼ 1; 1.3%) and ranibizumab þ laser (n ¼ 1; 1.4%) treatment groups, and lower than the laser monotherapy group (n ¼ 4; 5.4%).
DISCUSSION This study was undertaken to compare the clinical efficacy and safety of 0.5 mg ranibizumab as monotherapy
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or combination therapy (ranibizumab þ laser) with laser treatment over a 12-month treatment period. Ranibizumab treatment, whether alone or in combination with laser, induced significantly higher clinically meaningful improvements in VA at month 12, compared with laser monotherapy, and resulted in a rapid and sustained improvement in CRT over the 12-month treatment period. Similar to the RISE/RIDE studies, a significantly higher proportion of patients treated with ranibizumab 0.5 mg monotherapy achieved an improvement in BCVA Z15 letters at month 12, when compared with non–ranibizumab-treated patients. The higher proportion of patients in the RISE/ RIDE studies achieving this end point (39.2% and 45.7%, respectively) could possibly be explained by the monthly dosing schedule over a longer treatment period (24 months) in these studies as compared with this study’s 3-month loading phase followed by as needed dosing. One limitation of this study relates to the inadvertent bias of the laser monotherapy group having a significantly higher percentage of nonfocal DME, a subset of DME generally associated with a poorer visual prognosis in response to laser. However, the results presented are nonetheless consistent with 2 additional large phase III trials, the Ranibizumab or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE) Study and the Diabeteic Retinpathy Clincal Research Network (DRCR.net) Protocol I, both using a flexible individualized ranibizumab dosing schedule that approximates the design of this study, which examined the safety and efficacy of ranibizumab in the treatment of DME.6,11 Both trials indicated that ranibizumab monotherapy or combination therapy with laser was superior to laser alone in improving BCVA and reducing CRT in individuals with visual impairment caused by DME. The
Efficacy/safety of ranibizumab for DME—Berger et al. Table 3—Incidence of adverse events by preferred term: Safety population (incidence rate 4 1%)
Patients with at least 1 AE Preferred term Intraocular pressure increased Conjunctival hemorrhage Nasopharyngitis Vitreous hemorrhage Hypertension Cataract Visual acuity reduced Diabetic retinal edema Vitreous floaters Bronchitis Eye pain Headache Hypercholesterolemia Influenza Neuropathy peripheral Corneal abrasion Dry eye Localized infection Vision blurred Back pain Eye irritation Macular edema Vitreous detachment Cellulitis Contusion Corneal erosion Diabetes mellitus Glycosylated hemoglobin increased Hyperkalemia Lacrimation increased Macular fibrosis Pneumonia Procedural nausea Retinal neovascularisation Seasonal allergy Urinary tract infection
Ranibizumab 0.5 mg, (N ¼ 75)
Ranibizumab 0.5 mg þ Laser, (N ¼ 73)
Laser, n (%) (N ¼ 74)
All Safety Patients, (N ¼ 222)
53 (70.7%)
49 (67.1%)
44 (59.5%)
146 (65.8%)
10 6 5 2 5 6 3 1 3 2 3 4 2 1 1 3 2 2 1 4 0 1 2 3 1 3 0 2 1 1 2 1 0 0 1 2
8 11 5 5 2 0 2 3 3 1 3 1 2 3 5 2 2 1 4 0 4 0 1 0 0 0 2 0 1 2 0 1 2 2 2 1
(13.3%) (8.0%) (6.7%) (2.7%) (6.7%) (8.0%) (4.0%) (1.3%) (4.0%) (2.7%) (4.0%) (5.3%) (2.7%) (1.3%) (1.3%) (4.0%) (2.7%) (2.7%) (1.3%) (5.3%) (0.0%) (1.3%) (2.7%) (4.0%) (1.3%) (4.0%) (0.0%) (2.7%) (1.3%) (1.3%) (2.7%) (1.3%) (0.0%) (0.0%) (1.3%) (2.7%)
(11.0%) (15.1%) (6.8%) (6.8%) (2.7%) (0.0%) (2.7%) (4.1%) (4.1%) (1.4%) (4.1%) (1.4%) (2.7%) (4.1%) (6.8%) (2.7%) (2.7%) (1.4%) (5.5%) (0.0%) (5.5%) (0.0%) (1.4%) (0.0%) (0.0%) (0.0%) (2.7%) (0.0%) (1.4%) (2.7%) (0.0%) (1.4%) (2.7%) (2.7%) (2.7%) (1.4%)
3 2 4 7 5 3 3 3 1 3 0 1 2 2 0 0 1 2 0 0 0 3 1 0 2 0 1 1 1 0 1 1 1 1 0 0
(4.1%) (2.7%) (5.4%) (9.5%) (6.8%) (4.1%) (4.1%) (4.1%) (1.4%) (4.1%) (0.0%) (1.4%) (2.7%) (2.7%) (0.0%) (0.0%) (1.4%) (2.7%) (0.0%) (0.0%) (0.0%) (4.1%) (1.4%) (0.0%) (2.7%) (0.0%) (1.4%) (1.4%) (1.4%) (0.0%) (1.4%) (1.4%) (1.4%) (1.4%) (0.0%) (0.0%)
21 19 14 14 12 9 8 7 7 6 6 6 6 6 6 5 5 5 5 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3
(9.5%) (8.6%) (6.3%) (6.3%) (5.4%) (4.1%) (3.6%) (3.2%) (3.2%) (2.7%) (2.7%) (2.7%) (2.7%) (2.7%) (2.7%) (2.3%) (2.3%) (2.3%) (2.3%) (1.8%) (1.8%) (1.8%) (1.8%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%)
AE, adverse event.
long-term results from the DRCR.net, the Ranibizumab for Edema of the mAcula in Diabetes study (READ-2), and RESTORE extension studies further showed that response to ranibizumab is sustained through years two8,11 and three,12 with progressively declining number of injections over time required to control edema. Another possible limitation of this study is inherent to its openlabel design. However, given the nature of the 3 treatments compared, this design was appropriate. Furthermore, the nonsubjective nature of the visual and anatomic outcomes reported renders it unlikely that they were influenced by patient/physician knowledge of the treatment arm. In line with the clinical data, patients who received ranibizumab had a better vision-related quality of life at 12 months than those who were treated with laser monotherapy. These results are consistent with those reported in the comparable multicountry RESTORE study.6 Overall, ranibizumab was well tolerated and showed a comparable safety profile, although with slightly higher incidence of AEs than that of laser monotherapy. In summary, the results of this study have shown that treatment with ranibizumab intravitreal injections, either as monotherapy or in combination
with laser, in patients with visual impairment caused by DME was effective in rapidly and sustainably improving vision, reducing the risk for further vision loss and improving quality of life. Altogether, the findings from the RESPOND study further reinforce the well-documented efficacy and safety profile of ranibizumab.
Disclosures: A.B. has served on advisory boards for Novartis, Bayer, Alcon, and Allergan; his institution has received research funding from Novartis and fellowship funding from Novartis, Alcon, and Bayer. T.S. has been a member of advisory boards for Novartis, Bayer, and Alcon and has received research grant-in-aid funding from Novartis (42 years ago) and QLT (45 years ago). A. C. has served on advisory boards for Novartis, Alcon, and Bayer and has participated in company-sponsored clinical trials. J.-D.A. has no conflicts of interest. A.-S.C. and F.d.T. are employees of Novartis. Acknowledgements: Medical writing assistance was provided by JSS Medical Research Inc. The authors acknowledge Dr. Sophia Kajla for reviewing and supervising the development of the manuscript, as well as the study investigators: John Gonder, Laurent Lalonde, Michael Bense, Peter Kertes, Patrick Ma,
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Efficacy/safety of ranibizumab for DME—Berger et al. Vladimir Kozousek, John Chen, Michael Brent, Eric Tourville, Stan Shortt, Sébastien Olivier, Geoff Williams, Fareed Ali, Shelly Boyd, Christopher Jackman, Michel Giunta, Brian Leonard, Tom Sheidow, Kevin Colleaux, Danny Gauthier, and Patrick Saurel. Supported by: Pharmaceuticals.
The
study
was
funded
by
Novartis
APPENDIX Supplementary Materials
Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.jcjo.2014.12.014. REFERENCES 1. Fong DS, Aiello LP, Ferris FL III, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27:2540-53. 2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304:649-56. 3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-74.
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4. International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium; International Diabetes Federation, 2013. 5. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399-405. 6. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-25. 7. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2009;116:2175-81. 8. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146-51. 9. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801. 10. Photocoagulation therapy for diabetic eye disease. Early Treatment Diabetic Retinopathy Study Research Group. JAMA. 1985;254: 3086. 11. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-77. 12. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121:1045-53.
Efficacy/safety of ranibizumab monotherapy or with laser versus laser monotherpay in DME Alan Berger, MD,* Tom Sheidow, MD,† Alan F. Cruess, MD,‡ Jean Daniel Arbour, MD,§ Anne-Sophie Courseau, PharmD,║ Frederica de Takacsy, BSc║ ABSTRACT ● RÉSUMÉ Objective: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema. Design: Twelve-month, multicentre, open-label, parallel-group, randomized, active-control study. Participants: A total of 220 (ranibizumab monotherapy: n ¼ 75, ranibizumab þ laser: n ¼ 73, laser monotherapy: n ¼ 72) patients with a diagnosis of type I or II diabetes and visual impairment caused by macular edema were included in the efficacy analysis. Methods: Ranibizumab was initiated with a fixed loading phase of 3 monthly injections followed by as needed therapy until stable vision achievement. Efficacy end points were the change in best corrected visual acuity (BCVA), change in central retinal thickness (CRT) measured by optical coherence tomography, proportion achieving a 15-letter BCVA gain, and 12-month Visual Function Questionnaire-25 (VFQ-25) score. Safety was assessed with the incidence and severity of adverse events. Results: At 12 months, significant (p o 0.001) mean BCVA improvements were observed for both the ranibizumab monotherapy (þ8.9 [95% confidence interval (CI) 7.0–10.7] letters) and the ranibizumab þ laser (þ8.2 [95% CI 6.0–10.4] letters) groups compared with the laser monotherapy group (þ0.3 [95% CI –2.9 to 3.5] letters). Similarly, a better response in terms of CRT improvement, BCVA letter gain, and VFQ-25 was observed in both ranibizumab groups compared with laser monotherapy. The safety profile was comparable in the 2 ranibizumab groups. Conclusions: Ranibizumab as monotherapy or combined with laser resulted in significantly higher improvements in visual acuity and vision-related quality of life at month 12 as compared with laser monotherapy. Objet : Comparer l’efficacité et l’innocuité du ranibizumab (injections intravitréennes de 0,5 mg), en monothérapie et combiné au laser, avec celles de la monothérapie au laser chez des patients ayant une déficience visuelle due à un œdème maculaire diabétique. Nature : Étude à contrôle actif randomisée de douze mois, à groupes parallèles, ouverte et multicentres. Participants : 220 patients (ranibizumab en monothérapie : n = 75; ranibizumab + laser : n = 73; monothérapie au laser : n = 72) avec un diagnostic de diabète de type 1 ou 2 et une déficience visuelle due à un œdème maculaire ont été inclus dans l’analyse de l’efficacité. Méthodes : Le traitement au ranibizumab a commencé par une phase d’induction fixe de trois injections mensuelles, suivie d’un prolongement si nécessaire, jusqu’à l’obtention d’une vision stable. Les critères d’efficacité étaient : la variation de la meilleure acuité visuelle corrigée (MAVC); la variation de l’épaisseur centrale de la rétine mesurée par tomographie de cohérence optique; la proportion de patients présentant une amélioration de 15 lettres de la MAVC; et le score au questionnaire sur la fonction visuelle (VFQ-25) après 12 mois. L’innocuité était évaluée en fonction de l’incidence et de la gravité des événements indésirables. Résultats : À 12 mois, des améliorations moyennes (intervalles de confiance de 95 %) significatives (p o 0,001) de la MAVC ont été observées tant pour le groupe recevant le ranibizumab en monothérapie [+8,9 (7,0, 10,7) lettres] que pour le groupe traité avec le ranibizumab combiné au laser [+8,2 (6,0, 10,4) lettres], comparativement au groupe traité avec la monothérapie au laser [+0,3 (2,9, 3,5) lettre]. De la même manière, les deux groupes traités avec le ranibizumab ont affiché une meilleure réponse que le groupe traité avec la monothérapie au laser pour ce qui concerne l’amélioration de l’épaisseur centrale de la rétine, la proportion de patients présentant une amélioration de la MAVC ainsi que le score au questionnaire VFQ-25. Le profil d’innocuité était comparable dans les deux groupes traités avec le ranibizumab. Conclusions : Le ranibizumab, tant en monothérapie que combiné avec le laser, a produit des améliorations significativement plus prononcées de l’acuité visuelle et de la qualité de vie liée à la vision, à 12 mois, que la monothérapie au laser.
Diabetic macular edema (DME) is the most common microvascular retinal complication of diabetes and is a leading cause of visual impairment in the working-age population in developed countries.1,2 In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the point prevalence rate of DME in patients with type I
or II diabetes mellitus ranged from 2% to 6%, and the 10year incidence rate ranged from 13% to 25%.3 Moreover, the prevalence rate of DME increases from 0% to 3% in individuals with a recent diagnosis of diabetes to approximately 30% in those with diabetes for Z20 years.3 DME is closely associated to the type and duration of diabetes
From the *St. Michael’s Hospital, Toronto ; †Ivey Eye Institute, St. Joseph’s Hospital, London, Ont ; ‡Dalhousie University, Halifax, N.S; § CHUM, Notre-Dame Hospital & University of Montreal, Montreal ; and ║Novartis Pharmaceuticals, Dorval, Que
Correspondence to Tom Sheidow, MD, Ivey Eye Institute, 268 Grosvenor St., London ON N6A 4V2; [email protected]
Abstract presented at the Association for Research in Vision and Ophthalmology Meeting in Seattle, Wash., October 27, 2014.
Can J Ophthalmol 2015;50:209–216 0008-4182/15/$-see front matter & 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.12.014
Originally received Jul. 22, 2014. Final revision Nov. 3, 2014. Accepted Dec. 22, 2014 CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. and, if left untreated, may lead to vision loss and blindness. Currently, 382 million individuals worldwide are living with diabetes, and the prevalence rate is expected to increase by more than 55% by 2035, with the number of cases estimated to reach 592 million.4 With an aging population and an increasing prevalence of diabetes, the public health concern for DME is significant. Laser photocoagulation, the past standard of care in Canada for DME, has been demonstrated to stabilize central visual acuity (VA) and decrease vision loss but has limited effectiveness at improving VA in the majority of patients. Thus, there remains a clear unmet need for new therapies that are safe and can induce rapid and durable visual improvement. Ranibizumab is a recombinant humanized IgG1κ isotype monoclonal antibody fragment (Fab), designed for intraocular use, that selectively binds vascular endothelial growth factor and blocks its activity. Previous studies have reported that treatment with ranibizumab is well tolerated and effective in improving VA and reducing excess foveal thickness in patients with DME.5–9 In the pivotal phase III trials, RISE and RIDE, where patients were randomized to receive monthly injections of either 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham injection, with eligibility for rescue laser after month three of treatment, significant (p o 0.001) differences, in favour of ranibizumab, were observed in the proportion of patients gaining Z15 BCVA letters after 2 years of follow-up, compared with sham-treated patients (RISE: 18.1% sham vs 44.8% 0.3 mg vs 39.2% 0.5 mg; RIDE: 12.3% sham vs 33.6% 0.3 mg vs 45.7% 0.5 mg).9 Furthermore, the proportions of patients with resolution of macular edema and fluorescein leakage were also significantly greater among ranibizumab-treated patients. We are reporting the results of a Canadian phase IIIb trial, designed to evaluate the efficacy and safety of ranibizumab administered either as monotherapy or in combination with laser photocoagulation in comparison with current standard of care (laser photocoagulation monotherapy) in patients with visual impairment caused by DME (the RESPOND study).
METHODS Study design
This study is a 12-month, multicentre, open-label, 3-parallel-treatment arm, randomized study comparing the efficacy and safety of ranibizumab (Novartis Pharmaceuticals Canada Inc) 0.5 mg intravitreal injection as monotherapy or in combination with laser and active comparator treatment with laser monotherapy in Canadian patients with visual impairment caused by DME (RESPOND). The study was conducted according to the tenets of the Declaration of Helsinki and was approved by the Independent Ethics Committee or Institutional
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Review Board of each participating centre. The enrolment period was between July 7, 2010 and March 28, 2012. All participating patients provided written, informed consent before study entry. The study is registered at clinicaltrials. gov: NCT01135914. Patients
Patients enrolled in the study were males and females Z18 years of age with the following characteristics: (i) a diagnosis of type I or II diabetes mellitus as per the American Diabetes Association or World Health Organization (WHO) guidelines, considered to be stable and with glycosylated hemoglobin r 10%; and (ii) visual impairment caused by focal or diffuse DME with a best corrected visual acuity (BCVA) score between 78 and 39 letters, based on Early Treatment Diabetic Retinopathy Study (ETDRS)–like testing charts at a testing distance of 4 m. Key exclusion criteria were: (i) presence of a concomitant condition in the study eye that could, in the opinion of the investigator, prevent the improvement of VA while on study treatment; (ii) active intraocular inflammation or active infection in either eye; (iii) history of uveitis in either eye; (iv) uncontrolled glaucoma or neovascularization of the iris in either eye; (v) evidence of vitreomacular traction or active proliferative diabetic retinopathy in the study eye; (vi) panretinal laser photocoagulation (within 6 months) or focal/grid laser photocoagulation (within 3 months); (vii) history of vitrectomy or intraocular surgery (within 3 months) in the study eye; (viii) history of a stroke or renal failure; and (ix) blood pressure readings of systolic greater than 160 mm Hg or diastolic greater than 100 mm Hg, untreated hypertension, or change in antihypertensive treatment within 3 months before baseline. An exhaustive list of the inclusion/exclusion criteria is provided in Appendix 1 (available online). Treatment
Eligible patients were randomized at baseline in a 1:1:1 ratio to receive 0.5 mg ranibizumab intravitreal injections monotherapy, 0.5 mg ranibizumab intravitreal injections plus laser photocoagulation, or laser photocoagulation monotherapy. Randomization was stratified by centre and followed a permutated block size of 6. Laser photocoagulation was administered at day one in both the ranibizumab þ laser and laser monotherapy groups. Initial photocoagulation could be split into 2 sessions with 4 weeks in between. Subsequent laser treatments could be administered in accordance with the ETDRS guidelines10 at intervals no shorter than 3 months from the last treatment, and as per the discretion of the investigator. Ranibizumab treatment was initiated with a fixed loading phase of 3 monthly injections followed by as-needed therapy until achievement of stable vision. Stable vision was defined as: (i) stable BCVA scores (i.e., change in BCVA score of r2 letters) over the past 3 consecutive
Efficacy/safety of ranibizumab for DME—Berger et al. visits and no visible intraretinal fluid based on either spectral-domain or time-domain (TD) optical coherence tomography (OCT); or (ii) BCVA score of Z73 letters (approximate Snellen equivalent of 20/40) at the last 2 consecutive visits and no visible intraretinal fluid based on spectral-domain OCT or TD-OCT. Type of OCT technology used was not protocol mandated and was as per the routine clinical care of the site. If 1 of the earlier criteria was met, treatment was to be suspended and patients were followed monthly over a 10-month maintenance phase. After the suspension of treatment, intravitreal injections were to be reinitiated if at least 1 of the following criteria was met: (i) a decrease of BCVA of Z5 letters over the last 2 consecutive visits; (ii) a central retinal thickness (CRT) increase of Z10% by OCT over the last 2 consecutive visits, or (iii) visible intraretinal fluid or cysts by OCT. When treatment was reinitiated, the patient would be treated with at least 2 consecutive monthly injections until stable vision was reached again. Laser treatment in the ranibizumab combination therapy and laser photocoagulation monotherapy groups was administered on day one. If required, the initial photocoagulation could be split into 2 sessions, 4 weeks apart. Subsequent treatments could be readministered in accordance with the ETDRS guidelines at intervals no shorter than 3 months from the last treatment as per the judgement of the treating investigator. For combination therapy, laser treatment had to be administered before the intravitreal injections, allowing a minimum interval between these treatments of 30 minutes. This interval could be extended to a maximum of 48 hours, as judged required by the treating investigator. Patients in the ranibizumab combination group receiving re-treatment with active laser continued to be treated with monthly ranibizumab injections as long as the aforementioned treatment criterion for intravitreal injections was fulfilled. Decisions on re-treatment with laser and on administration of intravitreal injections were independent of one another.
Efficacy and safety assessments
Patients were followed for 12 months, and study visits were scheduled every 30 ⫾ 7 days. Efficacy assessments included BCVA, OCT, colour fundus photography, and fluorescein angiography. The primary outcome measure was the mean change in BCVA from baseline to 12 months. Secondary outcome measures were the mean change in BCVA at 3, 6, and 9 months, the change in CRT over time, the proportion of patients with a 15letter (3-line) gain in BCVA over time, and the mean health-related quality of life at 12 months (adjusted for baseline score) as measured with the Visual Function Questionnaire-25 (VFQ-25). Safety was assessed with the incidence and severity of adverse events (AEs) and serious AEs (SAEs), coded using MedDRA version 15.1.
Statistical analysis
Sample size estimations were based on the primary end point, namely, the change in BCVA between baseline and 12 months. Bonferroni correction was used to account for 2 pairwise comparisons (ranibizumab monotherapy vs laser monotherapy and ranibizumab combination therapy vs laser monotherapy). Based on 80% power and a 2.5% level of significance for a 2-sided unstratified Mann– Whitney test under the normal distribution, and assuming a 10% dropout rate, approximately 80 patients per arm for a total of 240 patients were to be recruited in the trial. The main efficacy analysis was conducted on the intentto-treat (ITT) population, consisting of all patients receiving at least 1 dose of either study treatment for monotherapy or 1 of the 2 study treatments for combination therapy, and had at least 1 postbaseline assessment. In addition, efficacy analyses were performed on the per-protocol (PP) population, which comprised all patients in the ITT population who adhered to the protocol without any major deviations and completed both baseline and the 12-month follow-up assessments, as well as all mandatory visits. Safety analyses were carried out on the safety population including all patients who received at least 1 dose of the study medication in any treatment group. Fifteen study patients from 1 participating centre were excluded from all efficacy analyses as a gesture of prospective due diligence because of concerns for the quality of the data. Therefore, 2 safety populations were defined: 1 excluding these patients (Safety, used for AEs) and another including them (Safety II, used for SAEs). Descriptive statistics (including number of observations, mean, standard deviation [SD], and confidence intervals [CIs]) were provided for continuous variables and frequency distributions for categorical variables. Primary efficacy analysis used t tests to compare treatment arms, focusing on ranibizumab monotherapy or ranibizumab þ laser versus laser monotherapy. The Hochberg step-up procedure was used to control family-wise type 1 error rate at alpha ¼ 0.05 due to multiple comparisons among the treatment groups. Within-group changes in BCVA over time were assessed for statistical significance with the paired t test, and estimates were presented with 95% CIs. Between-group differences in categorical variables were assessed with the χ2 test, whereas a generalized linear model, adjusting for baseline value, was used to compare the health-related quality of life at 12 months among the 3 groups. All analyses were conducted using SAS version 9.2 (SAS Institute Inc, Cary, N.C.).
RESULTS A total of 237 patients were randomized and received study treatment, of whom 220 comprised the ITT population (Fig. 1). Seventy-five (34.1%) ITT patients were treated with ranibizumab monotherapy, 73 (33.2%) CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. Safety Population II (N=237)
Excluded (n=15)
Safety Population (N=222)
Excluded (n=2)
ITT Population (N=220)
Ranibizumab 0.5 mg (n=75)
Laser (n=72)
Ranibizumab 0.5 mg + Laser (n=73)
Fig. 1 — Patient disposition. *Patients from 1 participating centre were excluded from all efficacy analyses as a gesture of prospective due diligence because of concerns for the quality of the data. †Patients did not have at least 1 postbaseline assessment.
with ranibizumab þ laser, and 72 (32.7%) with laser monotherapy. Overall, the mean (SD) age of the ITT population at baseline was 61.7 (9.8) years, with the majority being male (60.0%) and white (87.7%). Table 1 summarizes the baseline demographics and disease characteristics for the 3 treatment arms. Patient characteristics were comparable between groups; the only exceptions being the type of DME, which was focal in 42.7% of patients in the ranibizumab monotherapy group, 53.4% of patients in the ranibizumab þ laser group, and 36.1%
in the laser monotherapy group and CRT (448.5 vs 422.1 vs 458.0 μm, respectively). The mean (SD) time elapsed since diabetes diagnosis was 17.2 (10.4) years, and the mean (SD) duration of DME was 1.8 (2.8) without any remarkable differences between groups (Fig. 2). After 12 months of treatment, statistically significant (p o 0.001) improvements in the BCVA letter score were observed for both the ranibizumab monotherapy group (þ8.9 letters [95% CI 7.0–10.7]) and the ranibizumab þ
Table 1—Baseline demographics and disease characteristics: intent-to-treat population Parameter Mean age, y (SD) Race, n (%) White Asian Black Other Male sex, n (%) Type of diabetes, n (%) Type I Type II Other Mean years since diabetes diagnosis (SD) Mean years since DME diagnosis (SD) History of DME treatment, n (%) Study eye, n (%) Left eye Right eye Study eye DME type, n (%) Diffuse Focal BCVA study eye, letters, mean (SD) CRT study eye, μm, mean (SD) Mean HbA1c, % (SD)
Ranibizumab 0.5 mg (N ¼ 75)
Ranibizumab 0.5 mg þ Laser (N ¼ 73)
Laser (N ¼ 72)
61.5 (9.9)
60.8 (10.2)
62.8 (9.4)
65 4 2 4 42
(86.7) (5.3) (2.7) (5.3) (56.0)
64 3 2 4 47
(87.7) (4.1) (2.7) (5.5) (64.4)
64 3 0 5 43
(88.9) (4.2) (0.0) (6.9) (59.7)
9 66 0 16.5 1.6 46
(12.0) (88.0) (0.0) (9.0) (2.3) (61.3)
11 58 4 18.5 2.1 55
(15.1) (79.5) (5.5) (11.6) (3.1) (75.3)
8 63 1 16.6 1.7 48
(11.1) (87.5) (1.4) (10.7) (2.9) (66.7)
33 (44.0) 42 (56.0) 43 32 63.1 448.5 7.8
(57.3) (42.7) (10.6) (136.6) (1.3)
39 (53.4) 34 (46.6) 34 39 64.8 422.1 7.7
(46.6) (53.4) (9.3) (142.3) (1.1)
SD, standard deviation; DME, diabetic macular edema; BCVA, best corrected visual acuity; CRT, central retinal thickness; HbA1c, glycosylated hemoglobin.
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44 (61.1) 28 (38.9) 46 26 61.9 458.0 7.6
(63.9) (36.1) (10.6) (133.1) (1.3)
Efficacy/safety of ranibizumab for DME—Berger et al. A.
Change from Baseline to Month 12 in BCVA Letters
Mean (95% CI) BCVA Letters Gained
12 10 8
Ranibizumab 0.5mg
6
Ranibizumab 0.5mg + Laser 4
Laser
2 0 -2
B.
Change from Baseline to Month 12 in CRT (μm)
Mean Change (95% CI) in CRT (μm)
0 -20 -40 -60 -80
Ranibizumab 0.5mg
-100
Ranibizumab 0.5mg + Laser
-120
Laser
-140 -160 -180 -200
Fig. 2 — Change from baseline to month 12 in best corrected visual acuity (BCVA) and central retinal thickness (CRT).
laser group (þ8.2letters [95% CI 6.0–10.4]) compared with the laser monotherapy group (mean þ0.3 [95% CI – 2.9 to 3.5]; Table 2 and Fig. 2A.). PP analysis showed similar results (data not shown), with slightly higher within-group improvements in all treatment groups. Similar results were observed when looking at 3, 6, and 9 months of treatment with ranibizumab inducing statistically significant improvements in BCVA as early as 3 months and laser monotherapy being associated with modest nonsignificant changes in BCVA. With respect to CRT, rapid and sustained improvements were observed in both ranibizumab arms. The laser monotherapy arm showed a slower, although steady improvement. Change in CRT after 12 months was considerably better in the ranibizumab monotherapy (–143.5 mm (95% CI –177.5 to –109.4]) and ranibizumab þ laser (–152.2 mm [95% CI –185.5 to –119.0]) groups as compared with laser monotherapy (–107.1 mm [95% CI –143.9 to –70.2]; Table 2 and Fig. 2B). Furthermore, at month 12, 20.0% of patients in the ranibizumab monotherapy group and 23.3% of patients in the ranibizumab þ laser group had a gain of Z15 letters
from baseline, in comparison with 5.6% of patients in the laser monotherapy group. Similar results were observed when looking at the proportion of patients gaining Z5 letters (66.7% vs 58.9% vs 34.7% in the 3 groups, respectively) or Z10 letters (49.3% vs 32.9% vs 13.9%, respectively) at 12 months. Vision-related quality of life at 12 months was significantly higher in the 2 ranibizumab treatment groups as compared with laser monotherapy (p o 0.001). Upon adjusting for baseline values, the difference in mean composite VFQ-25 score between the ranibizumab monotherapy group and the laser monotherapy group was 6.0 (95% CI 2.7–9.4) and 6.3 (95% CI 2.9–9.6) for the ranibizumab þ laser group. Within the Safety population, treatment exposure was similar between the ranibizumab monotherapy group and the ranibizumab þ laser group, with patients receiving a mean (SD) of 9.2 (2.8) and 8.8 (2.9) injections in the 2 groups, respectively, during the trial. The mean (SD) number of laser treatments in the ranibizumab þ laser and laser monotherapy groups was 1.6 (1.0) and 2.6 (2.1), respectively. Although the safety profile was similar between groups, the incidence of AEs was slightly higher in the CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Efficacy/safety of ranibizumab for DME—Berger et al. Table 2—Efficacy outcomes: intent-to-treat population
Mean change from baseline in BCVA (letters) Month 12 (95% CI) Month 9 (95% CI) Month 6 (95% CI) Month 3 (95% CI) Mean change from baseline in CRT, μm Month 12 (95% CI) Month 9 (95% CI) Month 6 (95% CI) Month 3 (95% CI) Patients achieving a gain of Z15 letters† Month 12 Month 9 Month 6 Month 3 Patients achieving the following gain‡ at month 12 Z10 letters Z5 letters Mean baseline VFQ-25 (SD) Mean difference in VFQ-25 from laser monotherapy group at month 12‡ (95% CI)
Ranibizumab 0.5 mg (N ¼ 75)
Ranibizumab 0.5 mg þ Laser (N ¼ 73)
Laser (N ¼ 72)
p o 0.001* 8.9 (7.0, 10.7) 6.9 (4.0, 9.8) 7.1 (5.2, 8.9) 5.3 (3.5, 7.0)
p o 0.001* 8.2 (6.0, 10.4) 7.1 (5.2, 9.0) 5.6 (3.6, 7.6) 3.7 (1.1, 6.2)
— 0.3 (–2.9, 3.5) –0.2 (–3.0, 2.6) 0.9 (–0.9, 2.7) 1.4 (–0.1, 3.0)
–143.5 (–177.5, –109.4) –135.9 (–169.5, –102.3) –129.3 (–156.7, –102.0) –108.9 (–135.0, –82.9)
–152.2 (–185.5, –119.0) –138.1 (–168.3, –107.8) –114.2 (–140.7, –87.8) –105.7 (–135.9, –75.5)
–107.1 (–143.9, –70.2) –85.8 (–119.5, –52.2) –64.4 (–91.8, –36.9) –32.5 (–59.9, –5.1)
20.0% 20.0% 13.3% 9.3%
23.3% 12.3% 11.0% 8.2%
5.6% 0.0% 1.4% 2.8%
49.3% 66.7% 76.9 (15.4) 6.0 (2.7–9.4)
32.9% 58.9% 78.4 (16.0) 6.3 (2.9–9.6)
13.9% 34.7% 76.6 (16.2) —
BCVA, best corrected visual acuity; CI, confidence interval; CRT, central retinal thickness; SD, standard deviation; VFQ-25, Visual Function Questionnaire-25. *Between-group comparison with laser group. † Patients with missing information were considered as not achieving the target gain. ‡ Upon adjusting for baseline value.
2 ranibizumab groups compared with the laser monotherapy group (Table 3). Fifty-three (70.7%) patients in the ranibizumab monotherapy group experienced at least 1 AE, 49 (67.1%) in the ranibizumab þ laser group, and 44 (59.5%) in the laser monotherapy group. Intraocular pressure increase, conjunctival hemorrhage, vitreous hemorrhage, and nasopharyngitis were the most common AEs in patients who received active treatment. Overall, 26 (11.0%) patients in the Safety II population experienced 40 SAEs; 6 patients (7.6%) experienced at least 1 SAE in the laser monotherapy group, 11 patients (13.8%) in the ranibizumab monotherapy group, and 9 patients (11.5%) in the ranibizumab þ laser group. Vitreous hemorrhage (3.8% of patients in the laser monotherapy group vs 0% in the 2 ranibizumab groups), congestive cardiac failure (2.5% of patients in the laser monotherapy group vs 0% in the 2 ranibizumab groups), and cellulitis (2.5% of patients in the ranibizumab monotherapy group vs 0% in the other 2 groups) were the most common SAEs. One SAE (ischemic colitis) in the ranibizumab þ laser group was judged by the investigator to be related to the study treatment and none in the ranibizumab monotherapy and laser monotherapy groups. No fatal events were reported. The incidence of AEs leading to discontinuation in the Safety population was similar in the ranibizumab monotherapy (n ¼ 1; 1.3%) and ranibizumab þ laser (n ¼ 1; 1.4%) treatment groups, and lower than the laser monotherapy group (n ¼ 4; 5.4%).
DISCUSSION This study was undertaken to compare the clinical efficacy and safety of 0.5 mg ranibizumab as monotherapy
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or combination therapy (ranibizumab þ laser) with laser treatment over a 12-month treatment period. Ranibizumab treatment, whether alone or in combination with laser, induced significantly higher clinically meaningful improvements in VA at month 12, compared with laser monotherapy, and resulted in a rapid and sustained improvement in CRT over the 12-month treatment period. Similar to the RISE/RIDE studies, a significantly higher proportion of patients treated with ranibizumab 0.5 mg monotherapy achieved an improvement in BCVA Z15 letters at month 12, when compared with non–ranibizumab-treated patients. The higher proportion of patients in the RISE/ RIDE studies achieving this end point (39.2% and 45.7%, respectively) could possibly be explained by the monthly dosing schedule over a longer treatment period (24 months) in these studies as compared with this study’s 3-month loading phase followed by as needed dosing. One limitation of this study relates to the inadvertent bias of the laser monotherapy group having a significantly higher percentage of nonfocal DME, a subset of DME generally associated with a poorer visual prognosis in response to laser. However, the results presented are nonetheless consistent with 2 additional large phase III trials, the Ranibizumab or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE) Study and the Diabeteic Retinpathy Clincal Research Network (DRCR.net) Protocol I, both using a flexible individualized ranibizumab dosing schedule that approximates the design of this study, which examined the safety and efficacy of ranibizumab in the treatment of DME.6,11 Both trials indicated that ranibizumab monotherapy or combination therapy with laser was superior to laser alone in improving BCVA and reducing CRT in individuals with visual impairment caused by DME. The
Efficacy/safety of ranibizumab for DME—Berger et al. Table 3—Incidence of adverse events by preferred term: Safety population (incidence rate 4 1%)
Patients with at least 1 AE Preferred term Intraocular pressure increased Conjunctival hemorrhage Nasopharyngitis Vitreous hemorrhage Hypertension Cataract Visual acuity reduced Diabetic retinal edema Vitreous floaters Bronchitis Eye pain Headache Hypercholesterolemia Influenza Neuropathy peripheral Corneal abrasion Dry eye Localized infection Vision blurred Back pain Eye irritation Macular edema Vitreous detachment Cellulitis Contusion Corneal erosion Diabetes mellitus Glycosylated hemoglobin increased Hyperkalemia Lacrimation increased Macular fibrosis Pneumonia Procedural nausea Retinal neovascularisation Seasonal allergy Urinary tract infection
Ranibizumab 0.5 mg, (N ¼ 75)
Ranibizumab 0.5 mg þ Laser, (N ¼ 73)
Laser, n (%) (N ¼ 74)
All Safety Patients, (N ¼ 222)
53 (70.7%)
49 (67.1%)
44 (59.5%)
146 (65.8%)
10 6 5 2 5 6 3 1 3 2 3 4 2 1 1 3 2 2 1 4 0 1 2 3 1 3 0 2 1 1 2 1 0 0 1 2
8 11 5 5 2 0 2 3 3 1 3 1 2 3 5 2 2 1 4 0 4 0 1 0 0 0 2 0 1 2 0 1 2 2 2 1
(13.3%) (8.0%) (6.7%) (2.7%) (6.7%) (8.0%) (4.0%) (1.3%) (4.0%) (2.7%) (4.0%) (5.3%) (2.7%) (1.3%) (1.3%) (4.0%) (2.7%) (2.7%) (1.3%) (5.3%) (0.0%) (1.3%) (2.7%) (4.0%) (1.3%) (4.0%) (0.0%) (2.7%) (1.3%) (1.3%) (2.7%) (1.3%) (0.0%) (0.0%) (1.3%) (2.7%)
(11.0%) (15.1%) (6.8%) (6.8%) (2.7%) (0.0%) (2.7%) (4.1%) (4.1%) (1.4%) (4.1%) (1.4%) (2.7%) (4.1%) (6.8%) (2.7%) (2.7%) (1.4%) (5.5%) (0.0%) (5.5%) (0.0%) (1.4%) (0.0%) (0.0%) (0.0%) (2.7%) (0.0%) (1.4%) (2.7%) (0.0%) (1.4%) (2.7%) (2.7%) (2.7%) (1.4%)
3 2 4 7 5 3 3 3 1 3 0 1 2 2 0 0 1 2 0 0 0 3 1 0 2 0 1 1 1 0 1 1 1 1 0 0
(4.1%) (2.7%) (5.4%) (9.5%) (6.8%) (4.1%) (4.1%) (4.1%) (1.4%) (4.1%) (0.0%) (1.4%) (2.7%) (2.7%) (0.0%) (0.0%) (1.4%) (2.7%) (0.0%) (0.0%) (0.0%) (4.1%) (1.4%) (0.0%) (2.7%) (0.0%) (1.4%) (1.4%) (1.4%) (0.0%) (1.4%) (1.4%) (1.4%) (1.4%) (0.0%) (0.0%)
21 19 14 14 12 9 8 7 7 6 6 6 6 6 6 5 5 5 5 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3
(9.5%) (8.6%) (6.3%) (6.3%) (5.4%) (4.1%) (3.6%) (3.2%) (3.2%) (2.7%) (2.7%) (2.7%) (2.7%) (2.7%) (2.7%) (2.3%) (2.3%) (2.3%) (2.3%) (1.8%) (1.8%) (1.8%) (1.8%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%) (1.4%)
AE, adverse event.
long-term results from the DRCR.net, the Ranibizumab for Edema of the mAcula in Diabetes study (READ-2), and RESTORE extension studies further showed that response to ranibizumab is sustained through years two8,11 and three,12 with progressively declining number of injections over time required to control edema. Another possible limitation of this study is inherent to its openlabel design. However, given the nature of the 3 treatments compared, this design was appropriate. Furthermore, the nonsubjective nature of the visual and anatomic outcomes reported renders it unlikely that they were influenced by patient/physician knowledge of the treatment arm. In line with the clinical data, patients who received ranibizumab had a better vision-related quality of life at 12 months than those who were treated with laser monotherapy. These results are consistent with those reported in the comparable multicountry RESTORE study.6 Overall, ranibizumab was well tolerated and showed a comparable safety profile, although with slightly higher incidence of AEs than that of laser monotherapy. In summary, the results of this study have shown that treatment with ranibizumab intravitreal injections, either as monotherapy or in combination
with laser, in patients with visual impairment caused by DME was effective in rapidly and sustainably improving vision, reducing the risk for further vision loss and improving quality of life. Altogether, the findings from the RESPOND study further reinforce the well-documented efficacy and safety profile of ranibizumab.
Disclosures: A.B. has served on advisory boards for Novartis, Bayer, Alcon, and Allergan; his institution has received research funding from Novartis and fellowship funding from Novartis, Alcon, and Bayer. T.S. has been a member of advisory boards for Novartis, Bayer, and Alcon and has received research grant-in-aid funding from Novartis (42 years ago) and QLT (45 years ago). A. C. has served on advisory boards for Novartis, Alcon, and Bayer and has participated in company-sponsored clinical trials. J.-D.A. has no conflicts of interest. A.-S.C. and F.d.T. are employees of Novartis. Acknowledgements: Medical writing assistance was provided by JSS Medical Research Inc. The authors acknowledge Dr. Sophia Kajla for reviewing and supervising the development of the manuscript, as well as the study investigators: John Gonder, Laurent Lalonde, Michael Bense, Peter Kertes, Patrick Ma,
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Efficacy/safety of ranibizumab for DME—Berger et al. Vladimir Kozousek, John Chen, Michael Brent, Eric Tourville, Stan Shortt, Sébastien Olivier, Geoff Williams, Fareed Ali, Shelly Boyd, Christopher Jackman, Michel Giunta, Brian Leonard, Tom Sheidow, Kevin Colleaux, Danny Gauthier, and Patrick Saurel. Supported by: Pharmaceuticals.
The
study
was
funded
by
Novartis
APPENDIX Supplementary Materials
Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.jcjo.2014.12.014. REFERENCES 1. Fong DS, Aiello LP, Ferris FL III, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27:2540-53. 2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304:649-56. 3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-74.
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4. International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium; International Diabetes Federation, 2013. 5. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399-405. 6. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-25. 7. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2009;116:2175-81. 8. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146-51. 9. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801. 10. Photocoagulation therapy for diabetic eye disease. Early Treatment Diabetic Retinopathy Study Research Group. JAMA. 1985;254: 3086. 11. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-77. 12. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121:1045-53.