- Email: [email protected]
Stereotactic Radiotherapy for Neovascular Age-related Macular Degeneration
Stereotactic Radiotherapy for Neovascular Age-related Macular Degeneration 52-Week Safety and Efficacy Results of the INTREPID Study Timothy L. Jackson, PhD, FRCOphth,1 Usha Chakravarthy, MD, PhD,2 Peter K. Kaiser, MD,3 Jason S. Slakter, MD,4 Ernest Jan, MD, PhD,5 Francesco Bandello, MD,6 Denis O’Shaughnessy, PhD,7 Michael E. Gertner, MD,8 Linda Danielson, MSc,9 Darius M. Moshfeghi, MD,10 on behalf of the INTREPID Study Group* Purpose: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (nvAMD). Design: Randomized, double-masked, sham-controlled, multicenter, clinical trial. Participants: Two hundred thirty patients with onset of nvAMD within 3 years who received 3 or more injections of ranibizumab or bevacizumab within the preceding year and who needed continuing ranibizumab or bevacizumab treatment. Interventions: Participants were randomized 2:1:2:1 to 16 Gy plus pro re nata (PRN) ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, or sham 24 Gy plus PRN ranibizumab, respectively. Main Outcome Measures: The primary efficacy end point was the mean number of ranibizumab injections at 52 weeks. Secondary end points were change in mean best-corrected visual acuity (VA), loss of fewer than 15 Early Treatment Diabetic Retinopathy Study letters, gain of 0 or more and 15 or more letters, and change in angiographic total lesion size and choroidal neovascularization (CNV) lesion size. Results: Both the 16-Gy and 24-Gy SRT arms received significantly fewer ranibizumab treatments compared with the sham arms: mean number of treatments, 2.64 (median, 2), 2.43 (median, 2), and 3.74 (median, 3.5), respectively (P ⫽ 0.013 and P ⫽ 0.004, respectively, vs. sham). Change in mean VA was ⫺0.28, ⫹0.40, and ⫺1.57 letters for the 16-Gy, 24-Gy, and sham arms, respectively. The 16-Gy, 24-Gy, and sham arms lost fewer than 15 letters in 93%, 89%, and 91% of eyes, respectively, with 53%, 57%, and 56% gaining 0 or more letters, respectively, and 4% gaining 15 letters or more in all arms. Mean total angiographic lesion area changed by ⫺1.15 mm2, ⫹0.49 mm2, and ⫹0.75 mm2, respectively; mean CNV lesion area decreased by 0.16 mm2, 0.18 mm2, and 0.10 mm2, respectively. Optical coherence tomography central subfield thickness decreased by 85.90 m, 70.39 m, and 33.51 m, respectively. The number of adverse events (AEs) and number of serious AEs (SAEs) were similar across arms. No AEs were attributed to radiation. No SAEs occurred in the study eye. Conclusions: A single dose of SRT significantly reduces ranibizumab retreatment for patients with nvAMD, with a favorable safety profile at 1 year. Whereas chronic nvAMD typically results in loss of VA over time, SRT is associated with relatively well-preserved VA over 1 year. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2013;120:1893–1900 © 2013 by the American Academy of Ophthalmology. *Group members listed online in Appendix 1 (available at http://aaojournal.org).
Neovascular age-related macular degeneration (nvAMD) is a leading cause of blindness in the developed world.1 Intravitreal anti⫺vascular endothelial growth factor (VEGF) drugs have become the mainstay of treatment after the introduction of ranibizumab and bevacizumab in 2006.1⫺3 Ionizing radiation has been proposed as a treatment in nvAMD because it can inhibit inflammation and fibrosis and can induce regression of new blood vessels.4⫺7 Although pilot studies of external-beam radiotherapy suggested visual © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
benefits,8 randomized trials showed either no or small functional benefits compared with control arms.9 There may be several explanations for the disappointing results of the randomized trials. The first is that radiation had no therapeutic benefit and the findings merely reflected natural history. Another is that benefit from radiation therapy may have been muted because of collateral damage to the surrounding retina. The devices used in the early studies lacked precise beam collimation, which would have resulted in ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2013.02.016
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Ophthalmology Volume 120, Number 9, September 2013 larger areas of gratuitous radiation exposure, with the possibility of an adverse effect on vision.10 Consequently, in most previous studies, the entire posterior globe was included in the radiation field, imposing limits on the dose fractionation regimen to avoid radiation injury to healthy tissues. Recently, a radiotherapy device was developed specifically for use in the eye to address some of these limitations. Epimacular brachytherapy (EMBT) uses an intraocular probe containing a radioactive source that emits  radiation.11 This device (NeoVista, Newark, CA) delivers focal radiotherapy to the macula by means of a pars plana vitrectomy.12 The probe is positioned on the inner surface of the retina and is centered over the neovascular lesion. The probe is held in position for 3 to 5 minutes to deliver a dose of 24 Gy in a single continuous exposure. Although preliminary trials using this device suggested a dramatic reduction in the need for anti-VEGF therapy and improved vision,13 a pivotal phase 3, randomized, controlled trial failed to replicate these results (Choroidal Neovascularization Secondary to AMD Treated with Beta Radiation Epiretinal Therapy [CABERNET]).14 The IRay Radiotherapy System (Oraya Therapeutics, Newark, CA) is a low-voltage, external-beam, stereotactic radiotherapy (SRT) instrument that was developed to deliver ionizing radiation noninvasively to nvAMD lesions.10,15⫺24 The system generates low-energy x-rays with precise collimation of the beam and real-time tracking of eye movement to target small areas in the eye accurately. The phase 1 studies provided promising efficacy data and identified no safety concerns.22⫺24 The IRay in Conjunction with Anti-VEGF Treatment for Patients with Wet AMD (INTREPID) clinical trial was designed to test the hypothesis that a single dose of SRT, in conjunction with an anti-VEGF drug, could reduce the frequency of pro re nata (PRN) ranibizumab injections while maintaining or improving visual acuity in patients with nvAMD who previously had been treated with antiVEGF monotherapy. Herein, we report on the 52-week safety and efficacy results on behalf of the INTREPID Study Group (Appendix 1, available at http://aaojournal. org).
Methods Study Design Two hundred thirty patients with choroidal neovascularization (CNV) resulting from nvAMD who were treated previously with VEGF inhibitors were enrolled in a randomized, double-masked, sham-controlled clinical trial of stereotactic, low-voltage, x-ray irradiation with baseline ranibizumab at 21 European sites from December 7, 2009, through April 13, 2011 (www.clinicaltrials.gov identifier, NCT01016873; accessed November 3, 2012). The primary outcome was the number of PRN ranibizumab injections administered over 52 weeks. Secondary outcomes were: mean change in best-corrected visual acuity (BCVA) based on a protocol visual acuity measurement using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, loss of fewer than 15 letters, gain of 15 letters or more, gain of 0 letters or more, time from mandatory ranibizumab injection at day 0 to the first PRN ranibi-
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zumab injection, change in total lesion size on fluorescein angiography (FA), and change in CNV lesion size on FA. Safety outcomes included adverse events (AEs) and serious AEs (SAEs). Institutional review board approval was received at each study site. Approval for the use of the low-voltage stereotactic x-ray irradiation system was obtained from the health authorities in each country: Austria, Czech Republic, Germany, Italy, and the United Kingdom. The study complied with the tenets of the Declaration of Helsinki. Key eligibility criteria were age more than 50 years, a diagnosis of CNV resulting from nvAMD in the study eye within the previous 3 years, and treatment with 3 or more ranibizumab or bevacizumab injections within the preceding 52 weeks, with a continuing need for anti-VEGF treatment defined as the presence of any of the following: increased intraretinal or subretinal fluid on optical coherence tomography (OCT) from previous visits because of CNV, persistent intraretinal cysts on OCT, or active CNV leakage on FA. Women were required to have been postmenopausal for 1 year or more or to be sterilized surgically, or to have a negative test result for pregnancy before study entry and to agree to use a reliable form of contraception for the duration of the trial. The CNV lesion size was limited to less than 12 disc areas (1 disc area ⫽ 2.54 mm2), with the greatest linear dimension not to exceed 6 mm and the distance from the center of the fovea to the farthest point on the CNV lesion perimeter less than 3 mm. The distance from the center of the fovea to the margin of the optic disc was required to be 3 mm or more to ensure that the target area of the 3 radiation beams on the retina did not encroach on the optic disc. Baseline BCVA was required to be between 75 and 25 ETDRS letters in the study eye and 20 letters or more in the fellow eye. Full inclusion and exclusion criteria are listed in Appendix 2 (available at http://aaojournal.org).
Study Treatment All participants received a 0.5-mg intravitreal ranibizumab injection on day 0. Between days 1 and 14, participants were assigned randomly in a 2:1:2:1 ratio to 1 of 4 treatment arms: 16 Gy plus PRN ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, and sham 24 Gy plus PRN ranibizumab (Fig 1). The 2 sham radiation arms were pooled for all analyses. A dynamic randomization algorithm was used to balance for the following: whether the patient exhibited a dry macula at any time after previous anti-VEGF therapy, whether the diagnosis of wet AMD was fewer than 6 months, or 6 months or more before study entry, and whether the baseline (day 0) visual acuity score was 54 letters or fewer, or 55 letters or more. All patients and study personnel, including personnel from the sponsor, were masked to active or sham treatments. Treatment assignment and dose were acquired through a secure, password-protected website. A stochastic minimization algorithm,25 using a minimization probability parameter of 0.80, was used for dynamic randomization. The balance used for the minimization algorithm changed 3 times in the study, but the final intended ratio at the end of enrollment achieved the intended 2:1:2:1 distribution. To deliver SRT, a contact lens–like stabilization device was coupled to the cornea using minimal suction, and eye movements were tracked via 3 infrared reflectors located on the stabilization device. Radiotherapy was delivered using 3 points of entry through the inferior pars plana. The beams overlapped on the macula to deliver the desired treatment dose (5.33 Gy and 8 Gy per beam, for a total of 16 Gy or 24 Gy, respectively). The dose was controlled throughout the duration of exposure; eye movements were monitored in translational x-, y-, z-, and rotational axes through a multivariate algorithm that interrupted treatment if predetermined thresholds were exceeded (socalled gating). The process for sham treatment was identical, includ-
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study
Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
ing ocular tracking with the stabilization device and gating determination, but no radiation was given. The operator of the SRT device was not masked to whether the participant was receiving the 16-Gy or 24-Gy dose because the treatment times differed. However, all study personnel, including the operator, were masked to whether active or sham treatment was delivered for the chosen dose. Participants were assessed every 4 weeks with protocol ETDRS refraction and BCVA, slit-lamp biomicroscopy, dilated fundus examination, and time-domain OCT testing (Stratus OCT, Carl Zeiss Meditec, Jena, Germany). To be eligible for additional ranibizumab injections, participants had to meet 1 or more of the following retreatment criteria: a 100-m increase in central subfield thickness from the lowest previous OCT measurement, new or increased macular hemorrhage documented by fundus photographs, or a 5-letter or more decrease in BCVA since the last visit or the baseline BCVA, with disease activity, for example, persistent or increased fluid on OCT or leakage on FA.
Statistical Analysis The primary population for the efficacy analysis was the intentto-treat population, which consisted of all randomized patients. All efficacy analyses were performed by randomized arm assignment. The analysis population for safety consisted of all treated patients. All safety analyses were performed by actual treatment received. With an overall ␣ level of 0.05, the trial had 90% power to detect a difference of 1.15 injections between both active treatment
arms combined and sham arms combined (189 patients in total). Pairwise comparisons of each dose with sham provided 90% power to detect a difference of 1.45 injections between each active treatment arm and sham arms combined (126 patients in total; ␣ ⫽ 0.0249 after a conservative Bonferroni correction), and the sample size calculations assumed a 10% dropout rate. The primary end point, the number of PRN injections up to and including 52 weeks, was analyzed by comparing the mean of each treated arm with the sham arm, calculated by an analysis of variance adjusted for the number (ⱕ3 vs. ⬎3) and type (ranibizumab or bevacizumab versus other) of previous injections, whether the patient exhibited a dry macula after previous antiVEGF therapy, whether the diagnosis of nvAMD was within 6 months, or 6 months or more, and whether the baseline visual acuity score was 54 letters or fewer, or 55 letters or more. In addition, the analysis was adjusted for the minimization algorithm (protocol B vs. protocols C plus D plus E vs. protocol F). A proportional means model for recurrent events also was used to analyze the primary end point, adjusting for the same factors mentioned previously. The change in mean BCVA in each SRT arm compared with that in the pooled sham arms from baseline to 52 weeks was analyzed using a restricted maximum likelihood⫺based repeatedmeasures approach.26 Data from all scheduled postbaseline visits, up to and including the outcome visit (52 weeks), were used in the analysis. The model included fixed, categorical effects of visit; a previously fluid-free macula on OCT during VEGF therapy (an
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Figure 2. Graph showing cumulative probability of additional pro re nata injection requirement, by treatment arm, over 52 weeks.
indicator of VEGF responder status); duration of nvAMD of fewer than 6 months versus 6 months or more before study entry; treatment-by-visit interaction; and the continuous, fixed covariate effects of the baseline visual acuity score and baseline score-byvisit interaction. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. The test for the treatment effect at the end point visit (52 weeks) was obtained by using an appropriate contrast of the treatment-related model parameters. Time to first PRN injection was estimated using Kaplan-Meier methods, and the corresponding Kaplan-Meier curves are provided for each treated arm and the pooled sham arm (see Fig 2). The remaining efficacy end points are summarized descriptively. All of the aforementioned analyses were prespecified in the statistical analysis plan before data lock. Table 1. Baseline Patient Demographics
Mean age ⫾ SD (yrs) Male gender, no. (%) White race, no. (%) Right eye, no. (%) Mean duration of nvAMD ⫾ SD (mos) Prior treatment, no. (%)* Ranibizumab Bevacizumab Pegaptanib Other Mean no. of prior anti-VEGF injections ⫾ SD Time from last injection to study entry ⫾ SD (mos) Mean baseline visual acuity ⫾ SD Pseudophakic, no. (%)
16-Gy Arm (n ⴝ 75)
24-Gy Arm (n ⴝ 75)
Sham (n ⴝ 80)
73.4⫾7.2 32 (43) 75 (100) 39 (52) 12.8⫾7.3
73.8⫾8.3 27 (36) 75 (100) 39 (52) 16.7⫾10.1
73.5⫾7.1 31 (39) 80 (100) 43 (54) 16.2⫾13.6
61 (81) 17 (23) 1 (1) 0 4.99⫾3.87
54 (72) 29 (39) 1 (1) 1 (1) 6.23⫾4.76
63 (79) 23 (29) 4 (5) 1 (1) 5.48⫾4.19
3.74⫾2.89
3.73⫾2.41
3.41⫾2.29
57.9⫾12.7
58.8⫾12.8
59.3⫾13.1
19 (25)
16 (21)
15 (19)
nvAMD ⫽ neovascular age-related macular degeneration; SD ⫽ standard deviation; VEGF ⫽ vascular endothelial growth factor. *Several treatments are reported for some participants.
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Figure 3. Graph showing primary outcome: cumulative number of asrequired ranibizumab injections. Injections were administered to each arm, excluding the injection necessary for inclusion.
Results Primary Outcome: Number of Ranibizumab Retreatments The arms were balanced in terms of baseline demographics (Table 1). Mean time from diagnosis (⫾ standard deviation) was 12.8⫾7.3 months in the 16-Gy arm, 16.7⫾10.1 months in the 24-Gy arm, and 16.2⫾13.6 months in the sham arm. At 52 weeks, fewer PRN ranibizumab injections were given in both SRT arms compared with the sham arm (Fig 3). The mean number of treatments was 2.64⫾2.46 injections (median, 2; range, 0⫺10) in the 16-Gy arm, 2.43⫾2.40 injections (median, 2; range, 0⫺10) in the 24-Gy arm; and 3.74⫾2.57 injections (median, 3.5; range, 0⫺10) in the sham arm (Fig 4, available at http://aaojournal.org). On comparing the 16-Gy arm and 24-Gy arm with the sham arm, the differences were statistically significant (95% confidence interval [CI], ⫺1.78 to ⫺0.21 [P ⫽ 0.013, 16 Gy vs. sham], and ⫺1.95 to ⫺0.37 [P ⫽ 0.004, 24 Gy vs. sham]). The differences remained significant in the proportional means model. Reasons for PRN ranibizumab reinjection were similar across arms: of the 188 injections administered in the 16-Gy arm, 50% were for a more than 100-m increase in central subfield thickness, 52% were for a loss of more than 5 ETDRS letters, and 9%
Figure 5. Bar graph showing primary outcome: distribution of ranibizumab injections by treatment arm. Error bars show standard error.
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study Table 3. Summary of Adverse Events 16-Gy 24-Gy Arm Arm Sham (n ⴝ 74) (n ⴝ 73) (n ⴝ 79) Patients Patients Patients Patients Patients Patients
Figure 6. Graph showing change in visual acuity. Error bars show standard error. BCVA ⫽ best-corrected visual acuity.
were for new or increased macular hemorrhage (⬎1 reason could apply for each retreatment). Corresponding proportions in the 24-Gy arm (174 injections) were 43%, 48%, and 15%, and those in the sham arm (298 injections) were 55%, 41%, and 10%, respectively. The median times to the first PRN ranibizumab injection were longer in the SRT arms: 16.29 weeks (95% CI, 12.14⫺20.29), 16.64 weeks (95% CI, 12.57⫺26.29), and 13.14 weeks (95% CI, 12.14⫺16.14) in the 16-Gy, 24-Gy, and sham arms, respectively (Fig 2), although these differences were not statistically significant. The proportions of patients requiring no additional ranibizumab injections after the mandatory baseline injection were higher (17, 18, and 8 patients) in the 16-Gy and 24-Gy arms compared with the sham arm (P ⫽ 0.0159, CochranMantel-Haenszel test for trend; Fig 5).
Visual Acuity At 52 weeks, the mean change from baseline in visual acuity (number of ETDRS letters) was ⫺0.28⫾8.77 letters in the 16-Gy arm, ⫹0.40⫾10.33 letters in the 24-Gy arm, and ⫺1.57⫾11.90 letters in the sham arm (P ⫽ 0.73 and P ⫽ 0.19, 16 Gy and 24 Gy compared with sham, respectively; Fig 6). The proportions of patients losing fewer than 15 letters in the 16-Gy, 24-Gy, and sham arms were 93%, 89%, and 91%, respectively (Fig 7). The proportions of patients gaining 0 letters or more were 53%, 57%, and 56%, respectively. The proportion of patients gaining 15 letters or more was 4% in each arm.
with with with with with with
AEs AEs in study eye radiation-related AEs study device related SAEs serious AEs in study eye
41 (55) 23 (31) 0 14 (19) 11 (15) 0
49 (67) 36 (49) 0 19 (26) 6 (8) 0
49 (62) 32 (41) 0 8 (10) 6 (8) 0
AEs ⫽ adverse events; SAEs ⫽ serious adverse events. Data are presented as no. (%).
Fluorescein Angiography, Fundus Photographs, and Optical Coherence Tomography Mean total (⫾standard error) angiographic lesion area changed by ⫺1.15⫾0.66 mm2, 0.49⫾0.72 mm2, and 0.75⫾0.57 mm2 for the 16-Gy, 24-Gy, and sham arms, respectively, at 52 weeks (Table 2, available at http://aaojournal.org). Mean (⫾standard error) CNV lesion area decreased by 0.16⫾0.06 mm2, 0.18⫾0.06 mm2, and 0.10⫾0.04 mm2, respectively. Mean (⫾standard error) changes in OCT central subfield thickness at 52 weeks were ⫺85.90⫾11.51 m, ⫺70.39⫾12.47 m, and ⫺33.51⫾12.65 m, respectively. The mean foveal center point thickness was decreased compared with baseline thickness in all 3 arms at 4 weeks, and then gradually increased in the sham arm, whereas thickness in the 16-Gy and 24-Gy arms remained largely unchanged over the remainder of the year.
Safety The number of AEs and number of SAEs were similar across arms (Table 3). No AEs that were attributed to the delivery of radiation were observed in the study eye. Table 4 (available at http:// aaojournal.org) lists AEs occurring in the study eye. Table 5 (available at http://aaojournal.org) lists all systemic SAEs. Any FA images or fundus photographs that the reading center identified as having possible microvascular changes were referred to an expert clinician (J.S.S.) for review, who was masked with respect to both study arm and timing (baseline vs. week 52). Seven participants’ images underwent expert review: 2 from the sham arm (1 from baseline, 1 from week 52), 1 from the 16-Gy arm (week 52), and 4 from the 24-Gy arm (1 from baseline, 3 from week 52). No cases were labeled as having radiation retinopathy. Of the 4 eyes that had been exposed to radiation and were referred for expert review, 1 (the 16-Gy case) was determined not to have any distinct microvascular change, 1 had extremely poor quality images with a possible single small cotton wool spot but minimal change on FA, 1 had a focal flame-shaped hemorrhage in the papillomacular bundle but no significant vascular changes on the FA, and 1 had inferior staining and vascular abnormality in the mid-to-late phase of FA.
Discussion
Figure 7. Bar graph showing percent of patients with a loss of fewer than 15 letters over 52 weeks. Error bars show standard error.
The results of the INTREPID trial demonstrate that, in patients with previously treated CNV resulting from nvAMD, SRT reduces the need for PRN ranibizumab therapy compared with PRN ranibizumab monotherapy. Over-
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Ophthalmology Volume 120, Number 9, September 2013 all, there was approximately a one-third reduction in the number of ranibizumab retreatments in the SRT arms compared with the sham arm (3.75 injections in the control arm vs. 2.64 in the 16-Gy arm and 2.43 in the 24-Gy arm; see Figs 3 and 4, available at http://aaojournal.org). Additionally, one quarter of patients in the SRT arms required no additional PRN ranibizumab over 52 weeks, compared with 11.3% in the sham arm (see Fig 2). Findings in terms of visual acuity, OCT response, and FA results also were encouraging. The results of the INTREPID study are likely to be of interest, given the high prevalence of nvAMD and the heavy burden of treatment. For example, in the United States, treatment with anti-VEGF therapy is expected to cost in excess of $10 billion in 2015 alone.27 The INTREPID study used a 100-m increase in OCT thickness as one of the retreatment criteria. This criterion is less intensive when compared with that used in the Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT), which used a treat-until-dry regimen.28,29 However, the retreatment criteria used in INTREPID were typical of those used in other published trials at the time that our study was designed.30⫺32 Although present knowledge suggests that the 100-m criterion might be expected to yield less improvement in acuity (CATT year 2 and Inhibition VEGF in Age-related Choroidal Neovascularization trial [IVAN]33 year 1), it would not negate the differences observed between the various arms of the INTREPID study because the retreatment criteria were applied in an identical manner to both treated and sham subjects, as ensured by the double-masked trial design. The data from CATT were not available at the time the INTREPID study was conceived. The frequency of injections in clinical practice is far lower than in clinical trials. For example, according to a 2012 report on treatment patterns in more than 280 000 newly diagnosed patients with nvAMD receiving Medicare benefits, the mean number of ranibizumab injections was 4.5 per treated eye within 12 months of the first injection and did not increase appreciably over time. The mean number of injections with any anti-VEGF agent was 4.3.34 In terms of visual acuity outcome, the mean change in BCVA at 12 months in INTREPID was ⫺0.28 letters for the 16-Gy arm and ⫹0.40 letters for the 24-Gy arm and ⫺1.57 letters in the sham arm (see Fig 6). These changes in acuity seem to be inferior on comparison with change in acuity from baseline to year 2 in the CATT study. However, the CATT study enrolled treatment-naïve patients, whereas patients in INTREPID were not treatment naïve. Therefore, the most relevant comparison is the change in visual acuity from year 1 to year 2 in the CATT study, because it reflects outcome in previously treated patients and is more pertinent to the findings of the INTREPID study. Using this comparison, the change in acuity observed in INTREPID is similar; 3 of the 4 CATT treatment arms showed a reduction in mean visual acuity: ⫺0.3 letters for monthly ranibizumab, ⫺0.2 letters for monthly bevacizumab, ⫹0.1 letters for PRN ranibizumab, and ⫺0.5 letters for PRN bevacizumab. The fact that both INTREPID treatment arms achieved similar, or slightly better, outcomes despite less intensive retreatment regimens supports the hypothesis that SRT produces a
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benefit. Nonetheless, differences in study design suggest caution in the comparison of the findings of these 2 trials. Between year 1 and year 2 in the CATT study, there was an increase in lesion area on FA and no change in the OCT metrics of mean retinal thickness and the proportion of patients with residual fluid.28,29 In the combined SRT arms of the INTREPID study, there was a 17% increase (versus 30% in the sham arm) in total active lesion area and a 19% decrease in mean OCT retinal thickness (vs. 5% in the sham arm). Thus, the morphologic outcomes in the INTREPID study indicate that the therapeutic effects of SRT, in conjunction with anti-VEGF treatment, differ substantially from anti-VEGF monotherapy. It is not possible to compare the injection rate in the INTREPID study with that of the CABERNET study, because CABERNET recruited patients with treatment-naïve disease, whereas INTREPID recruited patients with previously treated disease.14 Also, CABERNET was not designed to determine whether EMBT reduced the frequency of anti-VEGF therapy. Patients in the active arm had 2 mandated injections, then PRN treatment. Patients in the control arm had 3 mandated injections, then both quarterly and PRN retreatment. In addition, the retreatment criteria in INTREPID and CABERNET differed: CABERNET imposed a higher threshold for retreatment in terms of vision (10 letters, confirmed with repeat testing, instead of 5 letters on 1 occasion in INTREPID), but a lower threshold for OCT-measured retinal thickness (an increase of 50 m in CABERNET vs. 100 m in INTREPID). Therefore, although the functional results of the INTREPID study, in terms of visual acuity, seem to be better than those observed in the CABERNET study, a direct comparison of the technologies is difficult because of differences in study design.14 Notwithstanding these differences, CABERNET failed to meet its coprimary end points of vision maintenance (⬎15-letter loss) or vision gain (also at a 15-letter margin). In addition, the final mean visual acuity in the treatment arm was 6.9 letters less than that in the control arm. In the INTREPID study, which did not enroll patients with treatment-naïve disease, the opportunity for improvement in BCVA was limited because most of the change in vision occurs within 3 months of initiating antiVEGF therapy. Thus, the demonstration of morphologic and functional benefits with a reduced need for retreatment in patients already receiving anti-VEGF therapy through the addition of radiotherapy is an important finding. The INTREPID study found that SRT had favorable safety, with similar AE and SAE profiles compared with the sham SRT controls. There were no cases of radiation retinopathy, similar to findings in the phase 1 studies.22⫺24 In comparison, the CABERNET study, which used a 24-Gy dose, reported retinal vascular changes consistent with radiation retinopathy in 3% of patients in the second year, although none of these patients had any visual or clinically meaningful sequelae.14 Radiation retinopathy may occur beyond 52 weeks; therefore, safety follow-up for the INTREPID study is ongoing to ensure that any potential ocular SAEs are identified and evaluated over a longer period. There are important differences in the devices used to deliver EMBT and SRT, which may explain the apparent
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study differences between the results of the CABERNET and INTREPID studies. First, EMBT uses a pars plana vitrectomy,10⫺14,35 which has been shown to decrease the halflife of intravitreal medications,36 possibly limiting the duration of action of anti-VEGF drugs. Second, the dose of EMBT delivered at the macula decreases in an approximately exponential manner with increasing distance from the probe.14 Correct placement of the probe by the surgeon is essential to ensure that all active areas receive an appropriate dose. By contrast, the SRT device used in the INTREPID study delivers a more even distribution of dose throughout the treatment zone. There was no clear dose response demonstrated by betweenarm differences in the 16-Gy and 24-Gy arms when the visual acuity, OCT, and angiographic outcomes are considered together. For this reason, the 16-Gy dose may be the more appropriate, given that it seems to produce a similar benefit but, theoretically, carries a lower risk of radiation damage. Strengths of this study include its randomized, doublemasked, sham-controlled design, with multicenter recruitment and independent FA and OCT gradings. A potential weakness is that the 100-m OCT retreatment criterion may not reflect usual clinical practice; many clinicians now would use a lower threshold for retreatment. Direct comparisons with trials such as CATT and CABERNET also are difficult, because the former used a more aggressive retreatment regimen, and unlike INTREPID, both recruited treatment-naïve patients. The INTREPID study was not designed to show superiority or noninferiority of visual acuity, and a larger phase 3 (pivotal) trial would be needed to draw conclusions on safety and visual efficacy. In summary, in patients with previously treated chronic, active CNV resulting from nvAMD, the addition of a single dose of 16 Gy or 24 Gy SRT resulted in a reduced frequency of anti-VEGF retreatment over a 12-month period compared with anti-VEGF monotherapy, and with encouraging structural and functional outcomes. Future studies could consider a more stringent retreatment regimen, similar to that for CATT, and would need to be powered to detect a difference in visual acuity and infrequent AEs.
References 1. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008;358:2606 –17. 2. Chakravarthy U, Evans J, Rosenfeld PJ. Age related macular degeneration. BMJ 2010;340:c981. 3. Coleman HR, Chan CC, Ferris FL III, Chew EY. Age-related macular degeneration. Lancet 2008;372:1835– 45. 4. Rodel F, Keilholz L, Herrmann M, et al. Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy. Int J Radiat Biol 2007;83:357– 66. 5. Hadjimichael C, Kardamakis D, Papaioannou S. Irradiation dose-response effects on angiogenesis and involvement of nitric oxide. Anticancer Res 2005;25:1059 – 65. 6. Hatjikondi O, Ravazoula P, Kardamakis D, et al. In vivo experimental evidence that the nitric oxide pathway is involved in the X-ray-induced antiangiogenicity. Br J Cancer 1996;74:1916 –23.
7. Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye (Lond) 2003;17:207–15. 8. Chakravarthy U, Houston RF, Archer DB. Treatment of agerelated subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol 1993;77:265–73. 9. Evans JR, Sivagnanavel V, Chong V. Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2010;(5):CD004004. 10. Petrarca R, Jackson TL. Radiation therapy for neovascular age-related macular degeneration. Clin Ophthalmol 2011;5: 57– 63. 11. Petrarca R, Richardson M, Nau J, et al. Safety testing of epimacular brachytherapy with microperimetry and indocyanine green angiography: 12 month results. Retina 2013;33:1232– 40. 12. Dugel PU, Petrarca R, Bennett M, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results. Ophthalmology 2012;119:1425–31. 13. Avila MP, Farah ME, Santos A, et al. Three-year safety and visual acuity results of epimacular 90 strontium/90 yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Retina 2012;32:10 – 8. 14. Dugel PU, Bebchuk JD, Nau J, et al, CABERNET Study Group. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013;120:317–27. 15. Moshfeghi AA, Canton VM, Quiroz-Mercado H, et al. 16-Gy low-voltage X-ray irradiation followed by as-needed ranibizumab therapy for AMD: 6-month outcomes of a “radiationfirst” strategy. Ophthalmic Surg Lasers Imaging 2011;42: 460 –7. 16. Barakat MR, Shusterman M, Moshfeghi D, et al. Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes. Arch Ophthalmol 2011;129:628 –32. 17. Gertner M, Chell E, Pan KH, et al. Stereotactic targeting and dose verification for age-related macular degeneration. Med Phys 2010;37:600 – 6. 18. Hanlon J, Firpo M, Chell E, et al. Stereotactic radiosurgery for AMD: a Monte Carlo-based assessment of patient-specific tissue doses. Invest Ophthalmol Vis Sci 2011;52:2334 – 42. 19. Hanlon J, Lee C, Chell E, et al. Kilovoltage stereotactic radiosurgery for age-related macular degeneration: assessment of optic nerve dose and patient effective dose. Med Phys 2009;36:3671– 81. 20. Lee C, Chell E, Gertner M, et al. Dosimetry characterization of a multibeam radiotherapy treatment for age-related macular degeneration. Med Phys 2008;35:5151– 60. 21. Taddei PJ, Chell E, Hansen S, et al. Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration. Phys Med Biol 2010; 55:7037–54. 22. Canton VM, Quiroz-Mercado H, Velez-Montoya R, et al. 16-Gy low-voltage x-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes. Ophthalmic Surg Lasers Imaging 2011;42:468 –73. 23. Canton VM, Quiroz-Mercado H, Velez-Montoya R, et al. 24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes. Ophthalmic Surg Lasers Imaging 2012;43:20 – 4. 24. Moshfeghi AA, Morales-Canton V, Quiroz-Mercado H, et al. 16-Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a ‘radiation-first’ strategy. Br J Ophthlamol 2012;96:1320 – 4.
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Ophthalmology Volume 120, Number 9, September 2013 25. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31:103–15. 26. Mallinckrod CH, Lane PW, Schnell D, et al. Recommendations for the primary analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J 2008;42:303–19. 27. Peregrine Pharmaceuticals licenses anti-VEGF antibodies to Affitech [press release]. Tustin, CA: Peregrine Pharmaceuticals Inc; July 22, 2009. Available at: http://ir.peregrineinc. com/releasedetail.cfm?releaseid⫽398241. Accessed June 7, 2012. 28. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–908. 29. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin F, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119:1388 –98. 30. Lalwani GA, Rosenfeld, PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58. 31. Larsen M, Schmidt-Erfurth U, Lanzetta P, et al, MONT BLANC Study Group. Verteporfin plus ranibizumab for cho-
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roidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC Study results. Ophthalmology 2012;119:992–1000. Holz FG, Amoaku W, Donate J, et al, SUSTAIN Study Group. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN Study. Ophthalmology 2011;118:663–71. IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119: 1399 – 411. Curtis LH, Hammill BG, Qualls LG, et al. Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 Medicare beneficiaries. Am J Ophthalmol 2012;152: 1116 –24. Avila MP, Farah ME, Santos A, et al. Twelve-month shortterm safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 2009;93:305–9. Beer PM, Bakri SJ, Singh RJ, et al. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 2003;110:681– 6.
Footnotes and Financial Disclosures Originally received: September 20, 2012. Final revision: February 13, 2013. Accepted: February 13, 2013. Available online: March 13, 2013. 1
Financial Disclosure(s): The author(s) have made the following disclosure(s): Timothy L. Jackson: Financial support—Oraya Therapeutics Manuscript no. 2012-1437.
King’s College London, London, United Kingdom.
2
Queen’s University of Belfast and the Belfast Health and Social Care Trust, Belfast, Northern Ireland.
3
Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
4
Digital Angiography Reading Center, Great Neck, New York.
5
Central Military Hospital Prague, Prague, Czech Republic.
6
University Vita-Salute, Scientific Institute, San Raffaele, Milano, Italy.
7
Oraya Therapeutics, Inc, Newark, California.
8
Department of Surgery, Stanford University, Stanford, California.
9
The International Drug Development Institute, Louvain-la-Neuve, Belgium.
10
Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California. *A full listing of the INTREPID Study Group is available at http:// aaojournal.org.
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Usha Chakravarthy: Consultant—Oraya Therapeutics Peter K. Kaiser: Consultant—Oraya Therapeutics Jason S. Slakter: Consultant—Oraya Therapeutics Denis O’Shaughnessy: Employee—Oraya Therapeutics Michael E. Gertner: Board member, Technology inventor, Equity owner— Oraya Therapeutics Linda Danielson: Employee—International Drug Development Institute Darius M. Moshfeghi: Consultant, Equity owner—Oraya Therapeutics Oraya Therapeutics participated in the design of the study, conducting the study, data collection, data management, data analysis, and review of the manuscript. The International Drug Development Institute received payment for services for this study. Correspondence: Darius M. Moshfeghi, MD, Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Room 2277, Palo Alto, CA 94303. E-mail: [email protected].
Neovascular age-related macular degeneration (nvAMD) is a leading cause of blindness in the developed world.1 Intravitreal anti⫺vascular endothelial growth factor (VEGF) drugs have become the mainstay of treatment after the introduction of ranibizumab and bevacizumab in 2006.1⫺3 Ionizing radiation has been proposed as a treatment in nvAMD because it can inhibit inflammation and fibrosis and can induce regression of new blood vessels.4⫺7 Although pilot studies of external-beam radiotherapy suggested visual © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
benefits,8 randomized trials showed either no or small functional benefits compared with control arms.9 There may be several explanations for the disappointing results of the randomized trials. The first is that radiation had no therapeutic benefit and the findings merely reflected natural history. Another is that benefit from radiation therapy may have been muted because of collateral damage to the surrounding retina. The devices used in the early studies lacked precise beam collimation, which would have resulted in ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2013.02.016
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Ophthalmology Volume 120, Number 9, September 2013 larger areas of gratuitous radiation exposure, with the possibility of an adverse effect on vision.10 Consequently, in most previous studies, the entire posterior globe was included in the radiation field, imposing limits on the dose fractionation regimen to avoid radiation injury to healthy tissues. Recently, a radiotherapy device was developed specifically for use in the eye to address some of these limitations. Epimacular brachytherapy (EMBT) uses an intraocular probe containing a radioactive source that emits  radiation.11 This device (NeoVista, Newark, CA) delivers focal radiotherapy to the macula by means of a pars plana vitrectomy.12 The probe is positioned on the inner surface of the retina and is centered over the neovascular lesion. The probe is held in position for 3 to 5 minutes to deliver a dose of 24 Gy in a single continuous exposure. Although preliminary trials using this device suggested a dramatic reduction in the need for anti-VEGF therapy and improved vision,13 a pivotal phase 3, randomized, controlled trial failed to replicate these results (Choroidal Neovascularization Secondary to AMD Treated with Beta Radiation Epiretinal Therapy [CABERNET]).14 The IRay Radiotherapy System (Oraya Therapeutics, Newark, CA) is a low-voltage, external-beam, stereotactic radiotherapy (SRT) instrument that was developed to deliver ionizing radiation noninvasively to nvAMD lesions.10,15⫺24 The system generates low-energy x-rays with precise collimation of the beam and real-time tracking of eye movement to target small areas in the eye accurately. The phase 1 studies provided promising efficacy data and identified no safety concerns.22⫺24 The IRay in Conjunction with Anti-VEGF Treatment for Patients with Wet AMD (INTREPID) clinical trial was designed to test the hypothesis that a single dose of SRT, in conjunction with an anti-VEGF drug, could reduce the frequency of pro re nata (PRN) ranibizumab injections while maintaining or improving visual acuity in patients with nvAMD who previously had been treated with antiVEGF monotherapy. Herein, we report on the 52-week safety and efficacy results on behalf of the INTREPID Study Group (Appendix 1, available at http://aaojournal. org).
Methods Study Design Two hundred thirty patients with choroidal neovascularization (CNV) resulting from nvAMD who were treated previously with VEGF inhibitors were enrolled in a randomized, double-masked, sham-controlled clinical trial of stereotactic, low-voltage, x-ray irradiation with baseline ranibizumab at 21 European sites from December 7, 2009, through April 13, 2011 (www.clinicaltrials.gov identifier, NCT01016873; accessed November 3, 2012). The primary outcome was the number of PRN ranibizumab injections administered over 52 weeks. Secondary outcomes were: mean change in best-corrected visual acuity (BCVA) based on a protocol visual acuity measurement using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, loss of fewer than 15 letters, gain of 15 letters or more, gain of 0 letters or more, time from mandatory ranibizumab injection at day 0 to the first PRN ranibi-
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zumab injection, change in total lesion size on fluorescein angiography (FA), and change in CNV lesion size on FA. Safety outcomes included adverse events (AEs) and serious AEs (SAEs). Institutional review board approval was received at each study site. Approval for the use of the low-voltage stereotactic x-ray irradiation system was obtained from the health authorities in each country: Austria, Czech Republic, Germany, Italy, and the United Kingdom. The study complied with the tenets of the Declaration of Helsinki. Key eligibility criteria were age more than 50 years, a diagnosis of CNV resulting from nvAMD in the study eye within the previous 3 years, and treatment with 3 or more ranibizumab or bevacizumab injections within the preceding 52 weeks, with a continuing need for anti-VEGF treatment defined as the presence of any of the following: increased intraretinal or subretinal fluid on optical coherence tomography (OCT) from previous visits because of CNV, persistent intraretinal cysts on OCT, or active CNV leakage on FA. Women were required to have been postmenopausal for 1 year or more or to be sterilized surgically, or to have a negative test result for pregnancy before study entry and to agree to use a reliable form of contraception for the duration of the trial. The CNV lesion size was limited to less than 12 disc areas (1 disc area ⫽ 2.54 mm2), with the greatest linear dimension not to exceed 6 mm and the distance from the center of the fovea to the farthest point on the CNV lesion perimeter less than 3 mm. The distance from the center of the fovea to the margin of the optic disc was required to be 3 mm or more to ensure that the target area of the 3 radiation beams on the retina did not encroach on the optic disc. Baseline BCVA was required to be between 75 and 25 ETDRS letters in the study eye and 20 letters or more in the fellow eye. Full inclusion and exclusion criteria are listed in Appendix 2 (available at http://aaojournal.org).
Study Treatment All participants received a 0.5-mg intravitreal ranibizumab injection on day 0. Between days 1 and 14, participants were assigned randomly in a 2:1:2:1 ratio to 1 of 4 treatment arms: 16 Gy plus PRN ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, and sham 24 Gy plus PRN ranibizumab (Fig 1). The 2 sham radiation arms were pooled for all analyses. A dynamic randomization algorithm was used to balance for the following: whether the patient exhibited a dry macula at any time after previous anti-VEGF therapy, whether the diagnosis of wet AMD was fewer than 6 months, or 6 months or more before study entry, and whether the baseline (day 0) visual acuity score was 54 letters or fewer, or 55 letters or more. All patients and study personnel, including personnel from the sponsor, were masked to active or sham treatments. Treatment assignment and dose were acquired through a secure, password-protected website. A stochastic minimization algorithm,25 using a minimization probability parameter of 0.80, was used for dynamic randomization. The balance used for the minimization algorithm changed 3 times in the study, but the final intended ratio at the end of enrollment achieved the intended 2:1:2:1 distribution. To deliver SRT, a contact lens–like stabilization device was coupled to the cornea using minimal suction, and eye movements were tracked via 3 infrared reflectors located on the stabilization device. Radiotherapy was delivered using 3 points of entry through the inferior pars plana. The beams overlapped on the macula to deliver the desired treatment dose (5.33 Gy and 8 Gy per beam, for a total of 16 Gy or 24 Gy, respectively). The dose was controlled throughout the duration of exposure; eye movements were monitored in translational x-, y-, z-, and rotational axes through a multivariate algorithm that interrupted treatment if predetermined thresholds were exceeded (socalled gating). The process for sham treatment was identical, includ-
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study
Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
ing ocular tracking with the stabilization device and gating determination, but no radiation was given. The operator of the SRT device was not masked to whether the participant was receiving the 16-Gy or 24-Gy dose because the treatment times differed. However, all study personnel, including the operator, were masked to whether active or sham treatment was delivered for the chosen dose. Participants were assessed every 4 weeks with protocol ETDRS refraction and BCVA, slit-lamp biomicroscopy, dilated fundus examination, and time-domain OCT testing (Stratus OCT, Carl Zeiss Meditec, Jena, Germany). To be eligible for additional ranibizumab injections, participants had to meet 1 or more of the following retreatment criteria: a 100-m increase in central subfield thickness from the lowest previous OCT measurement, new or increased macular hemorrhage documented by fundus photographs, or a 5-letter or more decrease in BCVA since the last visit or the baseline BCVA, with disease activity, for example, persistent or increased fluid on OCT or leakage on FA.
Statistical Analysis The primary population for the efficacy analysis was the intentto-treat population, which consisted of all randomized patients. All efficacy analyses were performed by randomized arm assignment. The analysis population for safety consisted of all treated patients. All safety analyses were performed by actual treatment received. With an overall ␣ level of 0.05, the trial had 90% power to detect a difference of 1.15 injections between both active treatment
arms combined and sham arms combined (189 patients in total). Pairwise comparisons of each dose with sham provided 90% power to detect a difference of 1.45 injections between each active treatment arm and sham arms combined (126 patients in total; ␣ ⫽ 0.0249 after a conservative Bonferroni correction), and the sample size calculations assumed a 10% dropout rate. The primary end point, the number of PRN injections up to and including 52 weeks, was analyzed by comparing the mean of each treated arm with the sham arm, calculated by an analysis of variance adjusted for the number (ⱕ3 vs. ⬎3) and type (ranibizumab or bevacizumab versus other) of previous injections, whether the patient exhibited a dry macula after previous antiVEGF therapy, whether the diagnosis of nvAMD was within 6 months, or 6 months or more, and whether the baseline visual acuity score was 54 letters or fewer, or 55 letters or more. In addition, the analysis was adjusted for the minimization algorithm (protocol B vs. protocols C plus D plus E vs. protocol F). A proportional means model for recurrent events also was used to analyze the primary end point, adjusting for the same factors mentioned previously. The change in mean BCVA in each SRT arm compared with that in the pooled sham arms from baseline to 52 weeks was analyzed using a restricted maximum likelihood⫺based repeatedmeasures approach.26 Data from all scheduled postbaseline visits, up to and including the outcome visit (52 weeks), were used in the analysis. The model included fixed, categorical effects of visit; a previously fluid-free macula on OCT during VEGF therapy (an
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Figure 2. Graph showing cumulative probability of additional pro re nata injection requirement, by treatment arm, over 52 weeks.
indicator of VEGF responder status); duration of nvAMD of fewer than 6 months versus 6 months or more before study entry; treatment-by-visit interaction; and the continuous, fixed covariate effects of the baseline visual acuity score and baseline score-byvisit interaction. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. The test for the treatment effect at the end point visit (52 weeks) was obtained by using an appropriate contrast of the treatment-related model parameters. Time to first PRN injection was estimated using Kaplan-Meier methods, and the corresponding Kaplan-Meier curves are provided for each treated arm and the pooled sham arm (see Fig 2). The remaining efficacy end points are summarized descriptively. All of the aforementioned analyses were prespecified in the statistical analysis plan before data lock. Table 1. Baseline Patient Demographics
Mean age ⫾ SD (yrs) Male gender, no. (%) White race, no. (%) Right eye, no. (%) Mean duration of nvAMD ⫾ SD (mos) Prior treatment, no. (%)* Ranibizumab Bevacizumab Pegaptanib Other Mean no. of prior anti-VEGF injections ⫾ SD Time from last injection to study entry ⫾ SD (mos) Mean baseline visual acuity ⫾ SD Pseudophakic, no. (%)
16-Gy Arm (n ⴝ 75)
24-Gy Arm (n ⴝ 75)
Sham (n ⴝ 80)
73.4⫾7.2 32 (43) 75 (100) 39 (52) 12.8⫾7.3
73.8⫾8.3 27 (36) 75 (100) 39 (52) 16.7⫾10.1
73.5⫾7.1 31 (39) 80 (100) 43 (54) 16.2⫾13.6
61 (81) 17 (23) 1 (1) 0 4.99⫾3.87
54 (72) 29 (39) 1 (1) 1 (1) 6.23⫾4.76
63 (79) 23 (29) 4 (5) 1 (1) 5.48⫾4.19
3.74⫾2.89
3.73⫾2.41
3.41⫾2.29
57.9⫾12.7
58.8⫾12.8
59.3⫾13.1
19 (25)
16 (21)
15 (19)
nvAMD ⫽ neovascular age-related macular degeneration; SD ⫽ standard deviation; VEGF ⫽ vascular endothelial growth factor. *Several treatments are reported for some participants.
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Figure 3. Graph showing primary outcome: cumulative number of asrequired ranibizumab injections. Injections were administered to each arm, excluding the injection necessary for inclusion.
Results Primary Outcome: Number of Ranibizumab Retreatments The arms were balanced in terms of baseline demographics (Table 1). Mean time from diagnosis (⫾ standard deviation) was 12.8⫾7.3 months in the 16-Gy arm, 16.7⫾10.1 months in the 24-Gy arm, and 16.2⫾13.6 months in the sham arm. At 52 weeks, fewer PRN ranibizumab injections were given in both SRT arms compared with the sham arm (Fig 3). The mean number of treatments was 2.64⫾2.46 injections (median, 2; range, 0⫺10) in the 16-Gy arm, 2.43⫾2.40 injections (median, 2; range, 0⫺10) in the 24-Gy arm; and 3.74⫾2.57 injections (median, 3.5; range, 0⫺10) in the sham arm (Fig 4, available at http://aaojournal.org). On comparing the 16-Gy arm and 24-Gy arm with the sham arm, the differences were statistically significant (95% confidence interval [CI], ⫺1.78 to ⫺0.21 [P ⫽ 0.013, 16 Gy vs. sham], and ⫺1.95 to ⫺0.37 [P ⫽ 0.004, 24 Gy vs. sham]). The differences remained significant in the proportional means model. Reasons for PRN ranibizumab reinjection were similar across arms: of the 188 injections administered in the 16-Gy arm, 50% were for a more than 100-m increase in central subfield thickness, 52% were for a loss of more than 5 ETDRS letters, and 9%
Figure 5. Bar graph showing primary outcome: distribution of ranibizumab injections by treatment arm. Error bars show standard error.
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study Table 3. Summary of Adverse Events 16-Gy 24-Gy Arm Arm Sham (n ⴝ 74) (n ⴝ 73) (n ⴝ 79) Patients Patients Patients Patients Patients Patients
Figure 6. Graph showing change in visual acuity. Error bars show standard error. BCVA ⫽ best-corrected visual acuity.
were for new or increased macular hemorrhage (⬎1 reason could apply for each retreatment). Corresponding proportions in the 24-Gy arm (174 injections) were 43%, 48%, and 15%, and those in the sham arm (298 injections) were 55%, 41%, and 10%, respectively. The median times to the first PRN ranibizumab injection were longer in the SRT arms: 16.29 weeks (95% CI, 12.14⫺20.29), 16.64 weeks (95% CI, 12.57⫺26.29), and 13.14 weeks (95% CI, 12.14⫺16.14) in the 16-Gy, 24-Gy, and sham arms, respectively (Fig 2), although these differences were not statistically significant. The proportions of patients requiring no additional ranibizumab injections after the mandatory baseline injection were higher (17, 18, and 8 patients) in the 16-Gy and 24-Gy arms compared with the sham arm (P ⫽ 0.0159, CochranMantel-Haenszel test for trend; Fig 5).
Visual Acuity At 52 weeks, the mean change from baseline in visual acuity (number of ETDRS letters) was ⫺0.28⫾8.77 letters in the 16-Gy arm, ⫹0.40⫾10.33 letters in the 24-Gy arm, and ⫺1.57⫾11.90 letters in the sham arm (P ⫽ 0.73 and P ⫽ 0.19, 16 Gy and 24 Gy compared with sham, respectively; Fig 6). The proportions of patients losing fewer than 15 letters in the 16-Gy, 24-Gy, and sham arms were 93%, 89%, and 91%, respectively (Fig 7). The proportions of patients gaining 0 letters or more were 53%, 57%, and 56%, respectively. The proportion of patients gaining 15 letters or more was 4% in each arm.
with with with with with with
AEs AEs in study eye radiation-related AEs study device related SAEs serious AEs in study eye
41 (55) 23 (31) 0 14 (19) 11 (15) 0
49 (67) 36 (49) 0 19 (26) 6 (8) 0
49 (62) 32 (41) 0 8 (10) 6 (8) 0
AEs ⫽ adverse events; SAEs ⫽ serious adverse events. Data are presented as no. (%).
Fluorescein Angiography, Fundus Photographs, and Optical Coherence Tomography Mean total (⫾standard error) angiographic lesion area changed by ⫺1.15⫾0.66 mm2, 0.49⫾0.72 mm2, and 0.75⫾0.57 mm2 for the 16-Gy, 24-Gy, and sham arms, respectively, at 52 weeks (Table 2, available at http://aaojournal.org). Mean (⫾standard error) CNV lesion area decreased by 0.16⫾0.06 mm2, 0.18⫾0.06 mm2, and 0.10⫾0.04 mm2, respectively. Mean (⫾standard error) changes in OCT central subfield thickness at 52 weeks were ⫺85.90⫾11.51 m, ⫺70.39⫾12.47 m, and ⫺33.51⫾12.65 m, respectively. The mean foveal center point thickness was decreased compared with baseline thickness in all 3 arms at 4 weeks, and then gradually increased in the sham arm, whereas thickness in the 16-Gy and 24-Gy arms remained largely unchanged over the remainder of the year.
Safety The number of AEs and number of SAEs were similar across arms (Table 3). No AEs that were attributed to the delivery of radiation were observed in the study eye. Table 4 (available at http:// aaojournal.org) lists AEs occurring in the study eye. Table 5 (available at http://aaojournal.org) lists all systemic SAEs. Any FA images or fundus photographs that the reading center identified as having possible microvascular changes were referred to an expert clinician (J.S.S.) for review, who was masked with respect to both study arm and timing (baseline vs. week 52). Seven participants’ images underwent expert review: 2 from the sham arm (1 from baseline, 1 from week 52), 1 from the 16-Gy arm (week 52), and 4 from the 24-Gy arm (1 from baseline, 3 from week 52). No cases were labeled as having radiation retinopathy. Of the 4 eyes that had been exposed to radiation and were referred for expert review, 1 (the 16-Gy case) was determined not to have any distinct microvascular change, 1 had extremely poor quality images with a possible single small cotton wool spot but minimal change on FA, 1 had a focal flame-shaped hemorrhage in the papillomacular bundle but no significant vascular changes on the FA, and 1 had inferior staining and vascular abnormality in the mid-to-late phase of FA.
Discussion
Figure 7. Bar graph showing percent of patients with a loss of fewer than 15 letters over 52 weeks. Error bars show standard error.
The results of the INTREPID trial demonstrate that, in patients with previously treated CNV resulting from nvAMD, SRT reduces the need for PRN ranibizumab therapy compared with PRN ranibizumab monotherapy. Over-
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Ophthalmology Volume 120, Number 9, September 2013 all, there was approximately a one-third reduction in the number of ranibizumab retreatments in the SRT arms compared with the sham arm (3.75 injections in the control arm vs. 2.64 in the 16-Gy arm and 2.43 in the 24-Gy arm; see Figs 3 and 4, available at http://aaojournal.org). Additionally, one quarter of patients in the SRT arms required no additional PRN ranibizumab over 52 weeks, compared with 11.3% in the sham arm (see Fig 2). Findings in terms of visual acuity, OCT response, and FA results also were encouraging. The results of the INTREPID study are likely to be of interest, given the high prevalence of nvAMD and the heavy burden of treatment. For example, in the United States, treatment with anti-VEGF therapy is expected to cost in excess of $10 billion in 2015 alone.27 The INTREPID study used a 100-m increase in OCT thickness as one of the retreatment criteria. This criterion is less intensive when compared with that used in the Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT), which used a treat-until-dry regimen.28,29 However, the retreatment criteria used in INTREPID were typical of those used in other published trials at the time that our study was designed.30⫺32 Although present knowledge suggests that the 100-m criterion might be expected to yield less improvement in acuity (CATT year 2 and Inhibition VEGF in Age-related Choroidal Neovascularization trial [IVAN]33 year 1), it would not negate the differences observed between the various arms of the INTREPID study because the retreatment criteria were applied in an identical manner to both treated and sham subjects, as ensured by the double-masked trial design. The data from CATT were not available at the time the INTREPID study was conceived. The frequency of injections in clinical practice is far lower than in clinical trials. For example, according to a 2012 report on treatment patterns in more than 280 000 newly diagnosed patients with nvAMD receiving Medicare benefits, the mean number of ranibizumab injections was 4.5 per treated eye within 12 months of the first injection and did not increase appreciably over time. The mean number of injections with any anti-VEGF agent was 4.3.34 In terms of visual acuity outcome, the mean change in BCVA at 12 months in INTREPID was ⫺0.28 letters for the 16-Gy arm and ⫹0.40 letters for the 24-Gy arm and ⫺1.57 letters in the sham arm (see Fig 6). These changes in acuity seem to be inferior on comparison with change in acuity from baseline to year 2 in the CATT study. However, the CATT study enrolled treatment-naïve patients, whereas patients in INTREPID were not treatment naïve. Therefore, the most relevant comparison is the change in visual acuity from year 1 to year 2 in the CATT study, because it reflects outcome in previously treated patients and is more pertinent to the findings of the INTREPID study. Using this comparison, the change in acuity observed in INTREPID is similar; 3 of the 4 CATT treatment arms showed a reduction in mean visual acuity: ⫺0.3 letters for monthly ranibizumab, ⫺0.2 letters for monthly bevacizumab, ⫹0.1 letters for PRN ranibizumab, and ⫺0.5 letters for PRN bevacizumab. The fact that both INTREPID treatment arms achieved similar, or slightly better, outcomes despite less intensive retreatment regimens supports the hypothesis that SRT produces a
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benefit. Nonetheless, differences in study design suggest caution in the comparison of the findings of these 2 trials. Between year 1 and year 2 in the CATT study, there was an increase in lesion area on FA and no change in the OCT metrics of mean retinal thickness and the proportion of patients with residual fluid.28,29 In the combined SRT arms of the INTREPID study, there was a 17% increase (versus 30% in the sham arm) in total active lesion area and a 19% decrease in mean OCT retinal thickness (vs. 5% in the sham arm). Thus, the morphologic outcomes in the INTREPID study indicate that the therapeutic effects of SRT, in conjunction with anti-VEGF treatment, differ substantially from anti-VEGF monotherapy. It is not possible to compare the injection rate in the INTREPID study with that of the CABERNET study, because CABERNET recruited patients with treatment-naïve disease, whereas INTREPID recruited patients with previously treated disease.14 Also, CABERNET was not designed to determine whether EMBT reduced the frequency of anti-VEGF therapy. Patients in the active arm had 2 mandated injections, then PRN treatment. Patients in the control arm had 3 mandated injections, then both quarterly and PRN retreatment. In addition, the retreatment criteria in INTREPID and CABERNET differed: CABERNET imposed a higher threshold for retreatment in terms of vision (10 letters, confirmed with repeat testing, instead of 5 letters on 1 occasion in INTREPID), but a lower threshold for OCT-measured retinal thickness (an increase of 50 m in CABERNET vs. 100 m in INTREPID). Therefore, although the functional results of the INTREPID study, in terms of visual acuity, seem to be better than those observed in the CABERNET study, a direct comparison of the technologies is difficult because of differences in study design.14 Notwithstanding these differences, CABERNET failed to meet its coprimary end points of vision maintenance (⬎15-letter loss) or vision gain (also at a 15-letter margin). In addition, the final mean visual acuity in the treatment arm was 6.9 letters less than that in the control arm. In the INTREPID study, which did not enroll patients with treatment-naïve disease, the opportunity for improvement in BCVA was limited because most of the change in vision occurs within 3 months of initiating antiVEGF therapy. Thus, the demonstration of morphologic and functional benefits with a reduced need for retreatment in patients already receiving anti-VEGF therapy through the addition of radiotherapy is an important finding. The INTREPID study found that SRT had favorable safety, with similar AE and SAE profiles compared with the sham SRT controls. There were no cases of radiation retinopathy, similar to findings in the phase 1 studies.22⫺24 In comparison, the CABERNET study, which used a 24-Gy dose, reported retinal vascular changes consistent with radiation retinopathy in 3% of patients in the second year, although none of these patients had any visual or clinically meaningful sequelae.14 Radiation retinopathy may occur beyond 52 weeks; therefore, safety follow-up for the INTREPID study is ongoing to ensure that any potential ocular SAEs are identified and evaluated over a longer period. There are important differences in the devices used to deliver EMBT and SRT, which may explain the apparent
Jackson et al 䡠 Safety and Efficacy Results of the INTREPID Study differences between the results of the CABERNET and INTREPID studies. First, EMBT uses a pars plana vitrectomy,10⫺14,35 which has been shown to decrease the halflife of intravitreal medications,36 possibly limiting the duration of action of anti-VEGF drugs. Second, the dose of EMBT delivered at the macula decreases in an approximately exponential manner with increasing distance from the probe.14 Correct placement of the probe by the surgeon is essential to ensure that all active areas receive an appropriate dose. By contrast, the SRT device used in the INTREPID study delivers a more even distribution of dose throughout the treatment zone. There was no clear dose response demonstrated by betweenarm differences in the 16-Gy and 24-Gy arms when the visual acuity, OCT, and angiographic outcomes are considered together. For this reason, the 16-Gy dose may be the more appropriate, given that it seems to produce a similar benefit but, theoretically, carries a lower risk of radiation damage. Strengths of this study include its randomized, doublemasked, sham-controlled design, with multicenter recruitment and independent FA and OCT gradings. A potential weakness is that the 100-m OCT retreatment criterion may not reflect usual clinical practice; many clinicians now would use a lower threshold for retreatment. Direct comparisons with trials such as CATT and CABERNET also are difficult, because the former used a more aggressive retreatment regimen, and unlike INTREPID, both recruited treatment-naïve patients. The INTREPID study was not designed to show superiority or noninferiority of visual acuity, and a larger phase 3 (pivotal) trial would be needed to draw conclusions on safety and visual efficacy. In summary, in patients with previously treated chronic, active CNV resulting from nvAMD, the addition of a single dose of 16 Gy or 24 Gy SRT resulted in a reduced frequency of anti-VEGF retreatment over a 12-month period compared with anti-VEGF monotherapy, and with encouraging structural and functional outcomes. Future studies could consider a more stringent retreatment regimen, similar to that for CATT, and would need to be powered to detect a difference in visual acuity and infrequent AEs.
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Footnotes and Financial Disclosures Originally received: September 20, 2012. Final revision: February 13, 2013. Accepted: February 13, 2013. Available online: March 13, 2013. 1
Financial Disclosure(s): The author(s) have made the following disclosure(s): Timothy L. Jackson: Financial support—Oraya Therapeutics Manuscript no. 2012-1437.
King’s College London, London, United Kingdom.
2
Queen’s University of Belfast and the Belfast Health and Social Care Trust, Belfast, Northern Ireland.
3
Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
4
Digital Angiography Reading Center, Great Neck, New York.
5
Central Military Hospital Prague, Prague, Czech Republic.
6
University Vita-Salute, Scientific Institute, San Raffaele, Milano, Italy.
7
Oraya Therapeutics, Inc, Newark, California.
8
Department of Surgery, Stanford University, Stanford, California.
9
The International Drug Development Institute, Louvain-la-Neuve, Belgium.
10
Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California. *A full listing of the INTREPID Study Group is available at http:// aaojournal.org.
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Usha Chakravarthy: Consultant—Oraya Therapeutics Peter K. Kaiser: Consultant—Oraya Therapeutics Jason S. Slakter: Consultant—Oraya Therapeutics Denis O’Shaughnessy: Employee—Oraya Therapeutics Michael E. Gertner: Board member, Technology inventor, Equity owner— Oraya Therapeutics Linda Danielson: Employee—International Drug Development Institute Darius M. Moshfeghi: Consultant, Equity owner—Oraya Therapeutics Oraya Therapeutics participated in the design of the study, conducting the study, data collection, data management, data analysis, and review of the manuscript. The International Drug Development Institute received payment for services for this study. Correspondence: Darius M. Moshfeghi, MD, Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Room 2277, Palo Alto, CA 94303. E-mail: [email protected].