Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Monthly Versus Treat-and-Extend Ranibizumab for Diabetic Macular Edema: A Prospective, Randomized Trial

David A. Eichenbaum, MD; Emily Duerr, BS; Hershel R. Patel, MD, MS; Scott M. Pollack, BS

Abstract

BACKGROUND AND OBJECTIVE:

Compare fixed monthly dosing of ranibizumab to treat-and-extend (T&E) ranibizumab during a period of 24 months for diabetic macular edema (DME) treatment.

PATIENTS AND METHODS:

Single-center, randomized, prospective pilot study that included 20 eyes of 20 subjects. Patients' best-corrected visual acuity (BCVA) was less than or equal to 20/40 and central foveal thickness on spectral-domain optical coherence tomography was greater than 325 µm. Intravitreal ranibizumab was dosed monthly or by protocol-specified treat-and-extend. Primary outcome was mean change in mean BCVA. Institutional review board approval was obtained.

RESULTS:

At month 24 (M24), there was a mean 8.3-letter gain in the monthly treatment group and an 8.5-letter gain in the T&E group (P = .082; 90% confidence interval). The average change from baseline BCVA was not statistically significantly different at any timepoint. At M24, the median number of injections in the monthly and T&E groups were 22.5 and 18.5, respectively (P = .287).

CONCLUSIONS:

Visual acuity with monthly dosing appears equivalent to T&E dosing during the course of 24 months. There was a trend toward a lower injection burden in the T&E arm.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e191–e197.]

Abstract

BACKGROUND AND OBJECTIVE:

Compare fixed monthly dosing of ranibizumab to treat-and-extend (T&E) ranibizumab during a period of 24 months for diabetic macular edema (DME) treatment.

PATIENTS AND METHODS:

Single-center, randomized, prospective pilot study that included 20 eyes of 20 subjects. Patients' best-corrected visual acuity (BCVA) was less than or equal to 20/40 and central foveal thickness on spectral-domain optical coherence tomography was greater than 325 µm. Intravitreal ranibizumab was dosed monthly or by protocol-specified treat-and-extend. Primary outcome was mean change in mean BCVA. Institutional review board approval was obtained.

RESULTS:

At month 24 (M24), there was a mean 8.3-letter gain in the monthly treatment group and an 8.5-letter gain in the T&E group (P = .082; 90% confidence interval). The average change from baseline BCVA was not statistically significantly different at any timepoint. At M24, the median number of injections in the monthly and T&E groups were 22.5 and 18.5, respectively (P = .287).

CONCLUSIONS:

Visual acuity with monthly dosing appears equivalent to T&E dosing during the course of 24 months. There was a trend toward a lower injection burden in the T&E arm.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e191–e197.]

Introduction

Diabetes mellitus is a disease affecting roughly 29.1 million people, or 9.3% of the population, in the United States. This number continues to grow, as the number of new cases has tripled from 1980 to 2014. It is estimated that 4.2 million of those affected aged 40 years or older are affected by diabetic retinopathy (DR), one of the most common complications of diabetes. DR is characterized by disease of the intraretinal vasculature.1,2,3,4 It is estimated that 4.4% of the DR cases are advanced, and many advanced cases of DR are associated with diabetic macular edema (DME).1 Center-involving (CI) DME is the leading cause of legal blindness in working-age adults.3,5

The landmark Early Treatment Diabetic Retinopathy Study (ETDRS) established focal laser photocoagulation as the standard of care for management of DME in 1985. Although the study found a reduction of severe and moderate vision loss, very few treated patients gained significant visual acuity (VA).5,6 More recently, studies of anti-angiogenic medications to treat DME, such as the RISE/RIDE studies, have modernized the standard of care in the care of DME, revealing significant improvements in anatomy and best-corrected VA (BCVA) with intravitreal anti-vascular endothelial growth factor (VEGF) injections. RISE/RIDE showed improvement at the 24-month primary endpoint with monthly intravitreal administration of ranibizumab (Lucentis; Genentech, South San Francisco, CA).5

Whereas fixed-interval monthly intravitreal anti-VEGF treatment has been proven effective, monthly visits are often inconvenient for the patient, care giver, and health care provider, and treatments become both costly and time-consuming. This study aims to prospectively evaluate the efficacy of a “treat-and-extend” (T&E) model with ranibizumab injections actively compared to monthly treatment. We report the outcomes of treating two groups of patients, each consisting of 10 subjects with CI visually significant DME, comparing monthly injections of ranibizumab with a protocol-specified T&E injection dosing model.

Patients and Methods

Twenty subjects from one site, Retina Vitreous Associates of Florida, Clearwater, Florida, were enrolled. All subjects completed prospective informed consent, overseen by the Western IRB. The study was performed in compliance with HIPAA regulations. Key inclusion criteria included BCVA ETDRS Snellen-equivalent less than or equal to 20/40 and central foveal thickness on spectral-domain optical coherence tomography (SD-OCT) greater than 325 µm. Phakic and pseudophakic patients were randomized. Key exclusion criteria included foveal ischemia on intravenous fluorescein angiography, intraocular surgery less than 6 months ago, epiretinal membrane of clinical significance, prior vitrectomy, macular or peripheral laser within 90 days from day 0 injection, intravitreal steroid injection within 90 days from day 0 injection, and intravitreal or systemic anti-VEGF within 30 days from day 0 injection. Patients were randomly assigned by the study center to either monthly ranibizumab treatment or to the T&E protocol. Primary outcome measure was the mean change in ETDRS vision at month 12. Secondary outcome measures included change in vision at months 12, 18, and 24, the mean number of injections through month 24, mean change in SD-OCT central subfield thickness (CST) at month 12, 18, and 24; the percentage of patients with BCVA Snellen-equivalent of 20/40 or better at months 12, 18, and 24; the percentage of patients anatomically “dry” at months 12, 18, and 24; and the safety and tolerability of ranibizumab though month 24.

Patients enrolled in the monthly treatment arm received intravitreal ranibizumab 0.3 mg every 4 weeks (plus or minus 7 days) for 24 months.

Patients enrolled in the standardized T&E treatment arm received intravitreal ranibizumab 0.3 mg (1) monthly until “dry,” as defined as less than 325 µm central foveal thickness (CFT) on SD-OCT macular mapping with no other anatomical markers of active disease (intraretinal fluid, subretinal fluid, intra-retinal cysts), or (2) monthly until “stable,” as defined as not showing any change ± up to 15 µm on SD-OCT and not showing any change ± up to 3 letters over three consecutive follow-ups and then (3) adding 2 weeks (± 3 days) to the previous evaluation and injection interval until there is an increase in 50 µm of CFT on SD-OCT macular mapping and / or anatomical changes consistent with active disease, and / or there is a drop in 5 or more letters on the ETDRS chart. The maximum time of extension allowed was 12 weeks (± 3 days) between visits. At the time, there was an increase in macular thickness greater than 15 µm or diminishment of vision the T&E subjects had the interval for evaluation and injection contracted by 2 weeks from the current interval. The subjects then returned at the shortened interval until the SD-OCT again met the definition of “dry” or stable. If there was continued increase in CST or further decrease in vision, the interval would again be shortened. Once the SD-OCT had returned to a “dry” or stable state, subjects in the T&E arm had the interval between evaluation and treatment again extended by 2-week increments.

Initial assessments included refraction with an ETDRS eye chart, SD-OCT imaging, fundus photography, and intravenous fluorescein angiography (FA). Assessments at every study visit included BCVA, ophthalmic exam, and SD-OCT.

Statistical Analysis

Area under the curve (AUC) approach based on trapezoidal rule was used to estimate BCVA and CFT average change from baseline over 12, 18, and 24 months. The actual visit days from baseline were used for AUC calculation. If no result was observed at the specified cutoff time point, the last time point with observed result prior to the specified cutoff time point was used as the end time point for AUC calculation. Student's t-test was used to compare between-group mean differences of BCVA and CFT average changes from baseline against a prespecified noninferiority (NI) margin (5 letters for BCVA, and −25um for CFT). The two-sided 90 % confidence limits of the mean difference were constructed using asymptotic normal approximation.

Fisher's exact unconditional test was used for comparing between-group proportion differences of patients with BCVA of 20/40 or better and patients gaining 3 lines or more at any time points over 12, 18, and 24 months against pre-specified NI margin (10% for both endpoints). The two-sided 90% exact unconditional confidence limits were estimated for the proportion difference accordingly.

Wilcoxon rank-sum test was performed to compare between-group difference of number of injections over 12, 18, and 24 months.

Statistical significance was based on one-sided nominal P value less than .05. No adjustment was made for multiple tests with various endpoints. Statistical analysis was performed with SAS version 9.4 (SAS Institute, Cary, NC).

Results

The demographic features of age and gender of both 10 patient cohorts are well-balanced in the study (Table 1), with an equal distribution of males and females in the monthly cohort and the T&E cohort and a mean age of 64.5 years and 60.4 years in the two groups, respectively. All patients had central-involved DME. Mean baseline ETDRS BCVA (monthly: 32.5 letters vs. T&E: 29.2 letters; P = .401) and CFT (monthly: 454.5 µm vs. T&E: 470.8 µm; P = .695) were comparable between the monthly and T&E groups. At 24 months, there was a mean 8.3-letter gain in the monthly group and an 8.5-letter gain in the T&E group (P = .082; 90% confidence interval [CI]). The average change from baseline BCVA over 12, 18, and 24 months was not statistically significantly different between the monthly and T&E groups at any timepoint (Table 2). The percentage of subjects in the monthly and T&E groups that had a 3-line gain in VA through 24 was 50% and 40%, respectively (P = .815; 90% CI) (Table 3). Similarly, the percentage of patients in the monthly and T&E groups who had a VA of 20/40 or better through the 24-month study period was statistically equivalent in both groups (Table 4). One hundred percent of the patients in the monthly group had 20/40 or better vision, whereas 80% of patients in the T&E group had 20/40 or better vision (P =1.00; 90% CI). There was a trend toward a drier SD-OCT in the monthly group versus the T&E group, by average change from baseline of CST (CFT, in µm) over 12, 18, and 24 months (Table 5). However, this was not statistically significant, with the mean change in CFT in the monthly cohort measured at −169.0 µm and −146.8 µm in the T&E cohort (P = .477, 90% CI). At 24 months, 80% and 70% of the patients in the monthly and T&E group were anatomically “dry” on SD-OCT (Table 6). There was a trend toward a smaller number of injections in the T&E cohorts per the study protocol. Over 24 months, the median number of injections in the monthly and T&E groups were 22.5 and 18.5, respectively (P = .287). The mean (standard deviation) number of injections of the monthly cohort was 19.4 (5.9) and 18.8 (2.9) in the T&E group (Table 7).

Demographics (ITT Population)

Table 1:

Demographics (ITT Population)

BCVA Average Change from Baseline (ITT Population)

Table 2:

BCVA Average Change from Baseline (ITT Population)

Proportion of BCVA Gaining 3 Lines or More at Any Timepoint (ITT Population)

Table 3:

Proportion of BCVA Gaining 3 Lines or More at Any Timepoint (ITT Population)

Proportion of BCVA 20/40 or Better at Any Timepoint (ITT Population)

Table 4:

Proportion of BCVA 20/40 or Better at Any Timepoint (ITT Population)

SD-OCT CFT Average Change from Baseline (ITT Population)

Table 5:

SD-OCT CFT Average Change from Baseline (ITT Population)

Proportion of Anatomically Dry at Any Timepoint (ITT Population)

Table 6:

Proportion of Anatomically Dry at Any Timepoint (ITT Population)

Number of Injections (ITT Population)

Table 7:

Number of Injections (ITT Population)

Discussion

Treatment groups had well-balanced demographic features at baseline. Subjects in both cohorts in this trial did well, with a similar, clinically significant improvement in mean change in ETDRS VA in both groups, and there was minimal numeric and no statistically significant difference between the groups regarding this primary endpoint. The improvement in VA was similar to the VA results seen in large, randomized, controlled trials of ranibizumab in DME. Although there was no trend toward better vision in either group, there was a trend toward reduced OCT thickness in the monthly group at every time point, likely reflecting less aggregate fluid fluctuation at any given interval with fixed monthly treatment. It is important to note that the protocol required retreatment and contraction of the interval between visits with the recurrence of even small amounts of intraretinal fluid on SD-OCT. The strict criteria for interval contraction in the T&E cohort may have contributed to good visual and anatomic results in that cohort. The criteria also contributed to a relatively high injection burden for the T&E cohort, reflected in the absence of a statistically significant reduction in injections over the 2 years of this trial. However, there was a trend toward a reduction in injection number in the T&E arm. During the period of 24 months, subjects in the monthly arm received a mean of 19.4 injections and a median of 22.5 injections, and subjects in the T&E arm received a mean of 18.8 injections and a median of 18.5 injections. It has been established in DRCR.net Protocol I, which enrolled treatment-naïve DME subjects and re-treated these subjects with regular monitoring and an algorithm that approximates a pro re nata (PRN) treatment approach, that there is a high injection burden in the first 12 months of treatment. The high burden of treatment in Protocol I's DME population is similar high injection burden in the this active-disease T&E population. T&E or PRN injection plans may be better-suited to populations or individual patients once their DME is well-controlled, perhaps in their second year of treatment or later. Of note, there was a widening difference in the median number of injections over time between the monthly and T&E groups, increasing from 1.0 to 4.0 injections from 12 to 24 months of follow-up, showing a trend toward a reduced injection and treatment burden later in the treatment course in the T&E population.

Like other larger, randomized, controlled trials of anti-VEGF treatment for DME, only 70% to 80% of the study population in either arm was anatomically dry at the 24-month timepoint. The presence of resistant disease in a significant minority of DME patients who do not completely respond to serial anti-VEGF injections may have increased the injection indication in the T&E arm. Post-hoc analysis of DRCR.net Protocol I has demonstrated that there may be an identifiable population of DME patients who do not respond well to anti-VEGF therapy, and that group of subjects is probably represented in this small pilot study, as well.7

There is limited published information on T&E dosing for DME. The RETAIN trial8 published data comparing T&E to PRN, but the criteria for extension in that trial was only stable BCVA, and interval extension was 1 month after visual stability was achieved instead of 2 weeks after anatomic and visual stability were achieved as in this trial. Retreatment criteria were also different, with the RETAIN retreatment criteria primarily being a decrease in vision, and retreatment criteria in this trial include anatomic change or a decrease in vision. The difference in extension plan and indication for retreatment may account for the increased number of injections as well as for the slight numerically better mean VA results in the T&E arm of this trial compared to RETAIN. The TREX-DME9 1-year outcomes show a nearly identical number of injections in the first year and mean VA gain and injection number compared to the T&E arm of this trial in the group randomized to treatment with or without navigated laser. TREX-DME also had a 2-week extension interval and utilized SD-OCT thickness as part of the algorithm for retreatment, which may help explain the similar results in these two trials.

There are several limitations to this pilot study. The small sample size limits the statistical power of the population, and there may not have been enough subjects to statistically demonstrate smaller yet clinically significant reductions in injection burden. There was a single center enrolling subjects for this trial, and images were interpreted by the primary investigator (DAE) instead of a centralized reading center. In addition, seven-field color fundus or widefield photographs were not collected, so a meaningful evaluation of whether there is regression of diabetic retinopathy with T&E cannot be performed in this population. There were follow-up fluctuations in the subjects randomized to monthly injections, which reduced the number of monthly injections received over the course of 24 months.

The results of T&E dosing for DME in this trial as well as the other trials studying this dosing strategy speak to the relative efficacy of this dosing modality. In the clinical setting, that efficacy shown across various T&E dosing approaches is important. That allows the treating physician some latitude in prescribing T&E dosing with ranibizumab in DME, yet also encourages the physician to expect reasonable results with a range of extension strategies. Another notable result in the DME T&E trials is that there is a trend toward a reduced burden of both injections and visits for the population prescribed T&E treatment compared to both monthly dosing trials or PRN trials with monthly observation. It is also important to note that this trend toward a reduction in burden is realized after a period of more frequent treatment in the first year of therapy. That reflects the relative plateau of visual and anatomic effect after about a year in fixed-interval trials such as the RISE and RIDE studies. It may also be a reasonable strategy to consider a fixed-dose injection interval at the outset of treatment and consider a T&E dosing strategy later in the treatment algorithm. Additional large-scale trials with well-defined extension criteria may further define the appropriate role of T&E dosing in DME.

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014. https://www.cdc.gov/diabetes/pdfs/data/2014-report-estimates-of-diabetes-and-its-burden-in-the-united-states.pdf. Accessed January 10, 2016.
  2. Annual Number (in Thousands) of New Cases of Diagnosed Diabetes Among Adults Aged 18–79 Years, United States, 1980–2014. (2015, December1). http://www.cdc.gov/diabetes/statistics/incidence/fig1.htm. Accessed January 10, 2016.
  3. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247–2254. doi:10.1016/j.ophtha.2014.05.006 [CrossRef]
  4. Stitt AW, Curtis TM. Advanced glycation and retinal pathology during diabetes. Pharmacol Rep. 2005;57Suppl:156–168.
  5. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema. Ophthalmology. 2012;119(4):789–801. doi:10.1016/j.ophtha.2011.12.039 [CrossRef]
  6. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991; 98(5 Suppl): 766–785.
  7. Dugel PU, Campbell J, Holekamp N, et al. Long-term response to anti-VEGF therapy for DME can be predicted after 3 injections: an analysis of Protocol I data. Paper presented at: The American Academy of Ophthalmology Annual Meeting. ; Nov 13–17, 2015. ; Las Vegas, NV. .
  8. Prunte C, Fajnkuchen F, Mahmood S, et al. Ranibizumab 0.5 mg treat-and- extend regimen for diabetic maacular oedema: The RETAIN study. Br J Ophthalmol. 2016;100(6):787–95. doi:10.1136/bjophthalmol-2015-307249 [CrossRef]
  9. Payne JF, Wykoff CC, Clark WL, et al. Randomized trial of treat and extend ranibizumab with and without navigated laser for diabetic macular edema. Ophthalmology. 2017;124(1):74–81. doi:10.1016/j.ophtha.2016.09.021 [CrossRef]

Demographics (ITT Population)

Monthly (N = 10)T&E (N = 10)Overall (N = 20)
Age (Years)n101020
Mean (SD)64.5 (9.3)60.4 (9.3)62.5 (9.3)
Median64.559.562.5
(Min, Max)(53, 86)(40, 71)(40, 86)
SexMale6 (60.0)6 (60.0)12 (60.0)
Female4 (40.0)4 (40.0)8 (40.0)

BCVA Average Change from Baseline (ITT Population)

Monthly (N = 10)T&E (N = 10)Overall (N = 20)Mean Difference (90% CI),P Value
Over 12 Monthsn101020
Mean (SD)8.2 (6.3)7.0 (8.6)7.6 (7.4)1.2 (−4.7, 7.0), .136
Median (Min, Max)8.2 (0, 20)4.4 (−1, 22)5.8 (−1, 22)

Over 18 Monthsn101020
Mean (SD)8.3 (6.8)8.2 (9.0)8.2 (7.8)0.1 (−6.1, 6.3), .093
Median (Min, Max)9.0 (−1, 22)5.5 (−3, 24)6.8 (−3, 24)

Over 24 Monthsn101020
Mean (SD)8.3 (7.2)8.5 (8.9)8.4 (7.9)−0.3 (−6.5, 6.0), .082
Median (Min, Max)9.2 (−2, 22)6.7 (−3, 24)7.9 (−3, 24)

Proportion of BCVA Gaining 3 Lines or More at Any Timepoint (ITT Population)

Monthly (N = 10), n (%)T&E (N = 10), n (%)Risk Difference 90% CI,P Value
Over 12 months5 (50.0)4 (40.0)10.0 (−36.9, 53.9), .815
Over 18 months5 (50.0)4 (40.0)10.0 (−36.9, 53.9), .815
Over 24 months5 (50.0)4 (40.0)10.0 (−36.9, 53.9), .815

Proportion of BCVA 20/40 or Better at Any Timepoint (ITT Population)

Monthly (N = 10), n (%)T&E (N = 10), n (%)Risk Difference 90% CI,P Value
Over 12 months10 (100.0)8 (80.0)20.0 (−27.9, 61.8), 1.000
Over 18 months10 (100.0)8 (80.0)20.0 (−27.9, 61.8), 1.000
Over 24 months10 (100.0)9 (90.0)10.0 (−36.9, 53.9), 1.000

SD-OCT CFT Average Change from Baseline (ITT Population)

Monthly (N = 10)T&E (N = 10)Overall (N = 20)Mean Difference (90% CI),P Value
Over 12 Monthsn101020
Mean (SD)−154.6 (97.9)−124.3 (123.3)−139.5 (109.5)−30.3 (−116.7, 56.0), .542
Median (Min, Max)−144.7 (−322, −41)−99.4 (−319, 19)−119.9 (−322, 19)

Over 18 Monthsn101020
Mean (SD)−162.3 (99.3)−138.3 (123.3)−150.3 (109.7)−24.0 (−110.8, 62.8), .492
Median (Min, Max)−152.0 (−331, −40)−120.5 (−330, 3)−128.7 (−331, 3)

Over 24 Monthsn101020
Mean (SD)−169.0 (98.5)−146.8 (122.0)−157.9 (108.6)−22.2 (−108.2, 63.9), .477
Median (Min, Max)−156.3 (−335, −39)−128.4 (−335, −6)−141.9 (−335, −6)

Proportion of Anatomically Dry at Any Timepoint (ITT Population)

Monthly (N = 10), n (%)T&E (N = 10), n (%)
Over 12 months5 (50.0)4 (40.0)
Over 18 months7 (70.0)7 (70.0)
Over 24 months8 (80.0)7 (70.0)

Number of Injections (ITT Population)

Monthly (N = 10)T&E (N = 10)P Value
Over 12 Monthsn1010
Mean (SD)10.9 (1.9)10.7 (1.6)
Median11.510.5.582
(Q1, Q3) (Min, Max)(11.0, 12.0) (6, 12)(10.0, 12.0) (8, 13)

Over 18 Monthsn1010
Mean (SD)15.6 (3.7)15.0 (2.4)
Median16.514.5.281
(Q1, Q3)(15.0, 18.0)(13.0, 17.0)
(Min, Max)(6, 18)(11, 18)

Over 24 Monthsn1010
Mean (SD)19.4 (5.9)18.8 (2.9)
Median22.518.5.287
(Q1, Q3)(15.0, 23.0)(17.0, 21.0)
(Min, Max)(6, 24)(14, 23)
Authors

From Retina Vitreous Associates of Florida, St. Petersburg, Florida (DAE); Morsani College of Medicine, University of South Florida, Tampa, Florida (ED, HRP); and Lincoln Memorial University, DeBusk College of Osteopathic Medicine, Harrogate, Tennessee (SMP).

This IST was reported as a podium abstract of an ongoing study at the American Society of Retina Specialists meeting in 2014.

The study was supported by an unrestricted grant and with investigative product from Genentech-Roche.

Dr. Eichenbaum is an investigator for Alcon / Novartis, Alimera, Allergan, Chegdu, Clearside, Genentech, Ophthotech; has received honoraria from Allergan, Allegro, Alimera, Genentech, Notal Vision, Regeneron, and Roche; and has equity or stock in Boston Image Reading Center, Clearside, Hemera Biopharmaceuticals, and US Retina. The remaining authors report no relevant financial disclosures.

The authors would like to acknowledge James Zhou and Steve Crockett for their assistance with statistics.

Address correspondence to David A. Eichenbaum, MD, Retina Vitreous Associates of Florida, 4344 Central Avenue, St. Petersburg, FL 33711; email: deichenbaum@retinavitreous.com.

Received: January 25, 2018
Accepted: May 02, 2018

10.3928/23258160-20181101-17

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