Dataset Information

Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A Randomized Clinical Trial.

ABSTRACT:

Importance

Polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative age-related macular degeneration among Asian individuals. To our knowledge, there are no large randomized clinical trials to evaluate intravitreal ranibizumab, with and without verteporfin photodynamic therapy (vPDT), for the treatment of PCV.

Objective

To compare the efficacy and safety of combination therapy of ranibizumab and vPDT with ranibizumab monotherapy in PCV.

Design, setting, and participants

A double-masked, multicenter randomized clinical trial of 322 Asian participants with symptomatic macular PCV confirmed by the Central Reading Center using indocyanine green angiography was conducted between August 7, 2013, and March 2, 2017.

Interventions

Participants were randomized 1:1 to ranibizumab, 0.5 mg, and vPDT (n = 168; combination therapy group) or ranibizumab, 0.5 mg, and sham PDT (n = 154; monotherapy group). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT/sham PDT on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions.

Main outcomes and measures

Step 1 assessed whether combination therapy was noninferior (5-letter margin) to monotherapy for change in best-corrected visual acuity from baseline and superior in complete polyp regression. If noninferiority was established, step 2 assessed whether combination therapy was superior to monotherapy measured by best-corrected visual acuity change at month 12.

Results

Baseline demographics of the 322 participants were comparable between the treatment groups. Mean (SD) age of the patients was 68.1 (8.8) years, and overall, 69.9% of the patients were men. At baseline, the overall mean best-corrected visual acuity and mean central subfield thickness were 61.1 letters and 413.3 μm, respectively. At 12 months, mean improvement from baseline was 8.3 letters with combination therapy vs 5.1 letters with monotherapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indicating that combination therapy met the predefined criterion for noninferiority as well as being superior to monotherapy (P = .01). Combination therapy was also superior to monotherapy in achieving complete polyp regression at month 12 (69.3% vs 34.7%; P < .001). Over 12 months, the combination therapy group received a median of 4.0 ranibizumab injections compared with 7.0 in the monotherapy group. Vitreous hemorrhage was the only ocular serious adverse event (combination therapy group, 1 [0.6%]; monotherapy group, 3 [2.0%]).

Conclusions and relevance

After 12 months, combination therapy of ranibizumab plus vPDT was not only noninferior but also superior to ranibizumab monotherapy in best-corrected visual acuity and superior in complete polyp regression while requiring fewer injections. Combination therapy should be considered for eyes with PCV.

Trial registration

clinicaltrials.gov Identifier: NCT01846273.

SUBMITTER: Koh A

PROVIDER: S-EPMC5710379 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceThe 2-year efficacy and safety of combination therapy of ranibizumab administered together with verteporfin photodynamic therapy (vPDT) compared with ranibizumab monotherapy in participants with polypoidal choroidal vasculopathy (PCV) are unclear.ObjectiveTo compare treatment outcomes of ranibizumab, 0.5 mg, plus prompt vPDT combination therapy with ranibizumab, 0.5 mg, monotherapy in participants with PCV for 24 months.Design, setting, and participantsThis 24-month, phase IV, double-masked, multicenter, randomized clinical trial (EVEREST II) was conducted among Asian participants from August 7, 2013, to March 2, 2017, with symptomatic macular PCV confirmed using indocyanine green angiography.InterventionsParticipants (N = 322) were randomized 1:1 to ranibizumab, 0.5 mg, plus vPDT (combination therapy group; n = 168) or ranibizumab, 0.5 mg, plus sham PDT (monotherapy group; n = 154). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT (combination group) or sham PDT (monotherapy group) on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions.Main outcomes and measuresEvaluation of combination therapy vs monotherapy at 24 months in key clinical outcomes, treatment exposure, and safety. Polypoidal lesion regression was defined as the absence of indocyanine green hyperfluorescence of polypoidal lesions.ResultsAmong 322 participants (mean [SD] age, 68.1 [8.8] years; 225 [69.9%] male), the adjusted mean best-corrected visual acuity (BCVA) gains at month 24 were 9.6 letters in the combination therapy group and 5.5 letters in the monotherapy group (mean difference, 4.1 letters; 95% CI, 1.0-7.2 letters; P = .005), demonstrating that combination therapy was superior to monotherapy by the BCVA change from baseline to month 24. Combination therapy was superior to monotherapy in terms of complete polypoidal lesion regression at month 24 (81 of 143 [56.6%] vs 23 of 86 [26.7%] participants; P < .001). Participants in the combination group received fewer ranibizumab injections (median, 6.0 [interquartile range (IQR), 4.0-11.0]) than the monotherapy group (median, 12.0 [IQR, 7.0-17.0]) up to month 24. The combination group required a median of 2.0 (IQR, 1.0-3.0) vPDT treatments for 24 months, with 75 of 168 participants (44.6%) requiring only 1 vPDT treatment.Conclusions and relevanceThe 24-month data findings confirm that ranibizumab therapy, given as monotherapy or in combination with vPDT, is efficacious and safe for treatment of PCV. Combination therapy with vPDT added to ranibizumab achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy.Trial registrationClinicalTrials.gov Identifier: NCT01846273.

Project description:ImportanceThe EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear.ObjectiveTo assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV.Design, setting, and participantsThis model-based, economic evaluation used 2018 unit cost data from a tertiary eye hospital in Singapore, first- and second-year outcomes and resource use data from a multicenter trial across various Asian countries (EVEREST II) to model a hypothetical cohort of patients with symptomatic PCV. Scenario analyses and deterministic and probabilistic sensitivity analyses were performed to examine uncertainty. Data were collected from October 2018 through April 2019 and analyzed from March through October 2019.InterventionsThis model used data from the EVEREST II trial, in which all participants were given 0.5 mg of intravitreal ranibizumab once every 4 weeks for the first 3 months. Subsequent administration occurred as needed. For participants receiving combination therapy, standard fluence (50 J/cm3) photodynamic therapy with 6-mg/m2 verteporfin was administered once during the first 3 months and thereafter as needed.Main outcomes and measuresIncremental cost per quality-adjusted life-year (QALY) gained for combination therapy relative to monotherapy for patients with PCV.ResultsIn this model based on a cohort of 1000 patients aged 68 years, a patient with PCV incurred a total cost in Singapore dollars (SGD) of 92 327 (US $67 399) with combination therapy and SGD 92 371 (US $67 431) with monotherapy during a lifetime horizon, generating a modest cost savings of SGD 44 (US $32) per patient undergoing combination therapy. Lifetime QALYs were estimated to be 7.87 for combination therapy and 7.85 for monotherapy, for an incremental gain of 0.02 QALYs. Combination therapy remained cost-saving or cost-effective in all lifetime scenarios modeled, but during shorter time horizons and at lower monotherapy costs, it may not be cost-effective.Conclusions and relevanceThis study found combination therapy to be a dominant (more effective and less costly) strategy, being similar in costs and slightly more effective than ranibizumab monotherapy during a lifetime horizon. However, decreasing the time horizon to less than 10 years and/or reductions in the cost of monotherapy may result in combination therapy no longer being cost-effective.

Project description:The optimal treatment for polypoidal choroidal vasculopathy (PCV) is still under debate. Little knowledge is known about the treatment effect of "1+pro re nata(PRN)" treatment regimen for PCV. The aim of this study was to compare the outcomes of photodynamic therapy (PDT), intravitreal ranibizumab injection (IVR) and combination therapy under the "1?+?PRN" treatment regimen for PCV.Fifty-seven eyes of 57 patients completed the 12 months' follow-up in this prospective study. The patients in the PDT arm(n?=?23), ranibizumab arm(n?=?18), or combination arm(n?=?16) underwent a session of PDT, IVR or combination of both at baseline followed by additional IVR as needed. Mean change of logarithm of the minimal angle of resolution (logMAR) visual acuity (VA), central foveal thickness (CFT) and the regression rate of polyps were evaluated. Cost-benefit analysis was also performed.At Month 12, the mean logMAR VA improved from 0.90?±?0.52 to 0.75?±?0.57 in the PDT group (P?<?0.05), from 0.96?±?0.58 to 0.77?±?0.41 in the IVR group (P?<?0.05), and from 0.94?±?0.55 to 0.72?±?0.44 in the combination group (P?<?0.05), respectively. The CFT decreased from 478.04?±?156.70 ?m, 527.5?±?195.90 ?m, and 522.63?±?288.40 ?m at the baseline to 366.43?±?148.28 ?m, 373.17?±?134.88 ?m and 328.44?±?103.25 in the PDT group (P?<?0.05), IVR group (P?<?0.01), and the combination group (P?<?0.05), respectively. However, no statistical difference was found between groups (P?>?0.05). PDT treatment (60.87%) was superior to the IVR therapy (22.22%) in achieving complete regression of polyps (P?<?0.05). Cost-benefit analysis showed that IVR treatment cost the least money for improving per 0.1logMAR units and the combination therapy demanded the least money for reducing per 100 ?m of CFT.PDT, IVR and the combination therapy have similar efficacy in the VA improvement as well as the reduction of CFT under the "1?+?PRN" treatment regimen.Current Controlled Trials NCT03459144 . Registered retrospectively on March 2, 2018.