Treatment of exudative age‐related macular degeneration with aflibercept combined with pranoprofen eye drops or nutraceutical support with omega‐3: A randomized trial

Abstract

Aims

The aim of this study was to determine whether a combination of intravitreal aflibercept (IVA) and pranoprofen eyedrops or nutraceutical support provides additional benefit over IVA monotherapy for the treatment of choroidal neovascularization (CNV) in age‐related macular degeneration.

Methods

This was a prospective, randomized, pilot study in 60 patients with treatment‐naïve CNV. Patients were randomized 1:1:1 into three groups: aflibercept monotherapy (AM), aflibercept plus pranoprofen (AP) or aflibercept plus nutraceutical (AN) tablets containing multivitamin antioxidant and mineral supplementation plus omega‐3.

Results

At 12 months, all groups showed significant improvement in both best‐corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was −0.26 ± 0.06 LogMAR, −0.30 ± 0.06 LogMAR and −0.24 ± 0.04 LogMAR in the AM, AP and AN groups, respectively. The mean CRT change from baseline to 12 months was −76.9 ± 10.9 μm, −129 ± 19.9 μm and −105 ± 11.6 μm in the AM, AP and AN groups, respectively. The AN group required one less IVA injection than the AM group.

Conclusions

Compared with AM, both combination groups acted synergistically, although no significant benefits in BCVA were found over AM. Nutraceutical support with omega‐3 leads to a reduced need for IVA.

What is already known about this subject

• Although evidence has clearly proved that intravitreal injection of vascular endothelial growth factor antagonists prevents vision loss and may even improve visual acuity in patients with neovascular AMD, a significant percentage of patients continue to lose visual acuity.

• Moreover, monthly intravitreal injections represent a burden for society as well as the caregiver.

What this study adds

• Combination therapy with either topical 0.1% pranoprofen or nutraceutical support with AREDS2 formula plus omega‐3 acts synergistically with intravitreal injection, offering valuable therapeutic support to aflibercept injections in patients requiring long‐term treatment.

1. INTRODUCTION

Age‐related macular degeneration (AMD) is a deterioration or breakdown of the eye's macula. At present, pharmacotherapy is available only for late neovascular form of AMD. Large‐scale clinical trials have proved that monthly or bimonthly intravitreal injection of vascular endothelial growth factor (VEGF) antagonists prevents vision loss and may even improve visual acuity in patients with neovascular AMD.1, 2 Unfortunately, 5–10% of patients continue to lose visual acuity, and many neovascular forms of AMD show some sign of activity by the end of follow‐up. Moreover, monthly intravitreal injections represent a burden for society as well as the caregiver.3 Hence, developing complementary or additive therapies to currently available anti‐VEGF injections may improve treatment success, regarding slow AMD evolution, and improve visual acuity outcomes.

VEGF is not the only contributing element in CNV; inter alia, free radicals and oxidized lipoproteins in the ageing retina are key local triggers of parainflammation, leading to a chronic inflammatory status accountable for the commencement and evolution of age‐related chorioretinal damage.4, 5 Hence, inflammation itself has a pivotal role in the pathogenesis of CNV, indeed topical non‐steroidal anti‐inflammatory drugs (NSAIDs) have been reported to complement the activity of anti‐VEGF in improving the central retinal thickness (CRT)6, 7 and the rate of re‐injection in CNV.8

Currently, several oral anti‐inflammatory nutraceuticals are available through various pharmaceutical industries to support anti‐VEGF drugs in the treatment of dry and neovascular AMD. In particular, a possible nutraceutical approach to decrease the evolution of wet AMD comes from directly regulating the cellular make‐up of the retina. In this regard, the outer retina is highly rich in diet‐derived long‐chain polyunsaturated fatty acids (LCPUFA) like docosahexaenoic acid of the omega‐3 family and arachidonic acid of the omega‐6 family.9, 10, 11 The faculty of lipids to have biological functions outside energy harvesting and membrane structure has long been acknowledged.12 Notably, deregulation in lipid signalling is a remarkable feature of disorders associated with chronic inflammation such as metabolic syndrome, atherosclerosis, asthma, allergic response, autoimmunity, hypertension, cancer, and prominently in the background of this study, ocular vasoproliferative diseases.9, 10, 13

In the AREDS14 large multicentre clinical trial, treatment with a combined supplement containing high doses of zinc and antioxidants (ascorbic acid [vitamin C], vitamin E, β carotene and copper) reduced the risk of progression to advanced AMD by around 25%. In the follow‐up study (AREDS2),15, 16 in which the carotenoids lutein and zeaxanthin were added to the AREDS formula, patients in the lowest quintile in terms of dietary lutein and zeaxanthin intake gained most from the addition of these carotenoids, with around 10% reduced risk of progression to advanced AMD. Also, when β carotene was replaced with lutein, the incremental benefit increased to 18%, probably because of reduced competitive carotenoid absorption. Therefore, lutein and zeaxanthin were considered a better addition to the AREDS supplement than β carotene, also allowing the potential increased risk of lung cancer from β carotene in past smokers to be avoided.15 High dietary intake of lutein and zeaxanthin were shown to be useful in reducing late AMD risk also in a large meta‐analysis.17

To better evaluate the potential of association therapies, we performed a 12‐month, randomized prospective study to assess the efficacy of three different arms of treatment over a 12‐month period in patients with CNV: (1) intravitreal aflibercept (IVA), (2) IVA plus 0.1% pranoprofen eye drops, and (3) IVA plus supplementation of nutraceutical tablets containing the AREDS2 formulation16, 18 plus omega‐3 (Azyr Mega, Sifi SpA, CT, Italy).

2. PATIENTS AND METHODS

2.1. Study design

This pilot study in “Eyes affected by new‐onset neovascular AMD” was conducted according to the ethical principles of the Declaration of Helsinki. The ethics committee of Spedali Civili di Brescia (Italy) approved the study protocol (registered with clinicaltrials.gov, identifier NCT03712670), and signed informed consent was obtained from all participants. This study adheres to CONSORT guidelines.

2.2. Outcome measures and endpoints

The primary outcomes aim (1) to evaluate the average change in visual acuity of the enrolled eye, and (2) to measure the average change in CRT. The secondary outcomes aim (1) to compare the number of required aflibercept retreatments over the 12‐month period among the treatment arms, and (2) to report any adverse ocular events at 12 months.

2.3. Participants

Sixty consecutive participants were enrolled over a 9‐month period at the Retina Unit (Spedali Civili, Ospedale di Montichiari) and were computer‐randomized into one of three groups at a ratio of 1:1:1. Group 1 (n = 20) received IVA monotherapy (AM group); group 2 (n = 20) received IVA along with 0.1% pranoprofen (AP group) three times a day; group 3 (n = 20) received IVA plus daily supplementation of nutraceutical tablets (AN group) containing the AREDS2 formulation16, 18 (lutein, zeaxanthin, astaxanthin, vitamin C and E, zinc, copper) plus omega‐3 (Table 1).

Table 1.

Nutrient formulations included in Azyr mega

Study formulation	Daily dose
DHA/EPA	140 mg/185 mg
Astaxanthin	4 mg
Lutein/Zeaxanthin	10 mg/2 mg
Vitamin C	60 mg
Vitamin E	30 mg
Zinc oxide	12.5 mg
Cupric oxide	1 mg

EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

All patients underwent monthly injections with IVA (2 mg/0.05 mL) for 3 months, followed by IVA as needed to treat any residual disease. Retreatment criteria were: (1) any intraretinal or subretinal fluid on optical coherence tomography (OCT), (2) new or persistent haemorrhage, and (3) diminished visual acuity as compared with the previous examination.

2.4. Inclusion and exclusion criteria

Patients qualified for this study if they met the following criteria: (1) written informed consent and fulfilment with study assessments for the full duration of the study, (2) age > 40 years, and (3) presence of new‐onset neovascular AMD, with fluid and/or haemorrhage underneath the fovea. The diagnosis was made by one investigator (Andrea Russo) and individually confirmed by a second investigator (Elena Gambicorti).

The exclusion criteria were as follows: (1) any prior intravitreal treatment, (2) prior retinal laser treatment, (3) myopia >7 diopters in the study eye, (4) coexisting eye disorder in the study, (5) concomitant corneal epithelial disorder or any circumstance that would disturb the capability of the cornea to heal.

2.5. Study treatments

Participants in all the groups underwent an initial injection of 2 mg IVA followed by two additional monthly injections. A blinded examiner (Francesco Morescalchi) prescribed further IVAs as per previously described retreatment criteria.

Patients in AP were given bottles of eyedrops for self‐administration of 0.1% pranoprofen, provided free of charge by the company (Sifi SpA, Aci Sant'Antonio, CT, Italy). Pranoprofen dosage was one drop in the study eye, three times a day, over the 12‐month study period. To control and improve compliance, patients were asked to return their used bottles of pranoprofen.

The patients in AN were given daily tablets of Azyr Mega provided free of charge by the company (Sifi SpA, Aci Sant'Antonio, CT, Italy).

2.6. Assessments

At every visit, the following evaluations were made by a certified examiner (Anna Cancarini) blinded to the treatment arm: (1) early treatment diabetic retinopathy study (ETDRS) best‐corrected visual acuity (BCVA), (2) fully dilated slit‐lamp ophthalmic examination, (3) measurement of CRT by OCT, and (4) assessment of any adverse ocular events. Retinography (fluorescein and indocyanine green angiography) was performed at baseline, 3 months, and 12 months, and at any monthly visit between 4 and 11 months according to retreatment criteria.

2.7. Statistical analysis

Descriptive statistics were used to describe the demographic and ocular baseline characteristics. To assess whether the changes in BCVA, CRT and the number of injections were significant, repeated measures of analysis of variance (ANOVA) with Greenhouse–Geisser correction was used. All statistical analyses were carried out using SPSS software v.20 by the principal investigator (Francesco Semeraro). P < 0.05 was considered to be statistically significant.

3. RESULTS

Table 2 shows the baseline demographic and clinical characteristics of the patients. The baseline data between the three arms was well distributed, with no significant differences among the groups. All 60 participants completed the study. Those in the AP and AN groups did not report any lack of compliance due to ocular or systemic adverse events during the 12 months of either pranoprofen or nutraceutical tablet use.

Table 2.

Baseline characteristics of the study participants

	AM group (n = 20)	AP group (n = 20)	AN group (n = 20)
Sex, n (%)
Male	8 (40)	10 (50)	9 (45)
Female	12 (60)	10 (50)	11 (55)
Age (years)
Mean ± SD	74.0 ± 7.6	76.7 ± 9.4	75.0 ± 7.6
Range	59–85	59–92	64–89
Visual acuity
Mean ± SD (LogMAR)	0.64 ± 0.33	0.63 ± 0.21	0.60 ± 0.20
Snellen equivalent	20/113 ± 76	20/98 ± 55	20/90 ± 46
Range	0.2–1	0.4–1	0.3–1
CRT (μm)
Mean ± SD	415 ± 57.0	411 ± 103	422 ± 88.4

AM, aflibercept monotherapy; AP, aflibercept plus off‐label topical 0.1% pranoprofen eye drops; AN, aflibercept plus nutraceutical tablets support; CRT, central retinal thickness.

3.1. Visual acuity

A significant increase in the mean BCVA score was detected in all patients, with a similar mean change from baseline observed in all the groups, without any significant difference between the groups at any time point. During the loading phase of the 3 monthly injections, the mean change ± standard error (SE) in BCVA improved quickly from baseline to 3 months by −0.19 ± 0.04 LogMAR, −0.28 ± 0.04 LogMAR and −0.18 ± 0.03 LogMAR in the AM, AP and AN groups, respectively. The mean change ± SE in BCVA from baseline to 12 months was −0.26 ± 0.06 LogMAR in AM, −0.30 ± 0.06 LogMAR in AP and −0.24 ± 0.04 LogMAR in AN. At 12 months, the mean ± SE difference between AM and AP was 0.05 ± 0.06 LogMAR (P = 0.65), that between AM and AN was 0.03 ± 0.06 LogMAR (P = 0.9) and that between AP and AN was −0.03 ± 0.06 LogMAR (P = 0.9). Table 3 shows the modifications in BCVA at each time point.

Table 3.

Changes in visual acuity and central retinal thickness at key time points

	Baseline	2 months	4 months	6 months	8 months	10 months	12 months
Visual acuity (mean ± SD)
AM group (LogMAR)	0.64 ± 0.33	0.46 ± 0.28*	0.43 ± 0.26*	0.42 ± 0.28*	0.39 ± 0.26*	0.39 ± 0.25*	0.39 ± 0.25*
AP group (LogMAR)	0.63 ± 0.21	0.35 ± 0.09*	0.32 ± 0.12*	0.30 ± 0.18*	0.30 ± 0.18*	0.32 ± 0.18*	0.34 ± 0.17*
AN group (LogMAR)	0.60 ± 0.20	0.42 ± 0.11*	0.40 ± 0.10*	0.40 ± 0.07*	0.38 ± 0.06*	0.38 ± 0.08*	0.36 ± 0.06*
CRT (mean ± SD)
AM group (μm)	415 ± 57	342 ± 101*	333 ± 64*	341 ± 45*	338 ± 47*	342 ± 50*	338 ± 47*
AP group (μm)	411 ± 104	314 ± 48*	306 ± 44*	293 ± 47*	287 ± 41*	282 ± 35*	282 ± 34*
AN group (μm)	422 ± 88	348 ± 48*	330 ± 43*	330 ± 43*	327 ± 42*	318 ± 39*	317 ± 39*

AM, aflibercept monotherapy; AP, aflibercept plus 0.1% pranoprofen eye drops; AN, aflibercept plus nutraceutical tablets support; CRT, central retinal thickness.

^* P < 0.05 vs baseline values for the same group.

3.2. Central retinal thickness

A persistent and significant decrease in mean CRT ± SE from baseline to 12 months was detected for the AM group (−76.9 ± 10.9 μm; P < 0.001), the AP group (−129 ± 19.9 μm; P < 0.001) and the AN group (−105 ± 11.6 μm; P < 0.001). Table 3 shows the 12‐month changes in all groups. At 12 months, the mean ± SE difference between AM and AP was 56.0 ± 12.8 μm (P = 0.001), that between AM and AN was 20.9 ± 12.8 μm (P = 0.24) and that between AP and AN was −35.0 ± 12.8 μm (P = 0.022). Table 3 shows the modifications in CRT at each time point.

3.3. Number of injections

The average number of required aflibercept injections was lower in the AP (6.6 ± 0.69; P = 0.24) and AN (6.2 ± 0.88; P < 0.001) groups compared with the AM group (7.2 ± 0.7). However, no significant changes were detected between the two combination treatments (P = 0.23).

3.4. Safety and adverse effects

The safety report of the three treatment groups was analogous at 12 months. The most commonly described ocular side effects are reported in Table 4. No serious adverse events were seen during the study period; all adverse events were slight to moderate. While slight burning/stinging was described more commonly in the arm with pranoprofen, there was no significant difference in the number of ocular side effects felt among the three groups.

Table 4.

Patients with ocular adverse events of the study eye during the 12‐month study period

	AM group n (%)	AP group n (%)	APS group n (%)
Abnormal sensation	4 (20)	9 (45)	4 (20)
Burning/stinging	5 (25)	11 (55)	6 (25)
Pain	2 (10)	5 (25)	2 (10)
Itchy eye	3 (15)	7 (35)	5 (25)
Headache	4 (20)	3 (15)	2 (10)
Sore eyelid	4 (20)	5 (25)	3 (15)
Retinal haemorrhage	0 (0)	1 (5)	0 (0)
Foreign body sensation	5 (25)	10 (50)	6 (25)
Conjunctivitis	3 (15)	3 (15)	3 (15)
Dry eye	3 (15)	7 (35)	4 (20)
Eye strain	4 (20)	7 (35)	6 (25)
Light sensitivity	7 (35)	7 (35)	5 (25)
Floaters	10 (50)	11 (55)	10 (50)

AM, aflibercept monotherapy; AP, aflibercept along with 0.1% pranoprofen eye drops; APS, aflibercept along with 0.1% pranoprofen eye drops plus anti‐vascular endothelial growth factor support.

4. DISCUSSION

Although AMD is not an archetypal inflammatory disease like uveitis, inflammation has been reported to play an important role in disease pathogenesis and progression.19, 20 Innate immunity and autoimmune constituents, like complement factors, chemokines, cytokines, macrophages and ocular microglia, are supposed to be deeply involved in AMD pathogenesis.21 Although anti‐VEGF is the first line of therapy against CNV in AMD, controlling these particular inflammatory cascades has recently been clinically investigated in an effort to synergistically enhance AMD treatment.6, 8, 22 Furthermore, association therapy with anti‐VEGF is supported by recent findings of a significant vitreous penetration by NSAIDs, reaching therapeutic concentrations that allow for a significant PGE2 and IL‐8 vitreous reduction.23, 24, 25 Our group showed that mean vitreous concentrations following topical NSAID administration were as follows: indomethacin 358.6 ± 83.2 pg/mL and 615.6 ± 267 pg/mL, bromfenac 234.3 ± 47.2 pg/mL and 355.6 ± 81.4 pg/mL, and nepafenac 183.8 ± 35.8 pg/mL and 385.0 ± 103.9 pg/mL, respectively for phakic and pseudophakic eyes.23

The results of this prospective study suggest that both AP and AN combination therapies may act synergistically with IVA in patients with CNV.

These findings are in agreement with the results of previous clinical studies by Flaxel et al.22 and Russo et al.,7 in which topical NSAIDs supplemented the activity of intravitreal anti‐VEGF in further reducing CRT in CNV. However, the improvement in BCVA we observed in our data is not as significant as it was previously described in a similar study by Semeraro et al.,6 which evaluated the association between ketorolac and ranibizumab. This could be partially explained by the stronger aflibercept affinity for VEGF compared with ranibizumab,26 thereby narrowing the NSAID potential, which, in turn, is responsible for a VEGF downregulation.27

Both AP and AN groups yielded a synergistic action, although to a different extent. In fact, if no significant differences were found in visual acuity results, a slight but significant difference in CRT was in favour of AP at 12 months. This is probably explained by the greater anti‐inflammatory effect of topical 0.1% pranoprofen at the retinal level. On the other hand, the AN group yielded a significant difference of 1 IVA less per 12 months compared with AM (P < 0.001). A delay in AMD progression with multivitamin antioxidant and mineral supplementation has been largely reported in various clinical trials17 and recently supported in a major meta‐analysis.28 Although the Age‐Related Eye Disease Study17 found that omega‐3 fatty acids had no effect on the formulation in reducing the risk of developing advanced AMD, the encouraging results we could observe with the omega‐3 supplementation might be due to their influence on the processes implicated in pathologic retinal angiogenesis in patients with CNV.13 Indeed, omega‐3 LCPUFA metabolites have a pronounced anti‐angiogenic effect, and an increased omega‐3 LCPUFA dietary intake reduces angiogenesis in experimental animal models on CNV.29, 30 Remarkably, Rezende et al.11 observed that omega‐3 supplementation combined with anti‐VEGF treatment is associated with decreased vitreal VEGF‐A levels in wet AMD patients. These findings might explain a reduced need for IVA over a 12‐month period, which is a pivotal aspect of CNV treatment, especially considering that intravitreal injections may be associated with serious adverse events, including endophthalmitis, retinal tears and retinal detachment. Our results, if confirmed in future larger studies, might have significant pharmacoeconomic implications, as the mean national Medicare drug payment per anti‐VEGF injection in the United States is reported to be $1,078 per injection.31

No serious adverse events were reported in our study. The safety results show that the treatments were well tolerated in all groups, with a safety profile comparable to that observed in previous studies. Compliance with eye drop use was very high, and the reported adverse events were of mild to moderate severity.

As this was only a pilot study, further studies using a larger sample size and longer follow‐up period are warranted to validate the results of our study and limit any possible artifacts.

In conclusion, combination therapy with either topical 0.1% pranoprofen or nutraceutical support with AREDS2 formula plus omega‐3 acts synergistically with IVA, offering valuable therapeutic support to aflibercept injections in patients requiring long‐term treatment.

COMPETING INTERESTS

There are no competing interests to declare.

CONTRIBUTORS

All authors contributed to the work. F.S. conceived the study and analysed the data. E.G. and A.C. acquired the data. F.M. and C.C. reviewed the manuscript and gave final approval. A.R. designed the study, drafted the manuscript, and run the statistical analysis.

Semeraro F, Gambicordi E, Cancarini A, Morescalchi F, Costagliola C, Russo A. Treatment of exudative age‐related macular degeneration with aflibercept combined with pranoprofen eye drops or nutraceutical support with omega‐3: A randomized trial. Br J Clin Pharmacol. 2019;85:908–913. 10.1111/bcp.13871