Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study

Abstract

Purpose: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study.

Patients and methods: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients.

Results: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported.

Conclusions: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice.

Trial registration: ClinicalTrials.gov NCT01318941.

Conflict of interest statement

Financial disclosures: Paul Mitchell: Consultant − Abbott, Allergan, Bayer, Genentech, Novartis, Roche. Tom G. Sheidow: Research support – Novartis, Pfizer; Advisory board – Novartis, Alcon, Bayer Michel E. Farah: Consultant: Allergan, Bayer, Novartis, Alcon, Zeiss; Advisor: Cristália, Latinofarma; Research grant: Fapesp, Capes, CNPq Sajjad Mahmood: Research Grant – Bayer, and Novartis; Personal Fees – Alcon, Allergan, Bayer, and Novartis. Angelo M. Minnella: Consultant – Theà Laboratoire; Travel and meeting grant- Allergan, Bayer, Novartis, Theà. Nicole Eter: Consultant – Allergan, Alimera, Bausch & Lomb, Bayer, Heidelberg Engineering, Novartis, Roche. Bora Eldem: Consultant – Alcon Laboratories, Bayer Healthcare, and Novartis. Hassan Al-Dhibi: Consultant –Bayer, AbbVie and Novartis. Wayne Macfadden: Employee of Novartis Pharma AG, Basel, Switzerland at the time of development of the manuscript. Soumil Parikh: Employee of Novartis Pharma AG, Basel, Switzerland. Cornelia Dunger-Baldauf: Employee of Novartis Pharma AG, Basel, Switzerland. Mohamed M. Mahgoub: Nothing to declare. Ursula Schmidt-Erfurth: Consultant – Alcon, Bayer, Boeringher-Ingelheim GmbH, and Novartis. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. LUMINOUS study overview: World map showing overall recruitment with countries enrolling highest treatment-naïve patients with DME.

The pop out boxes represent the number (%) of treatment-naïve patients with DME in the top. Equal recruitment numbers were achieved in Turkey and Germany. DME, diabetic macular edema.

Fig 2. Mean change in visual acuity by injection frequency in treatment-naïve patients with DME (N = 502; primary treated eye set).

Observed dataset for VA change. The primary treated eye set included all primary treated eyes in patients included in the safety set. The safety set consisted of patients in the enrolled set who were treated with at least one dose of ranibizumab during this study or prior to the start of the study and had at least one safety assessment after the first treatment. For treatment-naïve eyes, the date of first on-study injection with ranibizumab was considered the baseline date. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis. DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.

Fig 3. Mean change in visual acuity in patients with and without loading doses (primary treated eye set).

*Three initial consecutive injections at 4 weekly intervals. Observed dataset for VA change. The primary treated eye set included all primary treated eyes in patients included in the safety set. The safety set consisted of patients in the enrolled set who were treated with at least one dose of ranibizumab during this study or prior to the start of the study and had at least one safety assessment after the first treatment. For treatment-naïve eyes, the date of first on-study injection with ranibizumab was considered the baseline date. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis.BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.

Fig 4. Mean change in visual acuity by baseline visual acuity stratification (primary treated eye set).

Observed data set for VA change. The primary treated eye set included all primary treated eyes in patients included in the safety set. The safety set consisted of patients in the enrolled set who were treated with at least one dose of ranibizumab during this study or prior to the start of the study and had at least one safety assessment after the first treatment. *The values represent the final VA at year 1. For treatment-naïve eyes, the date of first on-study injection with ranibizumab was considered the baseline date. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis. ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.

Fig 5. Proportion of patients with a VA gain or loss (primary treated eye set).

*Includes patients with 0 letters loss. The primary treated eye set included all primary treated eyes in patients included in the safety set. The safety set consisted of patients in the enrolled set who were treated with at least one dose of ranibizumab during this study or prior to the start of the study and had at least one safety assessment after the first treatment. For treatment-naïve eyes, the date of first on-study injection with ranibizumab was considered the baseline date. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis. ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.

Fig 6. Frequency of injections over 12 months (N = 502, safety set).

The safety set consisted of patients in the enrolled set who were treated with at least 1 dose of ranibizumab during this study or prior to start of study and had at least 1 safety assessment after the first treatment. 1.4% (n = 7), 1.0% (n = 5), and 0.4% (n = 2) of patients received 10, 11, and 12 injections respectively. n = number of evaluable patients with baseline and year 1 data. For treatment-naïve eyes, the date of first on-study injection with ranibizumab was considered the baseline date. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis. VA, visual acuity.

Fig 7. Mean change in visual acuity, baseline visual acuity, and average injection numbers across various regions (primary treated eye set).

The primary treated eye set included all primary treated eyes in patients included in the safety set. Top recruiting countries (treatment-naïve DME) with highest evaluable baseline and year 1 data. For the 1-year time period, all patients with non-missing baseline VA and year 1 VA performed anywhere between Day 319 and Day 409 but who had been in the study for at least 365 days from baseline to last follow-up date were included in the analysis. DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.