Background and rationale {6a}
Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, accounting for 13% of visual impairment in diabetic patients [1]. Diabetic macular edema (DME) is a common manifestation of DR and one of the major causes of visual loss in diabetic patients. There are many treatments for DME. Photocoagulation therapy, intravitreal anti-vascular endothelial growth factor (VEGF) injection, and intravitreal corticosteroid injection are its main methods [2]. The current first-line treatment for DME is an intravitreal injection of anti-VEGF agents [3], with ranibizumab being most commonly used in China. At present, the consensus of intravitreal ranibizumab injection is 3 consecutive monthly injections, followed by monthly follow-up and pro re nata (PRN) treatment. Several studies have shown that the number of injections within a year ranges from 7 to 8 [4]. Because ranibizumab is expensive and many DME patients suffer from recurrence, multiple intravitreal injections are needed, which brings a heavy economic and psychological burden to DME patients in China. Moreover, as the number of intravitreal injections increases, the risk of complications such as endophthalmitis also increases.
In previous studies of traditional macular grid photocoagulation combined with anti-VEGF therapy to treat DME, the timing of combined treatment was divided into immediate laser therapy and delayed laser therapy. Study results showed that combined treatment did not improve the visual acuity of patients or reduce the number of anti-VEGF injections and it left visible laser scars, causing damage to the retina, resulting in complications such as decreased visual acuity and reduced visual field. Therefore, the use of traditional photocoagulation is gradually decreasing. The 2017 European Union DME treatment guidelines stated that micropulse laser treatment is a promising treatment strategy for DME [5]. Micropulse laser is a type of subthreshold laser, which minimizes the damage of the neuroepithelial layer by reducing exposure time and energy. The guidelines stated that a micropulse diode laser emits a low-energy micropulse that confines the energy to the retinal pigment epithelium and avoids the outward spread of heat. Some randomized clinical studies have confirmed that the efficacy of micropulse diode laser treatment is comparable to that of traditional macular grid photocoagulation. However, it takes more time to achieve the same visual function and anatomical results [6, 7]. Therefore, guidelines recommended micropulse laser treatment for early diffuse DME patients with better visual acuity to avoid the spread of thermal energy and secondary chorioretinal injury. Compared to the previous diode micropulse laser, the new IQ577 nm micropulse laser has more obvious advantages. First, located in the inner and outer plexiform layers of the macula, lutein seldom absorbs yellow light. Therefore 577 nm yellow light is more suitable for the treatment of the macular than diode red light [8] with less damage. Second, treatment parameters such as duty cycle changed from 15 to 5% so that laser duration is shorter and the damage to the retina is less. Third, it is improved to a low-energy high-density grid laser with a better effect in eliminating edema. Previously, conventional lasers and other subthreshold lasers are forbidden within 500 μm diameter of the macula. But being able to treat in this range has become the most important innovation and advantage of the IQ577 nm micropulse laser. At present, some foreign studies and our own clinical experience have confirmed that 577 nm micropulse laser treatment for mild to moderate DME can effectively relieve edema and improve the visual function of patients [9]. The technique is simple and easy to learn, convenient for promotion, and more importantly, it can be easily accepted by patients for its cheap price.
To our knowledge, there were few prospective randomized controlled studies of micropulsed laser combined with anti-VEGF drugs in the treatment of DME. Only two retrospective studies published in 2017 and 2021 suggested that anti-VEGF drugs combined with the micropulse laser group could reduce the number of intravitreal injections compared to the anti-VEGF monotherapy group in the treatment of DME [10, 11].
Objectives {7}
The purpose of this study is to evaluate the safety and efficacy of micropulse laser combined with intravitreal ranibizumab injections in the treatment of DME. Study subjects are 72 patients (more patients may be recruited) diagnosed with diabetic macular edema. By using a prospective randomized double-blind controlled study method, we hope to compare the changes of visual acuity and macular edema regression between micropulse laser combined with ranibizumab group with ranibizumab monotherapy group to determine whether the efficacy of micropulse laser combined treatment group in the treatment of DME is not lower than ranibizumab monotherapy and whether these two therapies are equally effective. Our goal is to reduce the number of intraocular injections and establish a new technique for the treatment of DME.
Trial design {8}
This study is a prospective, single-center, randomized controlled, double-blinded non-inferiority clinical trial. A flow chart of the study design is shown in Fig. 1. Study subjects are 72 patients (more patients may be recruited) diagnosed with diabetic macular edema.
Screening period: from day −14 to day −1
At screening (visit 1, between day −14 and day −1), after signing the informed consent (the model consent form is attached as a supplementary file), the patient is enrolled in the study and will undergo a series of examinations including ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity test, intraocular pressure measurement, slit-lamp, and indirect ophthalmoscopy, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), fundus fluorescein angiography (FFA), fundus color photography, vital signs, hematology, urinalysis, blood biochemistry, and glycosylated hemoglobin to assess eligibility for the study.
Treatment period: from day 1 to month 11
At baseline (visit 2, day 1), eligible patients will be randomized by 1:1 ratio into micropulse laser combined with ranibizumab group or ranibizumab monotherapy group. After baseline visit, all patients receive 3 consecutive monthly ranibizumab injections. Subjects will then return to the study site on day 90 (± 7 days) and according to the retreatment criteria, patients will either receive micropulse laser and sham intravitreal ranibizumab or sham micropulse laser and intravitreal ranibizumab. Thereafter, subjects will return to the study site every 30 days (± 7 days) for assessment (schedule shown in Fig. 2) and accept appropriate treatment according to the retreatment criteria.
Group I (micropulse laser combined with ranibizumab group): 3 consecutive injections of intravitreal ranibizumab, followed by monthly observation, if:
-
A.
Visual acuity decreases by greater than or equal to 5 ETDRS letters due to macular edema, then treat with micropulse laser therapy and sham intravitreal ranibizumab injection.
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B.
Visual acuity stays stable for at least two consecutive treatments (3 consecutive changes of no more than 5 letters), discontinue micropulse laser treatment.
Group II (ranibizumab monotherapy group): 3 consecutive injections of intravitreal ranibizumab, followed by monthly observation. According to the investigator’s judgment, if:
-
A.
Visual acuity decreases by greater than or equal to 5 ETDRS letters due to macular edema, then treat with sham micropulse laser and intravitreal ranibizumab injection.
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B.
Visual acuity stays stable for at least two consecutive treatments (3 consecutive changes of no more than 5 letters), discontinue intravitreal ranibizumab injection.
Post-treatment follow-up period: from month 11 to month 12
For all patients, the last study assessment will occur at month 12 (1 month after the last possible micropulse laser or intravitreal ranibizumab injection in the study).