Efficacy and safety of combined intravitreal injection of triamcinolone acetonide and ranibizumab in age-related macular degeneration: study protocol for a randomized controlled trial

Fen Wei, Xiu-lan Xiao

Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Tongji Medical School of Huazhong University of Science and Technology,Second Clinical Medical College of Yangtze University, Jingzhou, Hubei Province, China

INTRODUCTION

Research background

The term senile macular degeneration was first proposed by Gass in 1967, owing to the presence of drusen and degenerative changes of the retinal pigment epithelium and choroidal capillaries, and it was later renamed as age-related macular degeneration. Age-related macular degeneration typically occurs in middle-aged and older adults,1-6and is characterized by the presence of drusen in the fundus and macular pigment disorders. In severe cases, it can lead to severe macular hemorrhage, edema exudation, scar formation, and even blindness.7,8

In China, the prevalence of age-related macular degeneration is increasing yearly with increasing age.9,10Currently,there is no effective treatment for age-related macular degeneration.11-16Antioxidants and blood vessel dilators have been prescribed by most doctors with little effect.

Ranibizumab, an anti-vascular endothelial growth factor fusion protein, is an angiogenesis inhibitor that has been used in the treatment of wet (neovascular) age-related macular degeneration; however, patients treated with ranibizumab are at a high risk of endophthalmitis, rhegmatogenous retinal detachment, retinal tears, and iatrogenic traumatic cataract.17-20

Main objective

The purpose of this study is to validate the safety and efficacy of combined intravitreal injection of triamcinolone acetonide and ranibizumab in the treatment of age-related macular degeneration.

METHODS/DESIGN

Study design

A prospective, single-center, randomized controlled trial will be conducted in the Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology, China. The study population comprises 80 patients (160 eyes) with age-related macular degeneration who will be randomized into two groups to receive intravitreal injection of triamcinolone acetonide alone (control group) or in combination with ranibizumab (treatment group) for 3 continuous months. All the patients will be followed up for 6 months (Figure 1).

Study setting

Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology, China.

Study population

Eighty patients (160 eyes) with age-related macular degeneration from clinics and wards receiving treatment in the Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology will be enrolled in this study.

Strengths and limitations

· Combined intravitreal injection of triamcinolone acetonide and ranibizumab improves visual performance and pathological symptoms in exudative age-related macular degeneration.

· Short-term follow-up.

· Relatively small sample size.

Figure 1: Flow chart of the trial.

Inclusion criteria

· Patients who ful fill the clinical diagnostic criteria for agerelated macular degeneration proposed by the ocular fundus disease group, Chinese Medical Association in 198621

· Patients who have exudative age-related macular degeneration as con firmed by indocyanine green angiography

· Patients who are con firmed as having age-related macular degeneration for the first time and undergo appropriate treatments

· Aged over 50 years

· Provision of signed informed consent

Exclusion criteria

· Cases that are dif ficult to distinguish from other retinal macular degeneration by fundus examination

· Unwilling to receive treatment regimen

Withdrawal criteria

· Unable to comply with the treatment

· Unable to attend follow-up visits

Recruitment

A lea flet printed with the details of the study will be distributed to inpatients, outpatients, and their families. The patients and their families who are interested in this research project can contact the project manager by telephone. Eligible patients will sign the written informed consent prior to participation in the trial.

Randomization and blinding

A random number table will be generated by the first author using the SPSS 13.0 software (SPSS, Chicago, IL,USA). Patients will be numbered according to the visiting sequence. Eligible patients with odd-number hospital records will serve as the control group (40 patients with 80 eyes), while those with even-number records will serve as the treatment group (40 patients with 80 eyes). This study is an open trial, and all the participants will be aware of grouping and assessment.

Interventions

The patients in the control group will receive intravitreal injection of 1 mL triamcinolone acetonide (speci fications 1 mL:40 mg, produced by Bristol-Myers Squibb Company,Italy, with the product batch No. 111013), once daily. The patients in the treatment group will receive combined intravitreal injection of triamcinolone acetonide (0.025 mL once daily) and 0.05 mL of ranibizumab (speci fications 10 mg/mL, 0.2 mL per bottle, produced by Novartis Pharma Schweiz AG, Switzerland) once a month. The treatments in both groups will last for 3 months.

Outcome measures

Primary outcome measure

Foveal retinal thickness before and 6 months after the treatment will be measured using an OCT-1000 scanner (Chenxu Telecommunications Technology Co., Ltd.,Guangzhou, China). A higher value indicates more severe macular degeneration.

Secondary outcome measures

· The best corrected visual acuity before and 6 months after treatment will be tested by professional doctors.

· Intraocular pressure before and 6 months after treatment will be tested using a non-contact tonometer (Wufang Medical Devices Co., Ltd., Nanchang, China).

· Quality of life scores before and 6 months after treatment:Low-vision Quality of Life Questionnaire (Chinese version; CLVQOL) will be utilized to assess (1) far vision,movement, light perception; (2) adjustment capacity; (3)reading and fine work; and (4) daily living ability in all patients, with a range of 0–100 points. A higher score indicates higher ability.

· The incidence of adverse events at 6 months after treatment: Incidence of adverse events = the number of patients presenting with any adverse events/the total number of patients × 100%.

The schedule of outcome measurement assessments is shown in Table 1.

Table 1: Timing of outcome assessment

Safety assessment

We will record adverse events, including endophthalmitis,rhegmatogenous retinal detachment, retinal tears, iatrogenic traumatic cataracts, low back pain, transient blurred vision,elevated intraocular pressure, macular hemorrhage, and loss or loosening of fixation during follow-ups. If severe adverse events occur, the date of occurrence, type of events, and measures taken to treat the adverse events will be reported in detail to the principle investigator and the Institutional Review Board within 24 hours.

Audits

Initial stage

The study protocol should be approved by the Ethics Committee of the Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology in China, and a protocol agreement should be signed.

During the trial

During participant recruitment, regular audits will be necessary to ensure the eligibility of participation, strict implementation of the study protocol, and integrity of related data.

Final stage

At the end of all trial procedures, a final visit will be indispensable to avert the omission of relevant records.

Statistical analysis

Statistical design, method, and analysis principle

All data will be statistically analyzed using the SPSS13.0 software (SPSS, Chicago, IL, USA) and follow the intention-to-treat principle. Normally distributed measurement data will be expressed as the mean ± SD and non-normally distributed measurement data will be expressed as lower quartile (q1), median, and upper quartile (q3). Count data will be expressed as percentage.

Two-sample t-test will be used to compare foveal retinal thickness, best corrected visual acuity, intraocular pressure, and quality of life scores between the two groups.Paired t-test will be used for intragroup comparison of the above-mentioned indicators before and after treatment. A Pearson's correlation analysis will be used to compare the incidence of adverse events between the two groups, with a signi ficant level of α = 0.05 (two-sided).

Sample size

Based on our experience, we hypothesize that the foveal retinal thickness in the treatment and control groups will be decreased by 200 and 150 μm, respectively, with a standard deviation of 100 μm. Taking β = 0.1, power = 90%, and α = 0.05 (two-sided), the final sample size of 86 eyes per group was calculated using the PASS 11.0 software (PASS,Kaysville, UT, USA). Considering a loss rate of 20%, 40 cases (80 eyes) per group will be included in the study.

Baseline data collection

The baseline data of the included patients are shown in Table 2.

Table 2: Baseline data of patients

Data management

The case report form of each enrolled case should be completed by researchers and audited by an inspector. Data entry and management will be performed. After data transfer, the contents recorded in the case report form will not be modified. The database is locked by the data manager. Generally,locked database or files will not be altered.

Quality control of the clinical trial

During the clinical trial, sponsor inspectors will conduct regular periodic visits to the research center to ensure strict adherence to all aspects of the research program. In addition,the original data will be checked to ensure that the contents of the case report forms are true, complete, and accurate.

Ethical considerations and informed consent

This clinical trial follows the relevant laws and regulations of the Declaration of Helsinki. This manuscript is prepared and modi fied according to SPIRIT guidelines (Additional file 1). The researchers take the responsibility of providing the independent ethics committee with the clinical trial protocol and informed consent forms to obtain an independent approval for the implementation of the clinical trial. The trial cannot be initiated until approval is received from the ethics committee. This study was approved by the Ethics Committee of the Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology in China (approval No. 20170338).

TRIAL STATUS

Recruitment of patients will begin in January 2018. The analysis of outcome measures and completion of trial will be in September 2018.

DISCUSSION

Achievements and existing problems

There is no effective treatment for age-related macular degeneration. Ranibizumab has been used in the treatment of wet (neovascular) age-related macular degeneration;however, it is associated with many adverse reactions.

Significance of this study

This is a prospective, randomized controlled trial aiming to evaluate the ef ficacy and safety of combined intravitreal injection of triamcinolone acetonide and ranibizumab for the treatment of age-related macular degeneration, through a systematic observation of the clinical ef ficacy of the combined therapy and posttreatment adverse reactions.

Limitations of this study

Small sample size, lack of blinded assessment, and no longterm follow-up will impact the objectivity of the outcomes of this study.22-24

Evidence for contribution to future studies

In this study, we attempt to con firm that the combined intravitreal injection of triamcinolone acetonide and ranibizumab can effectively reduce foveal retinal thickness, improve corrected visual acuity, improve quality of life, and reduce incidence of adverse reactions in patients with age-related macular degeneration. Thus, the combined treatment of triamcinolone acetonide and ranibizumab is expected to be an effective therapeutic method for age-related macular degeneration with desired outcomes in the future.

Author contributions

FW conceived and designed the study protocol, wrote the manuscript. XLX gave some constructive suggestions for the study design.FW will complete the trial with the help of XLX. Both authors read and approved the final version of the manuscript for publication.

Conflicts of interest

None declared.

Research ethics

The study protocol was approved by the Ethics Committee of Jingzhou Hospital Af filiated to Tongji Medical School of Huazhong University of Science and Technology, China (approval No.20120630). The study will be performed in accordance with theDeclaration of Helsinki.

Declaration of patient consent

The authors certify that they will obtain patient consent forms.In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Data sharing statement

Datasets analyzed during this study will be available from the corresponding author on reasonable request.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under identical terms.

Additional file

Additional file 1: SPIRIT checklist.

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