What can we learn from negative results in clinical trials for proliferative vitreoretinopathy?

INTRODUCTION

Since the beginning of vitreoretinal surgery proliferative vitreoretinopathy (PVR) has been a constant complication.PVR is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD) resulting in multiple reoperations and vision loss. So far, there is no proven therapy to treat or prevent PVR. The incidence of PVR is estimated to be between 5% and 10% of all RRD repairs and generally occurs within 8wk of surgery. It often is difficult to predict which patients may develop PVR. A retinal break is a prerequisite for the development and almost all clinical risk factors for PVR are associated either with intravitreal dispersion of retinal pigment epithelial (RPE) cells or the breakdown of the blood-retinal barrier (BRB). Certain risk factors make the development of PVR more likely, such as the presence of intraocular hemorrhage, uveitis, preoperative or postoperative choroidal detachment, size of retinal tears,multiple retinal tears, chronic retinal detachments, and multiple previous surgeries or trauma

. Current strategies for PVR prevention are equally focused on timely and successful repair of RRD. The goal of surgical repair is to relieve traction and reattach the retina. To date, surgery remains the only management of PVR. In our current understanding PVR is a cellular reaction molded by many cytokines leading to fibrosis and scarring and redetachment and vision loss. Suitable pharmacological adjuncts moderate inflammation and cellular proliferation, thereby lessening PVR formation. The following trials tried to address the problem.

Daunomycin Trial (1998)

The 286 patients/eyes with advanced preoperative PVR in which surgery with silicone oil was planned were recruited in a prospective, randomized,controlled multicenter European clinical trial to assess the efficacy and safety of adjunctive daunorubicin during vitrectomy surgery in eyes with PVR (Grade C or higher).Standardized surgery alone (control) was compared with surgery plus adjunctive daunorubicin perfusion (study treatment). Outcomes appraised were retinal attachment without additional vitreoretinal surgery 6mo after standardized surgery, number of and time of vitreoretinal reoperations,and change in visual acuity. Six months after standardized surgery, complete retinal reattachment without additional vitreoretinal surgery was achieved in 62.7% (89/142) of eyes in the treatment group

54.1% (73/135) in the control group(

=0.07, one-sided). Although anatomic success rate after 6mo failed to show significance, some benefit of adjunctive daunomycin treatment exists, especially a tendency toward increased rates of reattachment and a significant reduction in the number of reoperations. No severe adverse effect related to daunorubicin was seen.

Ozurdex Slow-Release Dexamethasone Trial (2017)

To test the hypothesis that adjunctive slow-release dexamethasone implant (Ozurdex; Allergan Inc, Irvine, CA, USA) can improve the outcomes of surgery for established PVR a single center, prospective, masked randomized controlled clinical trial (EudraCT No.2011-004498-96) was performed.

A total of 140 patients requiring vitrectomy with silicone oil for retinal detachment with established PVR (Grade C) were randomized to standard (control) or study treatment (adjunct).Intraoperatively, the adjunct group received an injection of 0.7 mg of slow-release dexamethasone (Ozurdex) at the time of 1) vitrectomy surgery and 2) silicone oil removal. The control group received standard care.

Primary endpoint was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6mo. Secondary outcomes included 1) final visual acuity; 2) cystoid macular edema (CME), foveal thickness, and macular volume; 3)development of overt PVR recurrence; 4) complete and posterior retinal reattachment; 5) tractional retinal detachment;6) hypotony/increased intraocular pressure (IOP); 7) macula pucker/epiretinal membrane; 8) cataract; and 9) quality of life.Anatomic success between the 2 groups was similar (49.3%

46.3%, adjunct

control). Secondary anatomic outcomes(vision, complete/posterior reattachment rates and PVR recurrence) were comparable between the 2 groups. At 6mo,fewer dexamethasone patients had CME (42.7%) or an increased foveal thickness (47.6%) compared with controls(67.2% and 67.7%, respectively).

A slow-release dexamethasone implant did therefore not improve the anatomic success rate in eyes undergoing vitrectomy surgery with silicone oil for PVR.

Larger study might have had the statistical power to detect a smaller benefit. However, a too small benefit may not be clinically relevant. Some benefit of the adjunctive treatment for existing PVR exists, however: 1) a tendency toward increased rate of reattachment and a significant reduction in the number of reoperations for daunomycin and a greater reduction in CME for dexamethasone. 2) None of the treatments had major side effects, tolerable ocular concentrations can be determined.

知识经济和生态经济是不可截然分开的，它们代表未来社会经济发展的两个趋势，就像汽车的两个轮子一样，缺一不可。知识经济实际上也包含着生态经济，这是因为生态经济首先必须建立在知识的广泛运用和转化的基础上，建立在高科技的掌握和运用的基础上。与此同时，生态经济又为知识经济提供方向保证，只有把知识经济纳入生态经济的轨道，只有在生态经济的规律和原则指导下，才能保证经济社会的可持续发展。换句话说，知识的运用和转化，科学技术的运用和转化，只有严格按照生态化的运行模式，才能保证生态、经济、社会沿着可持续发展的方向进行。

在采用高压水力冲刷清淤时必须根据现场实际情况（管径、淤积程度和管渠形状等），选择合适的喷头、冲洗压力(70～140 Bar)和冲洗流速。若沉积物特别密实，则需要采用铣床钻头进行清理（见图1）。

A total of 325 subjects in 13 German trial sites had been randomized (Verum:

=163; placebo:

=162). There was no significant difference in PVR rate (Verum: 28%

placebo:23%). None of the secondary endpoints showed a significant difference between treatment groups. No relevant safety risks were observed.

GUARD (Gain Understanding Against Retinal Detachment)Trial Methotrexate (2023)

The rationale for use of intravitreal methotrexate for treatment of PVR is based on its property to suppress inflammation and inhibit cellular replication, both of which are key factors in the pathogenesis of PVR. In December 2019, enrollment began in the GUARD trial, a two-part multicenter, randomized, controlled, adaptive phase 3 clinical trial in the United States investigating the efficacy of ADX-2191 (intravitreal methotrexate 0.8%,Aldeyra Therapeutics) for the prevention of PVR-associated retinal redetachment. Only PVR eyes that achieve successful retinal reattachment are randomized into the GUARD trial,with a ratio of 1:1 intraoperatively between methotrexate or control, which is standard surgery. ADX-2191 has received orphan drug designation from the US FDA. Because the PVR life cycle lasts for several weeks, the GUARD trial involves serial injections of intravitreal methotrexate throughout the entire risk period rather than as a single injection at the time of surgery. Results from part 1 of the GUARD trial is expected in the second half of 2022.

Timely diagnosis, a thoughtful surgical approach and careful postoperative management are key to successful retinal reattachment and vision preservation. Despite all the refinement and improved efficacy and safety of modern-day vitreoretinal surgery this complication still eludes us and only modest progress in the treatment of PVR has been achieved.The most important step forward was the capacity to remove quite completely the vitreous, not done and not possible at the time of the daunomycin trial.

1928年10月28日，印尼第二届全国青年大会的“青年誓言”第3条开始提及印尼语的地位：“我们印尼儿女，尊重统一的语言，印尼语”。这条誓言把印尼语视作团结各民族的语言，明确了印尼语国民语言的地位。1945年8月17日印尼独立后，1945年宪法第15章第36条的规定将印尼语从国民语言提升至官方语言的地位。1950年临时宪法再次规定印尼语是印尼共和国的官方语言。综上所述，印尼语具有这样的法律地位：既是国语(National Language)又是行政语言(Official Language)。

The primary outcome was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) within 12wk after surgery.Secondary endpoints included re-detachment rate and bestcorrected visual acuity.

What can we learn from the negative results of the above trials?

I believe there are three points:

2) The Daunomycin and Dexamethasone study treated established PVR by a single infusion during surgery or onetime repeated injection (slow release), the Privent trial tried prevention with a single perfusion. The Guard trial intends to prevent recurrence of PVR with serial injections. This may be a better approach to effectively prevent recurrent PVR.Repeated injections are no problem today but were not even thought of 30 years ago.

In the preventive PRIVENT trial the rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD considered at high PVR risk.

在九头山汉墓中，出土了40多枚汉武帝和汉宣帝五铢钱，同时还出土了琉璃饰品，据考证可能来自东南亚或印度东海岸，从合浦登陆，经南流江、北流江西上柳江进口。这也证明了柳江早在汉朝时期便为柳州提供了航运便利和商贸通道。

In the therapeutic daunomycin trial against established PVR anatomic success rate after 6mo failed to show significance.Primary outcome assessment in the therapeutic dexamethasone trial showed similar results in anatomic success between the 2 groups.

Substantial advances have been made in understanding critical molecular and cellular mechanisms driving PVR. These findings have led to the discovery of a variety of molecular targets. The verdict is still out on whether intravitreal drugs will be a definitive therapeutic modality for treatment and/or primary prevention of PVR.

1) Anecdotal reports and small investigator-initiated trials have shown favorable results in preventing progression of PVR for all mentioned drugs (daunomycin, dexamethasone,fluorouracil, methotrexate). In the randomized clinical trial, the results were different.

综合分析，大伙房水库的浮游植物生长是磷限制的，减小各河流磷输入将会有效降低库内叶绿素a的浓度，控制苏子河的营养盐输入更为适宜。但是由于水库总氮浓度一直处于较高水平，对各河流氮排放总量进行控制也应引起足够的重视。

(Prophylactic Intravitreal 5-Fluorouracil and Heparin to Prevent PVR in High-risk Patients with Retinal Detachment (2022)

The objective of this randomized, controlled, double-blind, multicenter,interventional trial with one interim analysis in Germany was to examine the effect of adjuvant intravitreal therapy with 5-fluorouracil (5-FU) and low molecular weight heparin(LMWH), compared with placebo, on the incidence of PVR.Patients with primary RRD and preoperative elevated aqueous flare measurements as an indication of blood retinal barrier breakdown were considered high-risk for PVR and were included. Patients were randomized 1:1 to Verum (200 mg/mL 5-FU and 5 IU/mL Dalteparin) or placebo (balanced salt solution). These solutions were intravitreally applied during routine vitrectomy.

1.1 一般资料 选取2017年4—11月中国医科大学附属盛京医院择期行上腹部手术开放手术患者60例，纳入标准：年龄35～68岁，美国麻醉医师协会分级Ⅰ或Ⅱ级。排除标准：有内科基础疾病如心脑血管疾病、慢性阻塞性肺疾病和哮喘、肝肾功能障碍、慢性疼痛病史、精神神经系统疾病，手术前使用镇痛药物，阿片类药物过敏史及滥用病史。上述患者依据随机数字法分为S组、SB1组、SB2组，各20例。三组患者性别、年龄、体重和手术方式比较差异无统计学意义(P>0.05)，具有可比性，见表1。本研究经中国医科大学附属盛京医院伦理委员会批准(批准号：2017PS272K)，患者和家属均签署知情同意书。

不可否认，认可人工智能的法律人格，是对现行法律框架的一个非常大的冲击，故确要谨慎为之。当前是否确要为之，或如确要为之时具体应如何为之等等问题，此处不拟讨论。但无论如何，当前人工智能的发展，其实已经开始表现出“脱离人类控制而独立行动”的能力或具有这种能力的可能性。因此，我们至少有必要将认可人工智能的法律人格视为一个现实问题，而不是将其仅仅视作一个遥远的“科幻”问题。

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3) The results of the above studies suggest that we do not understand the basic pathobiology of the PVR as well as we thought. It is important to recognize that the efficacy of intravitreal drugs for treatment and prevention has not been established to date. However, the publication of initial treatment negative results is very important because it is this information which helps in designing newer studies attempting to treat the same condition with similar or other pharmaceutical agents.

We need to re-examine our assumptions about why some eyes demonstrate PVR after otherwise uncomplicated retinal detachment repair. It is not clear whether it is better to prevent development or to treat established PVR for longer period.There is a clear need for identification and validation of diagnostic, prognostic, and predictive biomarkers to help accelerate new treatments. As our understanding of the underlying molecular mechanisms in PVR pathogenesis continues to expand, so too is the list of novel drug targets.

We very much hope that the Guard trial will show significance.But it is good to know that several phase 2 trials are ongoing

.

None.

1 Wiedemann P, Yandiev Y, Prigliger S, Hui Y. Pathogenesis of proliferative vitreoretinopathy. In: Sadda SR, ed.

, 7th edition. Elsevier Health Sciences 2023;1978-1289.

2 Wiedemann P, Hilgers RD, Bauer P, Heimann K. Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy:results of a multicenter clinical trial. Daunomycin Study Group.

1998;126(4):550-559.

3 Banerjee PJ, Quartilho A, Bunce C, Xing W, Zvobgo TM, Harris N, Charteris DG. Slow-release dexamethasone in proliferative vitreoretinopathy.

2017;124(6):757-767.

4 Schaub F, Schiller P, Hoerster R,

, PRIVENT Study Group.Intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy: results from a randomized clinical trial.

2022;S0161-6420(22)00413-4. Epub ahead of print.

5 Eliott D, Stryjewski TP. Methotrexate for proliferative vitreoretinopathy.US Patent 2017. https://patents.google.com/patent/US10098884B2/en$Accessed on July 7, 2022.

6 The GUARD Trial part 1: a phase 3 clinical trial for prevention of proliferative vitreoretinopathy. Clinicaltrials.gov identifier NCT04136366. https://clinicaltrials.gov/ct2/show/NCT04136366.Accessed on July 7, 2022.

7 Clinical trials on proliferative vitreoretinopathy. https://ichgcp.net/clinical-trials-registry/research/list?cond=Vitreoretinopathy%252C%2 BProliferative#google_vignette. Accessed on July 7, 2022.