Day Regimes of CONbercept on CytokinEs of PDR Patients Undergoing Vitrectomy - Trial (CONCEPT) (CONCEPT)

Different Day Regimes of Preoperative CONbercept Administration on CytokinEs of Proliferative Diabetic Retinopathy Patients Undergoing Vitrectomy: a Prospective Randomized Controlled Clinical Trial (CONCEPT)

Patients with proliferative diabetic retinopathy requiring surgical intervention will receive a pre-operative injection of Conbercept. Patients will be recruited into different groups according to variable time intervals (1 to 7 days) between intravitreous injection and surgery. At initial, pre-injection aqueous humor and blood sample will be collected in order to provide baseline VEGF-A, -B, placental growth factor (PIGF), and other cytokine levels. At the onset of the vitrectomy, a second aqueous humor, blood, and vitreous sample will be taken to obtain intra-operative levels of , VEGF-A, -B, PIGF, and other cytokine levels.

Study Overview

• Status: Unknown
• Conditions: Proliferative Diabetic Retinopathy; VEGF Overexpression
• Intervention / Treatment: Drug: IVC; Procedure: Blood and aqueous humor at the time of IVC; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Procedure: IVC-sham

Detailed Description

Proliferative diabetic retinopathy (PDR), characterized by neovascularization and fibrous proliferation, is a severe and common complication of diabetes mellitus (DM). Persistent vitreous hemorrhage (VH) caused by neovascularization and tractional retinal detachment (TRD) caused by fibrous proliferation can lead to permanent vision loss or even blindness, which are the most common indications for surgical intervention.

As neovascularization is the basal pathophysiological change of PDR and vascular endothelial growth factor (VEGF) has been acknowledged as primary angiogenesis factor, the preoperative adjunctive use of VEGF blockade is rationally proposed. The anti-VEGF drugs have been reported to be effective in bringing about regression of retinal neovascularization, shortening surgical duration, avoiding risk of iatrogenic retinal hole and secondary operation for the recurrent VH.

Conbercept (KH902) is a newly developed anti-VEGF drug and has been applied in clinic. Because of its additional binding domain of VEGFR-2, conbercept can bind to all isoforms of VEGF-A, VEGF-B, and placental growth factor (PLGF). A number of studies have presented its high affinity in the treatment of fundus diseases such as wet age-related macular degeneration (wet-AMD), macular edema secondary to retinal vein occlusion[8] and diabetic retinopathy. Also, recent randomized controlled trials have shown its protective effect of conbercept for the surgical treatment of PDR.

Although the overwhelming clinical evidence supports the anti-VEGF drugs as the preoperative adjuncts for PDR, the optimal duration between anti-VEGF injection and surgical intervention has not yet reached a consensus. Longer duration is related to higher incidence of the development or progression of TRD. It might provide clues by investigation of the pattern of cytokine changes in humor aqueous, vitreous, and blood. No studies have been done to date in patients with PDR to quantify the reduction of intravitreal VEGF-A, -B, PLGF or other cytokines levels in these patients following intravitreal Conbercept injection or to evaluate the effects of VEGF or PIGF blockade on the neovascular regression and surgical outcome in patients with extensive diabetic proliferative neovascularization.

The goal of this study is to quantify the reduction of changes of VEGF-A, -B, PLGF levels in patients receiving r pre-operative intravitreal Conbercept after variable time intervals (1, 2, 3, 4, 5, 6, 7 days).

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • First Affiliated Hospital of Nanjing Medical University
      • Contact: Zizhong Hu, Dr; Phone Number: 15195960100; Email: huzizhong@njmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 years or older
• Type 1 or 2 diabetes
• PDR patients requiring surgical intervention for complications of vitreous hemorrhage or traction retinal detachment and pre-operative IVC treatment.
• women postmenopausal for 12 months before the study, surgically sterile, or not pregnant and on effective contraception.

Exclusion Criteria:

• previous retinal vein occlusion.
• any intraocular surgery within the previous 12 months.
• myopia of > or = to 8 diopters.
• active ocular or periocular infection
• treatment with an investigational agent for any condition 60 days prior to enrollment.
• evidence of severe cardiac disease.
• clinically significant peripheral vascular disease (previous surgery, amputation, or symptoms of claudication)
• uncontrolled hypertension (treated systolic blood pressure > 155 mmHg or diastolic blood pressure > 95 mmHg)
• stroke within the preceding 12 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IVC-1day; patients with proliferative diabetic retinopathy receiving IVC 1 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-2day; patients with proliferative diabetic retinopathy receiving IVC 2 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-3day; patients with proliferative diabetic retinopathy receiving IVC 3 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-4day; patients with proliferative diabetic retinopathy receiving IVC 4 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-5day; patients with proliferative diabetic retinopathy receiving IVC 5 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-6day; patients with proliferative diabetic retinopathy receiving IVC 6 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Experimental: IVC-7day; patients with proliferative diabetic retinopathy receiving IVC 7 days before surgery	Drug: IVC; Patients with PDR will receive intravitreal injection of conbercept (0.5 mg/0.05 mL; Chengdu Kanghong Biotech, Inc., Chengdu, Sichuan, China) in the inferior-temporal sector 4 mm from the sclerocorneal limbus before pars plana vitrectomy (PPV) surgery.; Procedure: Blood and aqueous humor at the time of IVC; Initial blood and aqueous humor will be harvested at the time of IVC.; Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.
Sham Comparator: IVC-sham; patients with proliferative diabetic retinopathy receiving sham IVC	Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.; Procedure: IVC-sham; Patients with PDR will receive sham intravitreal injection of conbercept in the inferior-temporal sector 4 mm from the sclerocorneal limbus 4 days before PPV surgery.
Placebo Comparator: non-DR; patients with other retinopathy (idiopathic macular hole or epiretinal membrane)	Procedure: Collect blood, aqueous humor, and initial vitreous at the time of surgery.; Blood, aqueous humor, and vitreous will be collected at the time of surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes of intraocular VEGF and PLGF of patients with proliferative diabetic retinopathy post-IVC (intravitreous injection of Conbercept).	1-7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of serum angiogenesis-related pro-cytokines in patients with proliferative diabetic retinopathy		1-7 days
Changes of intraocular and serum profibrotic cytokines in patients with proliferative diabetic retinopathy post-IVC.		1-7 days
Changes of intraocular and serum inflammatory cytokines in patients with proliferative diabetic retinopathy post-IVC.		1-7 days
Vitreous concentration of Conbercept	Detection of Vitreous concentration of the drug of Conbercept (Conbercept is a kind of fusion protein)	1-7 days
Effect of IVC on surgery time of surgery	surgery time of vitrectomy	Surgery day
Effect of IVC on intraoperative complication of surgery	Record the intraoperative complication: bleeding and iatrogenic retinal hole when surgically removing the proliferative membranes.	Surgery day
Effect of IVC on regression of neovascularization on vitreous fibrovascular membrane with optic coherence tomography angiography (OCTA)	OCTA monitor the changes of neovascularization on vitreous fibrovascular membrane after IVC and before surgery	1 to 7 days
Effect of IVC on postoperative visual acuity	Best-corrected visual acuity postoperatively	1 to12 months
Effect of IVC on postoperative complications	Record number of patient with vitreous re-bleeding and iris neovascularization postoperatively.	1 to12 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Investigators: Study Director: Qinghuai Liu, The First Affiliated Hospital with Nanjing Medical University

Publications and helpful links

General Publications

• Chen DY, Sun NH, Chen X, Gong JJ, Yuan ST, Hu ZZ, Lu NN, Korbelin J, Fukunaga K, Liu QH, Lu YM, Han F. Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating beta-catenin-dependent vascular remodeling. J Clin Invest. 2021 Feb 15;131(4):e135296. doi: 10.1172/JCI135296.

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2017
• Primary Completion (Anticipated): September 1, 2018
• Study Completion (Anticipated): December 31, 2018

Study Registration Dates

• First Submitted: March 9, 2018
• First Submitted That Met QC Criteria: April 12, 2018
• First Posted (Actual): April 24, 2018

Study Record Updates

• Last Update Posted (Actual): April 24, 2018
• Last Update Submitted That Met QC Criteria: April 12, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Conbercept; PLGF
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Diseases; Diabetic Retinopathy
• Other Study ID Numbers: CONCEPT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No