A Multicenter, Randomized, Double-blind Non-inferiority Trial to Evaluate the Efficacy and Safety of Entelon®

A Multicenter, Randomized, Double-blind Non-inferiority Trial to Evaluate the Efficacy and Safety of Entelon® as Compared to Doxium Tab. And Placebo for the Treatment of Nonproliferative Diabetic Retinopathy

This was a multicentre, randomised, double-blind controlled study that compared the efficacy and safety of V. vinifera extract, calcium dobesilate (CD), and placebo in subjects with DME. Patients made 6 clinic visits, namely the screening visit; baseline visit (T0); and follow-up visits at 3 (T3), 6 (T6), 9 (T9), and 12 (T12) months.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Drug: Vitis vinifera extract; Drug: Calcium Dobesilate; Drug: Placebo

Detailed Description

Eligible patients were randomised to one of the three study groups in a 1:2:2 ratio (placebo:GSPE:CD group). The randomization schedule was generated and prepared using cubeIWRS® solution (CRScube Inc., Seoul, South Korea, HQ). Randomization was performed using a complete randomization algorithm according to the order of the baseline visit. Subjects took three tablets of a masked study medication three times daily for 12 months; the first dose was taken in the morning of the baseline visit (T0) after baseline assessments were performed, and the last dose was taken in the evening before the month 12 visit (T12). Three daily oral doses of 50mg tablets of GSPE (Entelon®, Hanlim Pharm, Seoul, South Korea) were administered to patients in the GSPE group. Placebo tablets lacked GSPE, but their appearance was identical to that of the study group tablets. Commercially available 250mg CD tablets (Doxium®, Ilsung Pharm, Seoul, South Korea) were used in this study. The identity of the masked study medications was concealed by storing the medications in individually sealed envelopes at the study sites.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Singing a written informed consent prior to selection
• type 2 DM aged between 40 and 80 years
• Diabetes is well controlled with drugs for at least 3 months(HbA1c ≤9%)
• Best-corrected visual acuity over 0.5(20/40) by using ETDRS cisual acuity test
• Diabetic macular edema with hard exudates CSMT ≤300µm

Exclusion Criteria:

• Lase therapy or intravitreal injection(anti-VEGF, steroid) intraocular surgery within 6 months of enrollment
• Concomitant macular disease (such as retinal vascular occlusion, choroidal neovascularization, epiretinal membrane, etc)
• Poor image of optical coherence tomography(signal strength under 50% of narmal value)
• Concomitant therapy(Kallidinogenase, Vaccinium myrtillus extract, sulodexide)
• Non-controlled hypertension(systolic pressure >140mmHg or diastolic pressure <90mmHg)
• Severe renal insufficiency(creatinine >2.2mg/dL, or undergoing dialysis)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Entelon; Three daily oral doses of 50mg tablets were administered to patients	Drug: Vitis vinifera extract; Three daily oral doses of 50mg tablets of Vitis vinifera extract(Entelon®, Hanlim Pharm, Seoul, South Korea) were administered to patients in this group; Other Names: Experimental: Entelon
Active Comparator: Doxium; Three daily oral doses of 250mg tablets were administered to patients	Drug: Calcium Dobesilate; Three daily oral doses of 50mg tablets of Calcium Dobesilate(Doxium®, Ilsung Pharm, Seoul, South Korea) were administered to patients in this group; Other Names: Active comparator:Doxium
Placebo Comparator: Placebo; Three masking tablets were administered to patients	Drug: Placebo; Placebo tablets lacked Vitis vinifera extract or calcium dobesilate, but their appearance was identical to those of the study group tablets.; Other Names: Placebo comparator:Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change(Improvement)in the hard exduates	The improvement of HE was defined as a decrease in the HE severity by at least two categories of severity at T12 compared with the baseline visit.	T0(baseline), T12(12months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change of Best-corrected visual acuity(BCVA)	Using the Early Treatment Diabetic Retinopathy Study(ETDRS) protocol	T0(baseline), T3(3months), T6(6months), T9(9months), T12(12months)
The change of central subfield mean thickness(CSMT)	Using 6-radial scan protocol or cube scan protocol according to local guidelines of each center;the ETDRS style map	T0(baseline), T3(3months), T6(6months), T9(9months), T12(12months)
The change of total macular volum(TMV)	Using 6-radial scan protocol or cube scan protocol according to local guidelines of each center;the ETDRS style map	T0(baseline), T3(3months), T6(6months), T9(9months), T12(12months)

Collaborators and Investigators

• Sponsor: Hanyang University
• Collaborators: Hanlim Pharm. Co., Ltd.
• Investigators: Principal Investigator: Ha kyoung Kim, PhD, Hallym University Kangnam Sacred Heart Hospital

Publications and helpful links

General Publications

• Spadea L, Balestrazzi E. Treatment of vascular retinopathies with Pycnogenol. Phytother Res. 2001 May;15(3):219-23. doi: 10.1002/ptr.853.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2012
• Primary Completion (Actual): January 26, 2015
• Study Completion (Actual): January 26, 2015

Study Registration Dates

• First Submitted: May 16, 2019
• First Submitted That Met QC Criteria: May 23, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): May 24, 2019
• Last Update Submitted That Met QC Criteria: May 23, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Diabetic retinopathy, hard exudates
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Diseases; Diabetic Retinopathy; Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents; Hemostatics; Coagulants; Calcium; Calcium Dobesilate
• Other Study ID Numbers: ENTL_501

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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