DRESS: Diabetic Retinopathy Sulodexide Study

Sponsor

Ajou University School of Medicine (Other)

Overall Status

Completed

CT.gov ID

NCT01295775

Collaborator

(none)

127

Enrollment

Location

Arms

26.9

Duration (Months)

4.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this phase 2 controlled placebo study is to assess the effectiveness of Sulodexide in the treatment of non proliferative (background) retinopathy in patients with Type 1 and Type 2 Diabetes Mellitus.

This is a multicentre, double-blind, randomised study involving patients affected by non proliferative (background) diabetic mild to moderate retinopathy.

This study will involve 130 patients (65 for each group). At baseline visit (T0), the Investigator will grade the ocular lesions due to diabetic retinopathy according to color fundus photographs and the fluorescein angiography examination. He will subsequently send the negatives of photographs and the images -or negatives when available- of fluorescein angiography to an off-site Assessor -unaware of the Investigator assessment- nominated to confirm the quality of the images and the grade of the lesions. After positive assessment of the Investigator, at T0 the eligible patient will be blindly allocated to one of the 2 treatment groups according to a computer-generated randomisation list provided by the Sponsor.

The following treatments will be administered for 360 days:

A (SULODEXIDE GROUP): 50 mg a day by oral route;

B (PLACEBO GROUP): Sulodexide placebo at the same schedule and for the same lengths of time as group A.

Before breaking the randomisation code at the end of the study, an independent off site assessor will evaluate the photographs according to the Airlie House Classification and following modification by Early treatment Diabetic Retinopathy Study (ETDRS) and fluorescein angiography according to ETDRS.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Retinopathy	Drug: sulodexide	Phase 2

Detailed Description

Diabetic retinopathy is the leading cause of blindness in adults (20 to 74 years old) in the industrialised countries, affecting from 2 to 5% of entire population. All the complications of diabetes such as diabetic retinopathy, are caused by the chronic hyperglycaemia. Although a good metabolic control with therapy lowers the blood glucose levels enough to preserve life, this does not permit complete euglycemia nor prevent the long-term complications of chronic supernormal levels of blood glucose. The excess glucose causes flux through the polyol pathway, which results in structural tissue modifications.

Diabetic retinopathy is mainly a vascular disease, primarily affecting the capillaries. The first ultrastructural and microscopic changes reported are retinal capillary basement membrane thickening and pericyte degeneration, both of which compromise the integrity of the capillary wall, followed by pericyte loss.

The glycosaminoglycans (GAGs) of the basal membrane are progressively substituted by collagen, leading to a modification in vascular permeability due to the altered anionic charge. These changes lead to the clinical appearance of vascular leakage from retinal capillaries followed by microaneurysms. The lack of integrity of the vessel wall leads to haemorrhages, and to microthrombosis, which are responsible for the first ischemic lesions. If the vascular leakage lasts for a long time, the lipidic fraction of leaked plasma deposits in the retina forming hard exudates.

The substitution of GAGs by collagen leads to a basal membrane thickening also in the kidney. As in the retina, the modification of permeability occurs in the renal glomeruli and induces the selective loss of proteins (albuminuria).

Recent papers show a specific modification in GAGs metabolism occurring in diabetic patients that could be the common pathogenetic mechanism of vascular diabetic failure. Therefore, diabetic retinopathy and diabetic nephropathy may be regarded as the result of the alteration of a common underlying molecular mechanism whose expression is the depletion of GAGs from the basement membrane in both retinal and glomerular capillaries. In agreement with the previous statement, the Wisconsin Epidemiologic Study of Diabetic Retinopathy concluded that microalbuminuria is associated cross-sectionally with the presence of retinopathy in diabetic patients.

The progress of the clinical symptoms of the disease despite glycaemic therapy points to address the research towards new drugs able to slow or reverse the vessel micro-abnormalities responsible for the microangiopathy typical of diabetic retinopathy. Furthermore, the similarities of the vessel lesions between diabetic retinopathy and diabetic nephropathy suggest that new molecules effective in one of the two conditions should be effective in the other pathology as well.

Sulodexide (fast moving heparin fraction 80% and dermatan sulfate 20%) is a GAG with a high trophism for vessel wall. Clinical studies showed its efficacy in decreasing both microalbuminuria and macroalbuminuria in diabetic patients, suggesting that it could be able to slowdown the nephropathy progression, actually by partially restoring the glomerular GAGs content.

Preliminary observations regarding the use of Sulodexide in patients suffering from diabetic retinopathy show significant reduction in hard exudates, thus indirectly pointing out a benefit of this GAG at the retinal capillary level.

Based on the above mentioned physiopathological considerations and experimental findings, the investigators deem appropriate to evaluate the effects of Sulodexide on the diabetic retinopathy by the present multicentre, double-blind, placebo-controlled clinical trial.

Study Design

Study Type:

Interventional

Actual Enrollment :

127 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Multicentre, Double-Blind, Randomised, Placebo Controlled Study of the Activity of Sulodexide in Diabetic Patients With Mild to Moderate Non-Proliferative Retinopathy

Study Start Date :

Feb 1, 2009

Actual Primary Completion Date :

Apr 1, 2011

Actual Study Completion Date :

May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sulodexide group 50 mg of sulodexide a day will be administered by oral route (1+1 capsule/day) for 360 days	Drug: sulodexide A (SULODEXIDE GROUP): 50 mg a day by oral route (1+1 capsules/day) for 360 days B (PLACEBO GROUP): Sulodexide placebo at the same schedule dosage and for the same lengths of time as group A. Other Names: vessel due F
Placebo Comparator: Placebo group Sulodexide placebo will be administered at the same schedule (1+1 capsule/day) and for the same lengths of time (for 360 days) as Sulodexide group	Drug: sulodexide A (SULODEXIDE GROUP): 50 mg a day by oral route (1+1 capsules/day) for 360 days B (PLACEBO GROUP): Sulodexide placebo at the same schedule dosage and for the same lengths of time as group A. Other Names: vessel due F

Arm

Intervention/Treatment

Active Comparator: Sulodexide group

50 mg of sulodexide a day will be administered by oral route (1+1 capsule/day) for 360 days

Drug: sulodexide

A (SULODEXIDE GROUP): 50 mg a day by oral route (1+1 capsules/day) for 360 days B (PLACEBO GROUP): Sulodexide placebo at the same schedule dosage and for the same lengths of time as group A.

Other Names:

vessel due F

Placebo Comparator: Placebo group

Sulodexide placebo will be administered at the same schedule (1+1 capsule/day) and for the same lengths of time (for 360 days) as Sulodexide group

Drug: sulodexide

A (SULODEXIDE GROUP): 50 mg a day by oral route (1+1 capsules/day) for 360 days B (PLACEBO GROUP): Sulodexide placebo at the same schedule dosage and for the same lengths of time as group A.

Other Names:

vessel due F

Outcome Measures

Primary Outcome Measures

Hard exudates [T12: 360 +/- 7 days from T0]
The lesion will be evaluated by fundus photography and fluorescein angiography, graded according to Modefied Airlie House Classification and ETDRS.

Secondary Outcome Measures

microaneurysms [T12: 360 +/- 7 days from T0]
The lesion will be evaluated by fundus photography and fluorescein angiography, graded according to Modefied Airlie House Classification and ETDRS.
Vascular leakage [T12: 360 +/- 7 days from T0]
The lesion will be evaluated by fundus photography and fluorescein angiography, graded according to Modefied Airlie House Classification and ETDRS.
Haemorrhages [T12: 360 +/- 7 days from T0]
The lesion will be evaluated by fundus photography and fluorescein angiography, graded according to Modefied Airlie House Classification and ETDRS.
Intraretinal microvascular abnormalities (IRMA) [T12: 360 +/- 7 days from T0]
The lesion will be evaluated by fundus photography and fluorescein angiography, graded according to Modefied Airlie House Classification and ETDRS.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with Type 1 or Type 2 Diabetes Mellitus
Diabetes under good control with drugs for at least 6 months (Glycosylated hemoglobin <9% )
Patients with 300um ≤ the thickness of retina by optical coherence tomography
Patients with visual acuity test ≥0.4 (20/50)
Non-proliferative (background) retinopathy assessed by fundus photography and fluorescein angiography according to Airlie House Classification and ETDRS
Patients with non-proliferative (background) retinopathy attested by the presence of Hard exudates within grade 2 and 5
Patients with at leat one of the following lesions: Vascular leakages, Microaneurysms, Haemorrhages, Intraretinal microvascular abnormalities (IRMA)
Patients with controlled Arterial Blood Pressure since the last 6 months (Diastolic Blood Pressure ≤90mmHg and Systolic Blood Pressure ≤130 mmHg) with or without medication
Patients capable of conforming to the study protocol
Patients who have given their free and informed consent
The ability and willingness to comply with all study procedures

Exclusion Criteria:

Diabetic Retinopathy which is being treated with laser therapy or should be treated with laser therapy before the end of the study
Concomitant retinal disease due to causes other than diabetic microangiopathy
Concomitant antihypertensive treatment, unless administered at stable dosage at least 6 months before the start of the study
Concomitant Angiotensin-converting enzyme inhibitor / Angiotensin II receptor blocker therapy, unless administered at stable dosage for at least 6 months prior to the start of the study
Concomitant Warfarin therapy
Patients with laser therapy or intravitreal injection(avastin,steroid) within 3 months from enrolment
Concomitant treatment with hemorrheological, vasoactive drugs and antithrombotics except acetylsalicylic acid at stable dosage
Patients with severe liver impairment (Child-Pugh classification C)
Patients with severe renal insufficiency (creatinine >2.2 mg/dl)
Patients with severe cardiac insufficiency (New York Heart Association classes 3 - 4)
Patients with clinical history of diathesis and haemorrhagic disease
Individual hypersensitivity toward the product, heparin, low molecular weight heparin or heparin-like products
Intended or ascertained pregnancy or lactation
Participation to a trial within the past 6 months
Surgery or trauma within the past 6 months
Planned surgical intervention within 6 months from enrolment
Patients unable to conform to the study protocol