The CIRCLE Study
Research type
Research Study
Full title
A PHASE 2, RANDOMISED, DOUBLE MASKED, SHAM CONTROLLED, MULTI-CENTRE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OCRIPLASMIN IN INDUCING TOTAL POSTERIOR VITREOUS DETACHMENT (PVD) IN SUBJECTS WITH NON-PROLIFERATIVE DIABETIC RETINOPATHY (NPDR) (CIRCLE)
IRAS ID
189887
Contact name
Sheetal Dyall
Contact email
Sponsor organisation
ThromboGenics NV
Eudract number
2015-002415-15
Clinicaltrials.gov Identifier
126449, IND NUMBER:
Duration of Study in the UK
2 years, 9 months, 15 days
Research summary
Summary of Research
Diabetic retinopathy is one of the main complications of diabetes and is the leading cause of blindness in the working age population. Diabetic retinopathy is a progressive disease. The more advanced stage of the disease results in new blood vessel growth at the light-sensitive tissue in the back of the eye (the retina). These vessels are fragile, can leak blood easily and therefore may block vision.Summary of Results
Stroke is a devastating neural emergency that requires rapid diagnosis and treatment. For ischaemic strokes (caused by blood clots that reduce blood flow to a region of the brain) the quicker the clot can be removed, and blood flow restored, the better the final recovery for the patient. This suggests a need for new diagnostic methods that could be used at the point of injury to recognise stroke and prioritize those patients for specialised and rapid treatment.This trial set out to test whether substances known as purines, which are by products of energy metabolism in cells, could be used to detect cerebral ischaemia. The underlying hypothesis was that when energy metabolism is impeded in the brain, excess purines are generated in that energy starved region, and these reach the blood where they could in principle be detected via a finger prick test. In this trial we used carotid artery surgery, performed on certain patients who have suffered from mini-strokes to reduce their future risk of a major stroke. During this procedure one of the carotid arteries is clamped prior to clot-removal surgery and consequently all blood flow to the brain via that artery is blocked. This gives a mild episode of ischaemia in the brain that is precisely timed by the setting and release of the arterial clamps which can be used to test our hypothesis.
During the carotid artery surgery, which was performed under general anaesthetic, whole blood purines were measured before, during and after the clamping procedure. Under general anaesthetic, no effect on whole blood purines of carotid artery clamping was found. Furthermore, there was no difference between patients in which a shunt had been inserted into the carotid artery to maintain blood flow, and those in which this had not been done. This contrasted with an earlier study of the same procedure, which demonstrated robust increases of whole blood purines under local anaesthetic and sedation, and the efficacy of shunting when major cerebral ischaemia was evident under these conditions. We speculate that the reduction of cerebral metabolism caused by anaesthesia was protective and meant that the reduction of blood flow via the carotid artery during the procedure did not cause metabolic stress to the brain.
Given the lack of purine production and hence no evidence of metabolic stress in the brain, our study suggested that carotid artery surgery may best be performed under general anaesthesia. Furthermore, there appeared to be no benefit of shunting under these conditions. More studies are required to confirm this finding before a clear recommendation on the best way to perform this surgical procedure can be made.
With the help of ocriplasmin, an enzyme that can cut connections between the vitreous (gel-like material that fills the rear two-thirds of the eyeball) and the retina, it may be possible to stop these new blood vessels from growing into the retina. If the vitreous is not connected to the retina, the new blood vessels do not have any support to grow on and the progression of the disease to the advanced, sight-threatening stage may be avoided. Ocriplasmin is currently on the market as a single injection to treat people whose vitreous is partly attached to their retina (vitreomacular adhesion [VMA]).
The main purpose of this study is to evaluate whether ocriplasmin can safely cut all the connections between the vitreous and the retina in patients with less advanced diabetic retinopathy to reduce their risk of progression to the advanced stage and avoid vision loss from the disease. Patients taking part in the study will either receive up to 3 repeated injections of ocriplasmin one month apart into one of their eyes, or will serve as a control and will receive sham (fake) injections. Participants will be in the study for about 2 years and will need to attend at least 13 study visits at specific time intervals. Standard ophthalmology procedures will be performed to assess their eyes. About 230 people will take part in the study, around 20 of which will be enrolled in the UK at ophthalmology centres.
REC name
East Midlands - Leicester South Research Ethics Committee
REC reference
15/EM/0552
Date of REC Opinion
11 Feb 2016
REC opinion
Further Information Favourable Opinion