RAFTS: The Use of Bevacizumab as a Modulator of Wound Healing Following Trabeculectomy Surgery

Sponsor

Moorfields Eye Hospital NHS Foundation Trust (Other)

Overall Status

Completed

CT.gov ID

NCT02767219

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase III randomised controlled pilot study which aims to assess the effectiveness of the use of bevacizumab in patients who have undergone trabeculectomy surgery, which appear to be showing early signs of failure.

Condition or Disease	Intervention/Treatment	Phase
Glaucoma	Drug: bevacizumab Drug: 5-fluorouracil Drug: Dexamethasone	Phase 3

Detailed Description

Pharmacological enhancement of trabeculectomy using Mitomycin C (MMC) has significantly improved success rates. Despite this, some patients still mount aggressive scarring responses post-operatively and require additional subconjunctival injections of antifibrotic agents, such as 5-Fluorouracil (5-FU) to reduce scar formation and reduce the likelihood of surgical failure. There is concern that these agents are potentially toxic and may result in side effects such as keratopathy (loss of corneal epithelium) and are also painful for the patient. For those patients that are showing clinical evidence of potential scar formation, a more predictable and less toxic modulator of wound healing is desirable.

Vascular endothelial growth factor (VEGF) has been associated with angiogenesis in numerous pathological situations, including tumor growth, proliferative retinopathy, and rheumatoid arthritis. VEGF is also thought to play a pivotal role in ocular wound healing. It mediates the signal transduction cascade leading to tenon's fibroblast migration and proliferation and collagen gel contraction at the site of surgery, as well as angiogenesis. VEGF also causes persistent vascular permeability and vasodilation at the level of existing microvessels. Vessels with increased permeability are typically tortuous and dilated and this is the clinical appearance within the conjunctiva, suggestive of future excessive wound healing and scar formation following trabeculectomy. Early interventions such as subconjunctival injections of 5-Fluorouracil (5-FU) are therefore often considered when these clinical findings are apparent, in order to modify the course of wound healing.

The investigators propose a pilot study looking at the effect of serial injections of bevacizumab (an anti-VEGF agent) on modifying the wound healing response in patients showing early signs of future failure, compared to 5-Fluorouracil (5-FU). The purpose of the pilot is to also gather outcome data and information relating to safety and recruitment with a view to powering a definitive study addressing this issue.

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

The Use of Bevacizumab as a Modulator of Wound Healing Following Trabeculectomy Surgery: A Single Centre Randomised Controlled Phase III Pilot Study

Actual Study Start Date :

May 1, 2016

Actual Primary Completion Date :

Feb 1, 2019

Actual Study Completion Date :

May 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Dexamethasone and 5-fluorouracil The control arm consists of current standard therapy of subconjunctival injections of dexamethasone 3.3mg/ml and pre filled syringes of 5-fluorouracil as required for 4 consecutive weeks after entry into the trial.	Drug: 5-fluorouracil Patients will be randomised to study arms with a 1:1 ratio. Once randomised, Group 1 will receive a subconjunctival injection of 5-fluorouracil and a subconjunctival injection of dexamethasone 3.3mg/ml. This will be given as required for 4 consecutive weeks from time of entry into trial. This is current standard practice. Other Names: 5-FU Drug: Dexamethasone Both intervention groups will be given a subconjunctival injection of dexamethasone at the time of injection of either bevacizumab or 5-fluorouracil
Active Comparator: Dexamethasone and Avastin Subconjunctival injections of dexamethasone 3.3mg/ml and pre filled syringes of bevacizumab will be given for 4 consecutive weeks from time of entry into trial	Drug: bevacizumab Patients will be randomised to study arms with a 1:1 ratio. Once randomised, Group 2 will receive a subconjunctival injection of bevacizumab and a subconjunctival injection of dexamethasone 3.3mg/ml. This will be given for 4 consecutive weeks from time of entry into trial. Other Names: Avastin Drug: Dexamethasone Both intervention groups will be given a subconjunctival injection of dexamethasone at the time of injection of either bevacizumab or 5-fluorouracil

Arm

Intervention/Treatment

Other: Dexamethasone and 5-fluorouracil

The control arm consists of current standard therapy of subconjunctival injections of dexamethasone 3.3mg/ml and pre filled syringes of 5-fluorouracil as required for 4 consecutive weeks after entry into the trial.

Drug: 5-fluorouracil

Patients will be randomised to study arms with a 1:1 ratio. Once randomised, Group 1 will receive a subconjunctival injection of 5-fluorouracil and a subconjunctival injection of dexamethasone 3.3mg/ml. This will be given as required for 4 consecutive weeks from time of entry into trial. This is current standard practice.

Other Names:

5-FU

Drug: Dexamethasone

Both intervention groups will be given a subconjunctival injection of dexamethasone at the time of injection of either bevacizumab or 5-fluorouracil

Active Comparator: Dexamethasone and Avastin

Subconjunctival injections of dexamethasone 3.3mg/ml and pre filled syringes of bevacizumab will be given for 4 consecutive weeks from time of entry into trial

Drug: bevacizumab

Patients will be randomised to study arms with a 1:1 ratio. Once randomised, Group 2 will receive a subconjunctival injection of bevacizumab and a subconjunctival injection of dexamethasone 3.3mg/ml. This will be given for 4 consecutive weeks from time of entry into trial.

Other Names:

Avastin

Drug: Dexamethasone

Both intervention groups will be given a subconjunctival injection of dexamethasone at the time of injection of either bevacizumab or 5-fluorouracil

Outcome Measures

Primary Outcome Measures

Time taken to recruit 30 subjects (from start of study) [study start date to18 months]
Proportion of patients who are eligible who agree to be randomized [study start date to 18 months]
Proportion of patients who are lost to follow up or who withdraw from the study [Baseline to 36 months]

Secondary Outcome Measures

Intraocular pressure [Baseline to 18 months]
Bleb morphology (as determined by Moorfields Bleb Grading system) [Baseline to 18 months]
Number of additional postoperative interventions with 5-fluorouracil (5-FU) and subconjunctival dexamethasone, following the 4 week trial intervention period; bleb needling. [received between baseline and 18 months of follow up]
Time to failure [Baseline to 18 months]
Number of topical ocular hypotensive medications at 3 months and 18 months [3 months and 18 months]
The incidence of complications will be recorded: [Baseline to 18 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 to 85 years, inclusive
Patient must have undergone standard trabeculectomy augmented with Mitomycin C, within the past 4-6 weeks.
Patients who in the clinician's opinion are mounting an aggressive wound healing response and demonstrate objective increase in bleb vascularity (moderate or severe on MBGS). Bleb function still needs to be maintained in the clinicians opinion and flat, scarred blebs are not to be included.

Exclusion Criteria:

Unwilling or unable to give consent, unwilling to accept randomization, or unable to return for scheduled protocol visits.
Pregnant or nursing women.
A history of cardiovascular or cerebrovascular events in the previous 6 months, such as angina, arrhythmia, Transient Ischaemic Attack, strokes, myocardial infarction.
Uncontrolled hypertension defined as systolic blood pressure >160millimeters of mercury (mmHg) or diastolic blood pressure >90millimeters of mercury (mmHg)
Subject hypersensitive to bevacizumab, 5-Fluorouracil (5-FU), and Mitomycin-C (MMC) and its excipients
Failed trabeculectomy bleb
Persistent wound leak following trabeculectomy at the time of randomisation

The following exclusions apply to the study eye only (i.e. they may be present for the non study eye

No light perception.
Aphakia
Previous, or planned, ocular surgery: vitreo-retinal, conjunctival surgery, etc considered likely to interfere with trabeculectomy outcome
Complicated cataract surgery
Cataract surgery less than 6 months in duration
Secondary glaucoma, other than Pigment Dispersion Syndrome (PDS) and Pseudoexfoliative (PXF)
Ocular trauma within the past 3 months
Active iris neovascularization or active proliferative retinopathy.
Severe posterior blepharitis.
Unwilling to discontinue contact lens use after surgery.
Current or recent (<3months) use of bevacizumab into the study eye.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moorfields Eye Hospital, Clinical Research Facility	London		United Kingdom	EC1V 2PD

Sponsors and Collaborators

Moorfields Eye Hospital NHS Foundation Trust

Investigators

Principal Investigator: Rashmi Mathew, FRCOphthMBBS, Moorfields Eye Hospital NHS Trust
Principal Investigator: Jonathan Clarke, FRCOphthMBBS, Moorfields Eye Hospital NHS Trust
Principal Investigator: Keith Barton, FRCOphthMBBS, Moorfields Eye Hospital NHS Trust