Prophylactic intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy in high-risk patients with retinal detachment: study protocol for a randomized controlled trial

Abstract

Background: Proliferative vitreoretinopathy (PVR) is the major cause for postoperative failure after vitreo-retinal surgery for primary rhegmatogenous retinal detachment (RRD). Adjunct pharmaceutical therapy was found to be ineffective once PVR is established. Preliminary data suggest that prevention of PVR yields better functional outcome. So far, there is no standard therapy to prevent PVR.

Methods/design: This is a randomized, double-blind, controlled, multicenter, interventional trial with one interim analysis. High-risk patients for PVR with primary RRD will be allocated equally to the following treatment arms: (a) verum: intraoperative adjuvant application of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) and (b) placebo: routinely used intraocular infusion with balanced salt solution during routine PPV. PVR risk is assessed by non-invasive aqueous flare measurement by using laser flare photometry. The primary endpoint of the trial is the occurrence of PVR grade CP (C: full-thickness retinal folds or subretinal strands in clock hours; P: located posterior to equator) 1 or higher within 12 weeks after treatment. Secondary endpoints include PVR grade CA (A: located anterior to equator), best corrected visual acuity, number and extent of surgical procedures to achieve retinal re-attachment, and occurrence of drug-related adverse events within 12 weeks. It is assumed, on the basis of previously published results, that the incidence of PVR grade CP 1 is 35% in the control group and that a reduction by one third would be clinically relevant. Given the sequential design and adjustment for a dropout rate of 5%, a total sample size of 560 patients (280 per group) was calculated to ensure a power of 80% for the confirmatory analysis.

Discussion: The present trial uses intraoperative intravitreal 5-FU and LMWH as a prophylactic therapy in high-risk patients with primary RRD, aiming to reduce the incidence of PVR in the group that receives the trial drug. Using laser flare photometry to identify high-risk patients for PVR, this trial will test the effectiveness of a simple treatment to prevent PVR.

Trial registration: EudraCT no.: 2015-004731-12, registered October 21, 2015; ClinicalTrials.gov Identifier: NCT02834559 , registered July 12, 2016. Protocol version: Version 02. Date: September 18, 2016.

Keywords: 5-Fluorouracil; Complication; Heparin; Placebo; Proliferative vitreoretinopathy; Retinal detachment.

Conflict of interest statement

Ethics approval and consent to participate

Before the start of the clinical trial, all necessary documentation has been submitted to the competent supreme federal authority for approval (Federal Institute for Drugs and Medical Products, Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]) and the local IRBs of all attending centers. Favorable opinions have been received (ethics committee of the medical faculty at the University of Cologne; IRB no. 16–192). Written informed consent of participants is obtained.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Trial flow. Abbreviations: 5-FU 5-fluorouracil, ITT intention to treat, LMWH low-molecular-weight heparin, pc/ms photon counts per millisecond

Fig. 2

Schedule of enrolment, intervention, and assessments. Abbreviations: 5-FU 5-fluorouracil, AE adverse event, BCVA best-corrected visual acuity, LMWH low-molecular-weight heparin, SAE serious adverse event. *Human chorionic gonadotropin (hCG) urine test: For all female patients of childbearing age