Prophylactic Intravitreal 5-Fluorouracil and Heparin to Prevent PVR in High-risk Patients With Retinal Detachment. (PRIVENT)

This study investigates the effectiveness of a simple treatment to prevent proliferative vitreoretinopathy (PVR).

Intraoperative intravitreal 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) is used as a prophylactic therapy in high-risk patients with primary rhegmatogenous retinal detachment (RRD). Our major motivation is to reduce the incidence of PVR in the group that receives the trial drug.

Study Overview

• Status: Completed
• Conditions: Rhegmatogenous Retinal Detachment; High-risk for Proliferative Vitreoretinopathy (PVR)
• Intervention / Treatment: Drug: 5-fluorouracil and low molecular weight heparin; Drug: Placebo

Detailed Description

Proliferative vitreoretinopathy (PVR) is a common cause for postoperative failure after vitreoretinal surgery for primary RRD. There is no standard-therapy to prevent PVR. Several attempts using chemotherapeutic agents have been undertaken to prevent this proliferation-process, but none of these was introduced into routine clinical practice.

Until recently, it has been challenging to identify patients with high risk for postoperative PVR formation. This is especially important, because in this trial treatment with the trial drug will be restricted to patients at high risk for PVR only.

Patients are assigned to the following treatment arms (1:1):

(A) Intraoperative adjuvant application of 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) in high-risk patients for proliferative vitreoretinopathy (PVR) with primary rhegmatogenous retinal detachment (RRD).

Versus:

(B) Routinely used intraocular infusion with balanced salt solution (BSS) during routine PPV.

• Study Type: Interventional
• Enrollment (Actual): 326
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Göttingen, Germany
    • Universitätsaugenklinik Göttingen
  • Kiel, Germany
    • Universitätsaugenklinik Kiel
  • München, Germany
    • Augenklinik TU München
  • Regensburg, Germany
    • Universitätsaugenklinik Regensburg
  • BW
    • Freiburg, BW, Germany, 79106
      • Augenklinik Uniklinik Freiburg
    • Tübingen, BW, Germany, 72076
      • STZ eyetrial am Department für Augenheilkunde
  • HH
    • Hamburg, HH, Germany, 20246
      • Klinik und Poliklinik für Augenheilkunde Uniklinik Hamburg Eppendorf
  • NRW
    • Bonn, NRW, Germany, 53127
      • Augenklinik Uniklinik Bonn
    • Dusseldorf, NRW, Germany, 40255
      • Universitäts-Augenklinik Düsseldorf
    • Koln, NRW, Germany, 50931
      • Augenklinik der Universität zu Köln
    • Munster, NRW, Germany, 48145
      • Augenärzte am St. Franziskushospital Münster Augenklinik
  • Saarbrücken
    • Sulzbach, Saarbrücken, Germany, 66280
      • Knappschaftskrankenhaus Sulzbach Augenklinik Sulzbach
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Uniklinik Leipzig Klinik und Poliklinik für Augenheilkunde

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Primary rhegmatogenous retinal detachment (< 4 weeks) in study eye
2. Scheduled for pars plana vitrectomy for retinal detachment repair without combined cataract surgery in study eye
3. Elevated protein levels in anterior chamber fluid (laser-flare value ≥ 15.0 pc/ms) in study eye
4. Female or male patient ≥ 18 years of age
5. Written informed consent

Exclusion Criteria:

1. Retinal detachment lasting > 4 weeks in study eye
2. Traumatic retinal detachment in study eye
3. Giant retinal tears in study eye (size > 3 clock hours)
4. Visual pre-existing PVR grade C in study eye
5. Retinal dystrophies in study eye
6. Scheduled for combined pars plana vitrectomy and cataract surgery for retinal detachment repair in study eye
7. Chronic inflammatory conditions in study eye
8. Active retinal vascular disease in study eye
9. Proliferative diabetic retinopathy in study eye
10. Manifest uveitis in study eye
11. Endophthalmitis in study eye
12. Perforating and non-perforating trauma in study eye
13. Malignant intraocular tumor in study eye
14. Aphakia in study eye
15. Uncontrolled glaucoma or ocular hypertension in study eye (intraocular pressure ≥ 30 mmHg despite IOP lowering therapy)
16. Previous intraocular surgery except uncomplicated cataract surgery with posterior chamber lens implantation in study eye
17. Cataract surgery in study eye ≤ 3 months ago
18. Previous retinal procedures (laserpexy, cryopexy, intravitreal gas-injection, anti-VEGF or corticosteroid-injection) in study eye ≤ 6 months
19. Other uncontrolled ophthalmologic disorders
20. Single eyed patients (BCVA of fellow eye > 1.0 log MAR, < 0.1 decimal, < 1/10 tenth, or < 6/60 Snellen fraction [m])
21. Evidence or history of alcohol, medication or drug dependency within the last 12 months.
22. Evidence or history (within the last 12 months) of neurotic personality, psychiatric illness that requires or required treatment, epilepsy or suicide risk.
23. Systemic disorders not compatible with adjuvant application of 5-FU and LMWH via intraocular infusion, or not compatible with the local or general anesthesia
24. Any therapy with immunosuppressant or chemotherapy ≤ 3 months and during the trial period
25. Participation in another trial of IMPs or devices parallel to, or less than 3 months before screening, or previous participation in this trial.
26. Known to or suspected of not being able to comply with the protocol.
27. Inability to understand the rationale of this trial or the study aim
28. Any dependency of the patient to the Investigator or the trial site, e.g. employees with direct involvement in the proposed trial or in other trials under the direction of this Investigator or trial site, as well as family members of the employees or the Investigator.
29. Positive urine pregnancy test, pregnancy or breastfeeding mother.
30. Women of child bearing potential without satisfactory contraception, i.e. hormonal contraceptives for at least 14 days before trial enrolment, IUD, double barrier (women of child bearing age must be counselled about the use of adequate contraception).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Adjuvant therapy with 5-FU and LMWH; Intraoperative adjuvant application of 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) in high-risk patients for proliferative vitreoretinopathy (PVR) with primary rhegmatogenous retinal detachment (RRD).	Drug: 5-fluorouracil and low molecular weight heparin; Intraoperative adjuvant application of 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV).
Placebo Comparator: Standard of care; Routinely used intraocular infusion with balanced salt solution (BSS) during routine pars plana vitrectomy (PPV) in high-risk patients for proliferative vitreoretinopathy (PVR) with primary rhegmatogenous retinal detachment (RRD).	Drug: Placebo; Routinely used intraocular infusion with balanced salt solution (BSS) during routine pars plana vitrectomy (PPV).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proliferative Vitreoretinopathy (PVR) grade CP (posterior - full thickness retinal folds in clock hours) 1 or higher [yes/no]	within 12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
PVR grade CP 1 or higher [yes/no]	within 6 weeks
PVR grade CA (anterior - full thickness retinal folds in clock hours) 1 or higher [yes/no]	within 6 weeks and 12 weeks
Degree of PVR (PVR grade CA 1-12, PVR grade CP 1-12 (in clock hours))	within 6 weeks and 12 weeks
Best Corrected Visual Acuity (BCVA) measured by ETDRS charts	within 6 weeks and 12 weeks
Retinal reattachment after primary intervention [yes/no]	within 6 weeks and 12 weeks
Number of retinal re-detachments and if present due to PVR [yes/no]	within 6 weeks and 12 weeks
Number and extent of surgical procedures necessary to achieve retinal reattachment	within 12 weeks
Occurrence of at least one drug-related adverse event that affects the study eye [yes/no]	within 12 weeks

Collaborators and Investigators

• Sponsor: Universitätsklinikum Köln
• Collaborators: German Research Foundation; The Clinical Trials Centre Cologne; Pharmacy of the University Hospital Erlangen; Institute of Medical Statistics, Informatics and Epidemiology (IMSIE)
• Investigators: Principal Investigator: Friederike Schaub, PD. Dr., Department of Ophthalmology, University of Cologne

Publications and helpful links

General Publications

• Schaub F, Hoerster R, Schiller P, Felsch M, Kraus D, Zarrouk M, Kirchhof B, Fauser S. Prophylactic intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy in high-risk patients with retinal detachment: study protocol for a randomized controlled trial. Trials. 2018 Jul 16;19(1):384. doi: 10.1186/s13063-018-2761-x.

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2016
• Primary Completion (Actual): June 15, 2020
• Study Completion (Actual): June 15, 2020

Study Registration Dates

• First Submitted: July 12, 2016
• First Submitted That Met QC Criteria: July 12, 2016
• First Posted (Estimate): July 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 5, 2022
• Last Update Submitted That Met QC Criteria: April 4, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Eye Diseases; Retinal Diseases; Retinal Detachment; Dissociative Disorders; Vitreoretinopathy, Proliferative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anticoagulants; Fluorouracil; Heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: uni-koeln-1782; 2015-004731-12 (EudraCT Number)