PRevention of Macular EDema After Cataract Surgery (PREMED)

Cystoid macular edema (CME) is a common cause of vision loss after cataract surgery. In the last few years, several new treatments have been tried to address the problem of CME after cataract surgery in diabetic and non-diabetic patients. The investigators will perform a large RCT with the aim to provide more definite evidence-based recommendations for clinical guidelines to prevent the occurrence of CME after cataract surgery in patients with and without diabetes mellitus (DM).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Cataract; Cystoid Macular Edema
• Intervention / Treatment: Drug: Dexamethasone; Drug: Bevacizumab; Drug: Triamcinolone Acetonide; Drug: Bromfenac

Detailed Description

The objective of this study is to evaluate the effect of different preventive strategies on the occurrence of CME after cataract surgery in non-diabetic and diabetic patients. The design of the study is a multicentre randomised controlled clinical trial. The study population will consist of 926 non-diabetic patients and 209 patients with diabetes mellitus (DM) who require cataract surgery in at least one eye. All patients will receive a phacoemulsification for cataract and placement of a posterior chamber intraocular lens (IOL).

In the non-diabetic population, the patients will receive either bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative, dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week or a combination of both drugs.

In the diabetic population patients will receive either:

• Topical bromfenac 0.09% and dexamethasone 0.1% in the aforementioned dose;
• Topical bromfenac 0.09% and dexamethasone 0.1% in the aforementioned dose and a subconjunctival injection of 40 mg triamcinolone acetonide;
• Topical bromfenac 0.09% and dexamethasone 0.1% in the aforementioned dose and an intravitreal injection of 1.25 mg bevacizumab;
• Topical bromfenac 0.09% and dexamethasone 0.1% in the aforementioned dose, a subconjunctival injection of 40 mg triamcinolone acetonide and an intravitreal injection of 1.25 mg bevacizumab.

The primary endpoint is the change in central subfield mean macular thickness in the 1 mm area (central subfield macular thickness, CSMT) as compared to baseline within the first 6 weeks postoperative.

The secondary endpoint is the occurrence of postoperative clinically significant macular edema (CSME) within 12 weeks postoperatively. Other study endpoints are mean CDVA in logMAR at 6 weeks and 12 weeks postoperatively; OCT measured average retinal thickness in the central inner circle (3mm), the outer circle (6mm), and the macular volume at 6 weeks and 12 weeks postoperatively; intraocular pressure at 6 weeks and 12 weeks postoperatively.

In case of clinically significant macular edema, treatment will be initiated and its effect will be part of the evaluation at 12 weeks. Medical data of all patients who develop macular edema during this study will be checked at least 6 months after surgery.

• Study Type: Interventional
• Enrollment (Actual): 1127
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1140
    • Vienna Institute for Research in Ocular Surgery, Hanusch Krankenhaus
  • Vienna, Austria
    • Hospital of the Brothers of Saint John of God
• Belgium
  • Edegem, Belgium, B-2650
    • University Hospital Antwerp
• Germany
  • Frankfurt am Main, Germany, 60590
    • Goethe University
• Hungary
  • Budapest, Hungary, H-1085
    • Semmelweis University
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center
  • Amsterdam, Netherlands, 1081 HZ
    • VU University Medical Center
  • Breda, Netherlands
    • Amphia Hospital Breda
  • Heerlen, Netherlands, 6419 PC
    • Zuyderland Medical Center
  • Hilversum, Netherlands
    • Eye Hospital Zonnestraal
  • Maastricht, Netherlands, 6202 AZ
    • University Eye Clinic Maastricht UMC+
  • Tilburg, Netherlands
    • St. Elisabeth Hospital
  • Veldhoven, Netherlands
    • Maxima Medical Center Veldhoven
  • the Hague, Netherlands
    • Medical Centre Haaglanden
• Portugal
  • Coimbra, Portugal, 3000-075
    • University Hospital Coimbra
• Spain
  • Barcelona, Spain, 08035
    • Instituto Microcirurgia Ocular

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients undergoing routine phacoemulsification (one eye per patient)
• willing and/or able to comply with the scheduled visits and other study procedures.
• able to communicate properly and understand instructions.
• accepting possible off-label use of intravitreal bevacizumab and/or subconjunctival preservative-free TA.

Exclusion criteria will be different for non-diabetic and diabetic patients. All ophthalmic exclusion criteria are applicable to the study eye only, unless stated otherwise.

General exclusion criteria for participation in this study are:

1. age below 21 years old;
2. participation in another clinical study;
3. post-traumatic cataract;
4. combined surgery;
5. functional monoculus;
6. previous ocular surgery;
7. progressive glaucoma with severe visual field defects, use of anti-glaucomatous medication or steroid-induced IOP elevation that required IOP-lowering treatment;
8. IOP ≥ 25 mmHg;
9. history of any intraocular inflammation or uveitis;
10. history of pseudoexfoliation syndrome, which is expected to cause peroperative complications;
11. history of Fuchs' endothelial dystrophy or cornea guttata 3+;
12. history of retinal vein occlusion;
13. any macular pathology that might influence VA, other than DME;
14. use of intravitreal bevacizumab or ranibizumab in the previous 6 weeks or intravitreal aflibercept in the previous 10 weeks;
15. use of intra- or periocular corticosteroid injection in the previous 4 months;
16. current use of topical NSAIDs or corticosteroids;
17. use of systemic corticosteroids (≥ 20 mg prednisolone or equivalence);
18. history of relevant adverse events, including serious adverse events (SAE), occurring after administration of NSAIDs, acetylsalicylic acid, sodium sulphite, corticosteroids or bevacizumab;
19. contraindications for use of topical NSAIDs, topical or subconjunctival corticosteroids or intravitreal bevacizumab or related drugs;

Non-diabetic patients with a history of CME will be excluded from participation in the study.

Additionally, diabetic patients will be excluded from participation in case of:

1. macular edema with a CSMT ≥450 µm;
2. very severe NPDR or proliferative DR requiring panretinal photocoagulation or vitrectomy;
3. vitreous haemorrhage present during preoperative visit(s);
4. cerebrovascular accident (CVA), myocardial infarction (MI) or other thromboembolic events in the previous 3 months;
5. a history of recurrent thromboembolic events;
6. a history of severe systemic bleeding in the previous 3 months;
7. major surgery in the previous 3 months;
8. history of glaucoma;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Non diabetics: bromfenac; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperatively	Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198
Active Comparator: Non diabetics: dexamethasone; dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003
Active Comparator: Non diabetics: bromfenac & dexamethasone; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative & dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003; Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198
Active Comparator: Diabetics: eye drops; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative & dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003; Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198
Active Comparator: Diabetics: eye drops & TA; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative & dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week & a peroperative subconjunctival injection of 40 mg triamcinolone acetonide (TA, Triesence/Vistrec)	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003; Drug: Triamcinolone Acetonide; Other Names: Triesence or Vistrec; Product code (NL): RVG 106092; Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198
Active Comparator: Diabetics: eye drops & bevacizumab; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative & dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week & a peroperative intravitreal injection of 1.25 mg bevacizumab (Avastin)	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003; Drug: Bevacizumab; Other Names: Avastin; Product code: EU/1/04/300/002; Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198
Active Comparator: Diabetics: eye drops, TA & bevacizumab; bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperative, dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week & a peroperative subconjunctival injection of 40 mg triamcinolone acetonide (TA) & a peroperative intravitreal injection of 1.25 mg bevacizumab	Drug: Dexamethasone; Other Names: Dexamethasone ophthalmic solution; Product code (NL): RVG 56003; Drug: Bevacizumab; Other Names: Avastin; Product code: EU/1/04/300/002; Drug: Triamcinolone Acetonide; Other Names: Triesence or Vistrec; Product code (NL): RVG 106092; Drug: Bromfenac; Other Names: Yellox; Product code: EMEA/H/C/001198

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in central subfield mean macular thickness as a measurement of efficacy	The primary endpoint is the change in central subfield mean macular thickness in the 1 mm area (central subfield macular thickness, CSMT) as compared to baseline within the first 6 weeks postoperatively.	6 weeks postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
No. of subjects developing clinically significant macular edema as a measurement of efficacy	The secondary endpoint is the occurrence of postoperative clinically significant macular edema (CSME) within 12 weeks postoperatively.	12 weeks postoperatively

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in corrected distance visual acuity (CDVA) as a measurement of efficacy	CDVA measurements will be taken using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts (logMAR).	6 postoperatively
Change in retinal thickness in the central inner circle (3mm) as a measurement of efficacy	Measured using Optical Coherence Tomography (OCT)	6 weeks postoperatively
Intraocular pressure (IOP) as a measurement of safety	IOP (in mmHg) will be measured by Goldmann applanation tonometry	6 postoperatively
Health-related quality of life as a measurement of efficacy and tolerability	Using the Health Utility Index mark 3 (HUI-3)	12 weeks postoperatively
No. of subjects with Adverse Events as a measurement of safety and tolerability	An adverse event (AE) is defined as any undesirable experience occurring to a subject during the study, whether or not considered related to the investigational product. All adverse events reported spontaneously by the subject or observed by the principal investigator or his staff will be recorded. Most frequently reported adverse events which might occur while using the study medication: abnormal sensation in the eye, pain or irritation, redness or headache while using eye drops; increased IOP and masking of infections while using corticosteroids; retinal detachment, thrombo-embolic events, endophthalmitis and anterior chamber reactions after intravitreal injections of bevacizumab.	6 weeks postoperatively
Change in retinal thickness in the central outer circle (6mm) as a measurement of efficacy	Using OCT	6 weeks postoperatively
Change in macular volume as a measurement of efficacy	Using OCT	6 postoperatively
Vision-related quality of life as a measurement of efficacy and tolerability	Using the National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ 25)	12 weeks postoperatively
Cost-effectiveness	Incremental cost-effectiveness ratios of the costs per quality-adjusted life year (QALY) and costs per improved patient on the NEI VFQ-25 and HUI-3.	12 weeks postoperatively
Change in corrected distance visual acuity (CDVA) as a measurement of efficacy	CDVA measurements will be taken using ETDRS visual acuity testing charts (logMAR).	12 weeks postoperatively
Change in retinal thickness in the central inner circle (3mm) as a measurement of efficacy	Measured using Optical Coherence Tomography (OCT)	12 weeks postoperatively
Intraocular pressure (IOP) as a measurement of safety	IOP (in mmHg) will be measured by Goldmann applanation tonometry	12 weeks postoperatively
No. of subjects with Adverse Events as a measurement of safety and tolerability	An adverse event (AE) is defined as any undesirable experience occurring to a subject during the study, whether or not considered related to the investigational product. All adverse events reported spontaneously by the subject or observed by the principal investigator or his staff will be recorded. Most frequently reported adverse events which might occur while using the study medication: abnormal sensation in the eye, pain or irritation, redness or headache while using eye drops; increased IOP and masking of infections while using corticosteroids; retinal detachment, thrombo-embolic events, endophthalmitis and anterior chamber reactions after intravitreal injections of bevacizumab.	12 weeks postoperatively
Change in retinal thickness in the central outer circle (6mm) as a measurement of efficacy	Using OCT	12 weeks postoperatively
Change in macular volume as a measurement of efficacy	Using OCT	12 weeks postoperatively
Change in central subfield mean macular thickness as a measurement of efficacy	Using OCT	12 weeks postoperatively

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: European Society of Cataract and Refractive Surgeons
• Investigators: Principal Investigator: prof. Rudy MM Nuijts, MD, PhD, University Eye Clinic Maastricht, University Hospital Maastricht

Publications and helpful links

General Publications

• Simons RWP, Wielders LHP, Nuijts RMMA, Veldhuizen CA, van den Biggelaar FJHM, Winkens B, Schouten JSAG, Dirksen CD; ESCRS PREMED Study Group. Economic evaluation of prevention of cystoid macular edema after cataract surgery in diabetic patients: ESCRS PREMED study report 6. J Cataract Refract Surg. 2022 May 1;48(5):555-563. doi: 10.1097/j.jcrs.0000000000000785.
• Simons RWP, Wielders LHP, Dirksen CD, Veldhuizen CA, van den Biggelaar FJHM, Winkens B, Schouten JSAG, Nuijts RMMA; ESCRS PREMED Study Group. Economic evaluation of prevention of cystoid macular edema after cataract surgery in patients without diabetes: ESCRS PREMED study report 4. J Cataract Refract Surg. 2021 Mar 1;47(3):331-339. doi: 10.1097/j.jcrs.0000000000000449.

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2013
• Primary Completion (Actual): November 4, 2016
• Study Completion (Actual): November 4, 2016

Study Registration Dates

• First Submitted: January 7, 2013
• First Submitted That Met QC Criteria: January 21, 2013
• First Posted (Estimate): January 24, 2013

Study Record Updates

• Last Update Posted (Actual): April 14, 2017
• Last Update Submitted That Met QC Criteria: April 13, 2017
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Prevention
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Lens Diseases; Macular Edema; Cataract; Edema; Capsule Opacification; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Pharmaceutical Solutions; Dexamethasone; Dexamethasone acetate; BB 1101; Bevacizumab; Ophthalmic Solutions; Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Triamcinolone diacetate; Bromfenac
• Other Study ID Numbers: NL42463.068.12