PREMED: PRevention of Macular EDema After Cataract Surgery

Sponsor

Maastricht University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01774474

Collaborator

European Society of Cataract and Refractive Surgeons (Other)

1,127

Enrollment

Locations

Arms

39.9

Actual Duration (Months)

70.4

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Cystoid Macular Edema Cataract Diabetes Mellitus	Drug: Bromfenac Drug: Dexamethasone Drug: Bevacizumab Drug: Triamcinolone Acetonide	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

1127 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

Official Title:

PRevention of Macular EDema After Cataract Surgery

Actual Study Start Date :

Jul 10, 2013

Actual Primary Completion Date :

Nov 4, 2016

Actual Study Completion Date :

Nov 4, 2016

Arms and Interventions

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: Bromfenac Other Names: Yellox Product code: EMEA/H/C/001198 Drug: Dexamethasone Other Names: Dexamethasone ophthalmic solution Product code (NL): RVG 56003
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: Bromfenac Other Names: Yellox Product code: EMEA/H/C/001198 Drug: Dexamethasone Other Names: Dexamethasone ophthalmic solution Product code (NL): RVG 56003
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: Bromfenac Other Names: Yellox Product code: EMEA/H/C/001198 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
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: Bromfenac Other Names: Yellox Product code: EMEA/H/C/001198 Drug: Dexamethasone Other Names: Dexamethasone ophthalmic solution Product code (NL): RVG 56003 Drug: Bevacizumab Other Names: Avastin Product code: EU/1/04/300/002
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: Bromfenac Other Names: Yellox Product code: EMEA/H/C/001198 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

Outcome Measures

Primary Outcome Measures

Change in central subfield mean macular thickness as a measurement of efficacy [6 weeks postoperatively]
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.

Secondary Outcome Measures

No. of subjects developing clinically significant macular edema as a measurement of efficacy [12 weeks postoperatively]
The secondary endpoint is the occurrence of postoperative clinically significant macular edema (CSME) within 12 weeks postoperatively.

Other Outcome Measures

Change in corrected distance visual acuity (CDVA) as a measurement of efficacy [6 postoperatively]
CDVA measurements will be taken using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts (logMAR).
Change in retinal thickness in the central inner circle (3mm) as a measurement of efficacy [6 weeks postoperatively]
Measured using Optical Coherence Tomography (OCT)
Intraocular pressure (IOP) as a measurement of safety [6 postoperatively]
IOP (in mmHg) will be measured by Goldmann applanation tonometry
Health-related quality of life as a measurement of efficacy and tolerability [12 weeks postoperatively]
Using the Health Utility Index mark 3 (HUI-3)
No. of subjects with Adverse Events as a measurement of safety and tolerability [6 weeks postoperatively]
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.
Change in retinal thickness in the central outer circle (6mm) as a measurement of efficacy [6 weeks postoperatively]
Using OCT
Change in macular volume as a measurement of efficacy [6 postoperatively]
Using OCT
Vision-related quality of life as a measurement of efficacy and tolerability [12 weeks postoperatively]
Using the National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ 25)
Cost-effectiveness [12 weeks postoperatively]
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.
Change in corrected distance visual acuity (CDVA) as a measurement of efficacy [12 weeks postoperatively]
CDVA measurements will be taken using ETDRS visual acuity testing charts (logMAR).
Change in retinal thickness in the central inner circle (3mm) as a measurement of efficacy [12 weeks postoperatively]
Measured using Optical Coherence Tomography (OCT)
Intraocular pressure (IOP) as a measurement of safety [12 weeks postoperatively]
IOP (in mmHg) will be measured by Goldmann applanation tonometry
No. of subjects with Adverse Events as a measurement of safety and tolerability [12 weeks postoperatively]
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.
Change in retinal thickness in the central outer circle (6mm) as a measurement of efficacy [12 weeks postoperatively]
Using OCT
Change in macular volume as a measurement of efficacy [12 weeks postoperatively]
Using OCT
Change in central subfield mean macular thickness as a measurement of efficacy [12 weeks postoperatively]
Using OCT

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Vienna Institute for Research in Ocular Surgery, Hanusch Krankenhaus	Vienna	Austria	A-1140
2	Hospital of the Brothers of Saint John of God	Vienna	Austria
3	University Hospital Antwerp	Edegem	Belgium	B-2650
4	Goethe University	Frankfurt am Main	Germany	60590
5	Semmelweis University	Budapest	Hungary	H-1085
6	VU University Medical Center	Amsterdam	Netherlands	1081 HZ
7	Academic Medical Center	Amsterdam	Netherlands
8	Amphia Hospital Breda	Breda	Netherlands
9	Zuyderland Medical Center	Heerlen	Netherlands	6419 PC
10	Eye Hospital Zonnestraal	Hilversum	Netherlands
11	University Eye Clinic Maastricht UMC+	Maastricht	Netherlands	6202 AZ
12	Medical Centre Haaglanden	the Hague	Netherlands
13	St. Elisabeth Hospital	Tilburg	Netherlands
14	Máxima Medical Center Veldhoven	Veldhoven	Netherlands
15	University Hospital Coimbra	Coimbra	Portugal	3000-075
16	Instituto Microcirurgia Ocular	Barcelona	Spain	08035