SAPPHIRE: Suprachoroidal Injection of Triamcinolone Acetonide With IVT Aflibercept in Subjects With Macular Edema Following RVO

• Sponsor: Clearside Biomedical, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02980874
• Collaborator: (none)
• Enrollment: 460
• Locations: 110
• Arms: 2
• Actual Duration (Months): 22.3
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a Phase 3, multicenter, randomized, masked, controlled, parallel group study of 12 months duration in treatment naïve subjects with RVO.

Condition or Disease	Intervention/Treatment	Phase
Macular Edema; Retinal Vein Occlusion	Drug: suprachoroidal CLS-TA; Drug: suprachoroidal sham; Drug: IVT aflibercept	Phase 3

Detailed Description

A randomized, masked, controlled trial to study the safety and efficacy of suprachoroidal CLS-TA in conjunction with intravitreal aflibercept in subjects with retinal vein occlusion

Study Design

• Study Type: Interventional
• Actual Enrollment: 460 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: SAPPHIRE: A Randomized, Masked, Controlled Trial To Study The Safety And Efficacy Of Suprachoroidal CLS-TA In Conjunction With Intravitreal Aflibercept In Subjects With Retinal Vein Occlusion
• Actual Study Start Date: Jan 31, 2017
• Actual Primary Completion Date: Dec 10, 2018
• Actual Study Completion Date: Dec 10, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections	Drug: suprachoroidal CLS-TA; suprachoroidal injection of CLS-TA; Other Names: Triamcinolone acetonide ; Drug: IVT aflibercept; 2 mg intravitreal injection of aflibercept; Other Names: Aflibercept
Active Comparator: Control IVT aflibercept (2 mg/0.05 mL) + sham SC procedure	Drug: suprachoroidal sham; suprachoroidal sham procedure; Drug: IVT aflibercept; 2 mg intravitreal injection of aflibercept; Other Names: Aflibercept

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects Demonstrating ≥ 15 Letter Improvement From Baseline in Early Treatment of Diabetic Retinopathy Study (ETDRS) [2 months]

   Best corrected visual acuity (BCVA) refers to the measurement of the best possible vision that can be achieved following refraction or correction. BCVA was assessed following the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and was measured in the number of letters read correctly on an ETDRS eye chart. An increase from the pre-treatment state in BCVA of 15 letters or more represents a clinically meaningful improvement.

Secondary Outcome Measures

1. Mean Change From Baseline in Best Corrected Visual Acuity [6 months]

   Best corrected visual acuity (BCVA) refers to the measurement of the best possible vision that can be achieved following refraction or correction. BCVA was assessed following the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and was measured in the number of letters read correctly on an ETDRS eye chart. A positive change from baseline value represents an improvement in vision.

2. Mean Change From Baseline in Central Subfield Thickness [6 months]

   Central subfield thickness (CST) is a diagnostic measurement used in identifying the presence of edema in the circular area 1 mm in diameter centered around the fovea. CST was measured using spectral domain optical coherence tomography (SD-OCT). A masked reading center graded the SD-OCT digital images. A negative change from baseline value represents a reduction in macular edema.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has a clinical diagnosis of RVO in the study eye

• Has a CST of ≥ 300 µm in the study eye

• Has an ETDRS BCVA score of ≥ 20 letters read and ≤ 70 letters read in the study eye;

• Is naïve to local pharmacologic treatment for RVO in the study eye;

Exclusion Criteria:

• Any active ocular disease or infection in the study eye other than RVO

• History of glaucoma, intraocular pressure > 21 mmHg or ocular hypertension requiring more than one medication

• Any uncontrolled systemic disease that, in the opinion of the Investigator, would preclude participation in the study

• Any evidence of neovascularization in the study eye

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Associated Retina Consultants, Ltd.	Peoria	Arizona	United States	85381
2	Retinal Consultants of Arizona and Retinal Research Institute	Phoenix	Arizona	United States	85014-2709
3	Arizona Retina and Vitreous Consultants	Phoenix	Arizona	United States	85021
4	Associated Retina Consultants, Ltd.	Phoenix	Arizona	United States	85381
5	Retina Centers P.C.	Tucson	Arizona	United States	85704
6	California Retina Research Consultants	Bakersfield	California	United States	93309
7	Retina Vitreous Medical Group Clinical Research	Beverly Hills	California	United States	90211-1841
8	Atlantis Eyecare	Huntington Beach	California	United States	92647
9	Jacobs Retina Center at the Shiley Eye Institute, UCSD	La Jolla	California	United States	92093
10	Northern California Retina Vitreous Associates	Mountain View	California	United States	94040
11	East Bay Retina Consultants Inc.	Oakland	California	United States	95409
12	Southern California Desert Retina Consultants	Palm Desert	California	United States	92211
13	Retina Institute of California	Palm Desert	California	United States	92260
14	Retina Consultants San Diego	Poway	California	United States	92064-2526
15	Orange County Retina Medical Group	Santa Ana	California	United States	92705
16	California Retina Consultants CRC	Santa Barbara	California	United States	93103
17	Bay Area Retina Associates	Walnut Creek	California	United States	94599
18	Colorado Retina Associates	Golden	Colorado	United States	80401
19	New England Retina Associates	Hamden	Connecticut	United States	06518
20	MedEye Associates	Miami	Florida	United States	33143-5188
21	Retina Specialty Institute	Pensacola	Florida	United States	32503
22	Retina Vitreous Associates of Florida	Saint Petersburg	Florida	United States	33711
23	Sarasota Retina Institute	Sarasota	Florida	United States	34239
24	Center for Retina and Macular Disease	Winter Haven	Florida	United States	33880
25	Emory Eye Center	Atlanta	Georgia	United States	30322
26	Southeast Retina Center, PC	Augusta	Georgia	United States	30909
27	Marietta Eye Clinic	Marietta	Georgia	United States	30060
28	Retina Consultants of Hawaii	'Aiea	Hawaii	United States	96701
29	Illinois Eye and Ear Infirmary, UIC	Chicago	Illinois	United States	60612
30	Illinois Retina Associates	Chicago	Illinois	United States	60657
31	Carle Foundation Hospital	Urbana	Illinois	United States	61801
32	Midwest Eye Institute	Indianapolis	Indiana	United States	46290
33	Retina Associates, PA	Shawnee Mission	Kansas	United States	66204
34	Retina and Vitrous Associates of Kentucky	Lexington	Kentucky	United States	40509
35	Wilmer Eye Institute John Hopkins University	Baltimore	Maryland	United States	21287-0005
36	Cumberland Valley Retina Consultants	Hagerstown	Maryland	United States	21740-5940
37	The Retina Institute	Saint Louis	Missouri	United States	63128
38	Retina Associates of NJ	Teaneck	New Jersey	United States	07666
39	Western Carolina Retinal Associates, PA	Asheville	North Carolina	United States	28803
40	Cincinnati Eye Institute	Cincinnati	Ohio	United States	45242
41	Cleveland Clinic Foundation/Cole Eye Institute	Cleveland	Ohio	United States	44195
42	Oregon Retina Institute	Medford	Oregon	United States	97504
43	Casey Eye Institute/Oregon Health & Science University	Portland	Oregon	United States	97239
44	Eye Care Specialists	Kingston	Pennsylvania	United States	18704
45	Wills Eye Hospital	Philadelphia	Pennsylvania	United States	19107
46	Black Hills Regional Eye Institute	Rapid City	South Dakota	United States	57701-7374
47	Retina Research Institute of Texas	Abilene	Texas	United States	79606-1224
48	Texas Retina Associates-Arlington	Arlington	Texas	United States	76012-2505
49	Austin Retina Associates	Austin	Texas	United States	78705
50	Texas Retina Associates	Dallas	Texas	United States	75231
51	Retina Consultants of Houston	Houston	Texas	United States	77030
52	Valley Retina Institute	McAllen	Texas	United States	78503
53	Medical Center Ophthalmology Associates	San Antonio	Texas	United States	78240-1502
54	Retina Consultants of Houston	The Woodlands	Texas	United States	77384
55	University of Utah HSC - John A. Moran Eye Center	Salt Lake City	Utah	United States	84132
56	Retina Institute of Virginia	Richmond	Virginia	United States	23235
57	Virginia Retina Center	Warrenton	Virginia	United States	20186
58	University of Wisconsin-Madison	Madison	Wisconsin	United States	53705
59	Strathfield Retina Clinic	Strathfield	New South Wales	Australia	2135
60	Save Site Institute, University of Sydney, Sydney Eye Hospital	Sydney	New South Wales	Australia	2000
61	Sydney Retina Clinic and Day Surgery	Sydney	New South Wales	Australia	2000
62	Marsden Eye Specialists	Sydney	New South Wales	Australia	2150
63	The Royal Victorian Eye and Ear Hospital	East Melbourne	Victoria	Australia	3002
64	Specialist Eye Group	Melbourne	Victoria	Australia	3150
65	University of Graz-Department of Ophthalmology	Graz		Austria
66	Kepler University Hospital	Linz		Austria
67	UBC/VGH Eye Care Centre	Vancouver	British Columbia	Canada	V5Z 3N9
68	St. Joseph's Health Care London, Ivey Eye Institute	London	Ontario	Canada	N6A 4V2
69	University of Ottawa Eye Institute	Ottawa	Ontario	Canada	K1H 8L6
70	Institut de l'oeil des Laurentides	Boisbriand	Quebec	Canada	J7H 1S6
71	CIUSSS de l'Est-de-l'Ile-de-Montreal. Hospital Maisonneuve-Rosemont, Comite d'ethique de la recherche	Montréal	Quebec	Canada	H1T 2M4
72	Rigshospitalet	Glostrup		Denmark
73	Dept. of Ophthalmology, Sjællands Universitetshospital, Roskilde	Roskilde		Denmark
74	Semmelweis Egyetem, Szemeszeti Klinika	Budapest		Hungary	1083
75	Bajcsy-Zsilinszky Korhaz es Rendelointezet, Szemeszeti Osztaly	Budapest		Hungary	1106
76	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest		Hungary	1162
77	Budapest Retina Associates	Budapest		Hungary
78	Debreceni Egyetem Klinikai Kozpont, Szemklinika	Debrecen		Hungary	4032
79	Ganglion Orvosi Kozpont	Pecs		Hungary	7621
80	M&J Western Regional Institute of Ophthalmology	Ahmedabad	Gujarat	India	380016
81	T.N. Medical College and B.Y.L. Nair Charitable Hospital	Mumbai	Maharashtra	India	400008
82	Department of Medical Ophthalmology, Retina & Uvea	Delhi	New Delhi	India	110029
83	Aravind Eye Hospitals & Postgraduate Institute of Ophthalmology	Madurai	Tamil Nadu	India	625020
84	Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases	Hyderabad	Telangana	India	500034
85	Disha Eye Hospital Private Limited	Kolkata	West Bengal	India	700120
86	Bnai Zion Medical Center	Haifa		Israel	3104802
87	ASST Fatebenefratelli Sacco - P.O.L., University of Milan, Dep. of Ophthalmology	Milan		Italy	20157
88	Cebu Doctor's University Hospital	Cebu City		Philippines	6000
89	Peregrine Eye & Laser Institute	Makati City		Philippines	1209
90	The Medical City	Pasig City		Philippines	1600
91	Oftalmika sp. z o. o.	Bydgoszcz		Poland	85-631
92	Optimum Profesorskie Centrum Okulistyki	Gdansk		Poland	80-809
93	Uniwersytet Medyczny w Lublinie	Lublin		Poland	20-079
94	Centrum Diagnostyki i Mikrochirurgii Oka Lens	Olsztyn		Poland	10-424
95	Centro Clinico Academico Braga - 2CA-Braga	Braga		Portugal	4710-243
96	Centro Hospitalar e Universitario de Coimbra, E.P.E.	Coimbra		Portugal	3000-075
97	Centro Hospitalar de Sao Joao, E.P.E.	Porto		Portugal	4200-319
98	Fakultna nemocnica s poliklinikou Zilina	Žilina		Slovakia	01207
99	Instituto Cinico Quirurgico de Oftalmologia	Bilbao	Vizcaya	Spain	48006
100	Hospital General de Catalunya	Barcelona		Spain
101	Hospital Universitari de Bellvitge	Barcelona		Spain
102	Hospital Clinico San Carlos	Madrid		Spain	28040
103	Instituto Oftalmologico Fernandez-Vega	Oviedo		Spain	33012
104	Clinica Universidad de Navarra	Pamplona		Spain	31008
105	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
106	Hospital Clinico Universitario	Zaragoza		Spain
107	Kaohsiung Veterans General Hospital	Kaohsiung		Taiwan	81362
108	Taipei Veterans General Hospital	Taipei		Taiwan	112
109	Queens University Royal Victoria Hospital Trust	Belfast		United Kingdom	BT12 6BJ
110	Sunderland Eye Infirmary	Sunderland		United Kingdom

Sponsors and Collaborators

• Clearside Biomedical, Inc.

Investigators

• Study Director: Thomas Ciulla, MD MBA, Clearside Biomedical, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 31, 2017

More Information

Publications

None provided.

• Responsible Party: Clearside Biomedical, Inc.
• ClinicalTrials.gov Identifier: NCT02980874
• Other Study ID Numbers: CLS1003-301
• First Posted: Dec 2, 2016
• Last Update Posted: Apr 14, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Clearside Biomedical, Inc.: RVO; ME; Central Subfield Thickness; OCT; Optical Coherence Tomography; Cystoid Macular Edema; Subretinal Fluid; Eylea; Aflibercept; Anti-VEGF; Suprachoroidal; Triamcinolone acetonide
• Additional relevant MeSH terms: Macular Edema; Retinal Vein Occlusion; Edema; Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Aflibercept; Triamcinolone diacetate

Study Results

Participant Flow

Arm/Group Title	Active	Control
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept	IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept
Period Title: Overall Study
STARTED	231	229
COMPLETED	128	127
NOT COMPLETED	103	102

Baseline Characteristics

Arm/Group Title	Active	Control	Total
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept	IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept	Total of all reporting groups
Overall Participants	231	229	460
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	89 38.5%	107 46.7%	196 42.6%
>=65 years	142 61.5%	122 53.3%	264 57.4%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.4 (12.31)	64.9 (12.42)	65.7 (12.37)
Sex: Female, Male (Count of Participants)
Female	97 42%	105 45.9%	202 43.9%
Male	134 58%	124 54.1%	258 56.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.9%	0 0%	2 0.4%
Asian	33 14.3%	40 17.5%	73 15.9%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.2%
Black or African American	10 4.3%	12 5.2%	22 4.8%
White	181 78.4%	177 77.3%	358 77.8%
More than one race	1 0.4%	0 0%	1 0.2%
Unknown or Not Reported	3 1.3%	0 0%	3 0.7%
Region of Enrollment (Count of Participants)
Hungary	6 2.6%	1 0.4%	7 1.5%
United States	182 78.8%	183 79.9%	365 79.3%
Philippines	0 0%	3 1.3%	3 0.7%
United Kingdom	4 1.7%	2 0.9%	6 1.3%
Portugal	3 1.3%	2 0.9%	5 1.1%
India	13 5.6%	19 8.3%	32 7%
Spain	3 1.3%	2 0.9%	5 1.1%
Canada	2 0.9%	3 1.3%	5 1.1%
Taiwan	2 0.9%	1 0.4%	3 0.7%
Denmark	2 0.9%	1 0.4%	3 0.7%
Poland	5 2.2%	5 2.2%	10 2.2%
Slovakia	0 0%	1 0.4%	1 0.2%
Australia	9 3.9%	6 2.6%	15 3.3%
Type of Retinal Vein Occlusion (Count of Participants)
Branch retinal vein occlusion	124 53.7%	124 54.1%	248 53.9%
Central retinal vein occlusion	107 46.3%	105 45.9%	212 46.1%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects Demonstrating ≥ 15 Letter Improvement From Baseline in Early Treatment of Diabetic Retinopathy Study (ETDRS)
Description	Best corrected visual acuity (BCVA) refers to the measurement of the best possible vision that can be achieved following refraction or correction. BCVA was assessed following the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and was measured in the number of letters read correctly on an ETDRS eye chart. An increase from the pre-treatment state in BCVA of 15 letters or more represents a clinically meaningful improvement.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all randomized subjects who received at least one study treatment.

Arm/Group Title	Active	Control
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept	IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept
Measure Participants	231	229
Count of Participants [Participants]	114 49.4%	127 55.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active, Control
	Comments	Based on a Pearson chi-square test, a total sample size of approximately 460 subjects provided 90% power to detect a difference of 15% between the Active and Control arms assuming the Control arm showed a proportion of 0.50 at 8 weeks. The primary analysis was a test of superiority of the Active arm over the Control arm, and was based on a Cochran-Mantel-Haenszel chi-square test stratified by type of retinal vein occlusion.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.187
	Comments	The a priori threshold for statistical significance was 0.050. Prior to evaluating the results of the CMH test, a Breslow-Day test with Tarone's adjustment was conducted to confirm the homogeneity of the odds ratios between RVO strata.
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH test was stratified by the type of retinal vein occlusion, i.e., branch vs. central.
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-6.1
	Confidence Interval	(2-Sided) 95%; -15.2 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value was calculated as the percentage of subjects in the Active arm meeting the primary endpoint minus the percentage of subjects in the Control arm meeting the primary endpoint.

2. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity
Description	Best corrected visual acuity (BCVA) refers to the measurement of the best possible vision that can be achieved following refraction or correction. BCVA was assessed following the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and was measured in the number of letters read correctly on an ETDRS eye chart. A positive change from baseline value represents an improvement in vision.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all randomized subjects who received at least one study treatment.

Arm/Group Title	Active	Control
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept	IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept
Measure Participants	231	229
Least Squares Mean (Standard Error) [Letters]	15.5 (0.85)	20.5 (0.85)

3. Secondary Outcome

Title	Mean Change From Baseline in Central Subfield Thickness
Description	Central subfield thickness (CST) is a diagnostic measurement used in identifying the presence of edema in the circular area 1 mm in diameter centered around the fovea. CST was measured using spectral domain optical coherence tomography (SD-OCT). A masked reading center graded the SD-OCT digital images. A negative change from baseline value represents a reduction in macular edema.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all randomized subjects who received at least one study treatment.

Arm/Group Title	Active	Control
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept	IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept
Measure Participants	231	210
Least Squares Mean (Standard Error) [Microns]	-354.3 (8.01)	-416.2 (8.05)

Adverse Events

Time Frame	Adverse events were collected over 48 weeks of follow-up.
Arm/Group Title	Active		Control
Arm/Group Description	IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections suprachoroidal CLS-TA: suprachoroidal injection of CLS-TA IVT aflibercept: 2 mg intravitreal injection of aflibercept		IVT aflibercept (2 mg/0.05 mL) + sham SC procedure suprachoroidal sham: suprachoroidal sham procedure IVT aflibercept: 2 mg intravitreal injection of aflibercept
All Cause Mortality
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/231 (0%)		0/229 (0%)
Serious Adverse Events
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/231 (10.8%)		28/229 (12.2%)
Blood and lymphatic system disorders
Anaemia	0/231 (0%)	0	3/229 (1.3%)	3
Cardiac disorders
Acute coronary syndrome	1/231 (0.4%)	1	0/229 (0%)	0
Atrial fibrillation	2/231 (0.9%)	2	1/229 (0.4%)	1
Coronary artery disease	0/231 (0%)	0	2/229 (0.9%)	2
Myocardial infarction	0/231 (0%)	0	2/229 (0.9%)	2
Eye disorders
Cataract	1/231 (0.4%)	1	0/229 (0%)	0
Retinal detachment	0/231 (0%)	0	1/229 (0.4%)	1
Ulcerative keratitis	0/231 (0%)	0	1/229 (0.4%)	1
Visual acuity reduced	2/231 (0.9%)	2	0/229 (0%)	0
Vitreous haemorrhage	0/231 (0%)	0	1/229 (0.4%)	1
Gastrointestinal disorders
Gastritis	1/231 (0.4%)	1	0/229 (0%)	0
Intestinal obstruction	0/231 (0%)	0	1/229 (0.4%)	1
Large intestinal obstruction	0/231 (0%)	0	1/229 (0.4%)	1
Pancreatitis acute	1/231 (0.4%)	1	0/229 (0%)	0
General disorders
Abasia	1/231 (0.4%)	1	0/229 (0%)	0
Chest pain	1/231 (0.4%)	1	2/229 (0.9%)	2
Pyrexia	1/231 (0.4%)	1	0/229 (0%)	0
Infections and infestations
Appendicitis perforated	0/231 (0%)	0	1/229 (0.4%)	1
Bronchitis	0/231 (0%)	0	1/229 (0.4%)	1
Colonic abscess	0/231 (0%)	0	1/229 (0.4%)	1
Diverticulitis	0/231 (0%)	0	1/229 (0.4%)	1
Empyema	1/231 (0.4%)	1	0/229 (0%)	0
Endophthalmitis	0/231 (0%)	0	1/229 (0.4%)	1
Hepatitis C	0/231 (0%)	0	1/229 (0.4%)	1
Perirectal abscess	0/231 (0%)	0	1/229 (0.4%)	1
Pneumonia	1/231 (0.4%)	1	0/229 (0%)	0
Pyelonephritis	0/231 (0%)	0	1/229 (0.4%)	1
Urinary tract infection	2/231 (0.9%)	2	0/229 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	1/231 (0.4%)	1	0/229 (0%)	0
Facial bones fracture	0/231 (0%)	0	1/229 (0.4%)	1
Fall	1/231 (0.4%)	1	0/229 (0%)	0
Head injury	1/231 (0.4%)	1	0/229 (0%)	0
Multiple fractures	1/231 (0.4%)	1	0/229 (0%)	0
Pelvic fracture	1/231 (0.4%)	1	0/229 (0%)	0
Rib fracture	1/231 (0.4%)	1	0/229 (0%)	0
Road traffic accident	1/231 (0.4%)	1	0/229 (0%)	0
Spinal fracture	1/231 (0.4%)	1	0/229 (0%)	0
Sternal fracture	1/231 (0.4%)	1	0/229 (0%)	0
Investigations
Intraocular pressure increased	3/231 (1.3%)	3	0/229 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/231 (0.4%)	1	0/229 (0%)	0
Hyponatraemia	2/231 (0.9%)	2	0/229 (0%)	0
Lactic acidosis	1/231 (0.4%)	1	0/229 (0%)	0
Musculoskeletal and connective tissue disorders
Rotor cuff syndrome	0/231 (0%)	0	1/229 (0.4%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cancer metastatic	1/231 (0.4%)	1	0/229 (0%)	0
Paraganglion neoplasm malignant	0/231 (0%)	0	1/229 (0.4%)	1
Squamous cell carcinoma	0/231 (0%)	0	1/229 (0.4%)	1
Nervous system disorders
Balance disorder	0/231 (0%)	0	1/229 (0.4%)	1
Cerebrovascular accident	1/231 (0.4%)	1	1/229 (0.4%)	1
Coma	1/231 (0.4%)	1	0/229 (0%)	0
Dizziness	1/231 (0.4%)	1	1/229 (0.4%)	1
Facial paralysis	1/231 (0.4%)	1	0/229 (0%)	0
Hemiplegia	1/231 (0.4%)	1	0/229 (0%)	0
Syncope	2/231 (0.9%)	2	0/229 (0%)	0
Transient global amnesia	1/231 (0.4%)	1	0/229 (0%)	0
Transient ischaemic attack	0/231 (0%)	0	3/229 (1.3%)	3
Psychiatric disorders
Major depression	1/231 (0.4%)	1	0/229 (0%)	0
Mental status changes	0/231 (0%)	0	1/229 (0.4%)	1
Renal and urinary disorders
Acute kidney injury	1/231 (0.4%)	1	1/229 (0.4%)	1
Haematuria	1/231 (0.4%)	1	0/229 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/231 (0.4%)	1	0/229 (0%)	0
Pelvic pain	1/231 (0.4%)	1	0/229 (0%)	0
Prostatomegaly	0/231 (0%)	0	1/229 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/231 (0.4%)	1	1/229 (0.4%)	1
Lung disorder	1/231 (0.4%)	1	0/229 (0%)	0
Pulmonary congestion	1/231 (0.4%)	1	0/229 (0%)	0
Vascular disorders
Aortic arteriosclerosis	1/231 (0.4%)	1	0/229 (0%)	0
Aortic stenosis	0/231 (0%)	0	1/229 (0.4%)	1
Hypertension	1/231 (0.4%)	1	0/229 (0%)	0
Other (Not Including Serious) Adverse Events
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	128/231 (55.4%)		83/229 (36.2%)
Eye disorders
Cataract	21/231 (9.1%)	29	9/229 (3.9%)	12
Cataract subcapsular	20/231 (8.7%)	22	3/229 (1.3%)	3
Conjunctival haemorrhage	42/231 (18.2%)	65	28/229 (12.2%)	31
Eye pain	20/231 (8.7%)	24	11/229 (4.8%)	11
Macular oedema	8/231 (3.5%)	11	13/229 (5.7%)	16
Visual acuity reduced	16/231 (6.9%)	18	6/229 (2.6%)	7
Vitreous detachment	13/231 (5.6%)	16	9/229 (3.9%)	10
Infections and infestations
Nasopharyngitis	9/231 (3.9%)	9	13/229 (5.7%)	13
Investigations
Intraocular pressure increased	33/231 (14.3%)	51	9/229 (3.9%)	13
Vascular disorders
Hypertension	15/231 (6.5%)	18	15/229 (6.6%)	17

Limitations/Caveats

Due to the early termination of the trial by sponsor all planned study visits were not completed by all treated subjects; therefore, all planned data was not collected.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The institutions and Investigators participating in this study shall have no right to publish or present the results of this study without the prior written consent of Clearside Biomedical, Inc.