TYBEE: Suprachoroidal CLS-TA With Intravitreal Aflibercept Versus Aflibercept Alone in Subject With Diabetic Macular Edema

• Sponsor: Clearside Biomedical, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03126786
• Collaborator: (none)
• Enrollment: 71
• Locations: 29
• Arms: 2
• Actual Duration (Months): 9.2
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this trial is to evaluate the safety and efficacy of suprachoroidal CLS-TA used with intravitreal aflibercept in subjects with DME.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: IVT aflibercept; Drug: Sham SC; Drug: SC CLS-TA	Phase 2

Detailed Description

This is a Phase 2, multicenter, randomized, double-masked, controlled, parallel-group study of 6 months duration in treatment-naïve subjects with DME. This study is projected to enroll approximately 60 subjects, randomly assigned 1:1 to one of two treatment groups.

The study design includes up to 8 clinic visits over approximately 24 weeks. Subjects will attend visits for Screening (Visit 1, Days -30 to 0); Randomization and Baseline (Visit 2, Day 0 before dosing); Dosing and Evaluation (Visit 2 after dosing to Visit 5, Day 0 through Week 12); As-needed (PRN) Dosing and Follow up (Visit 6 through Visit 7, Week 16 through Week 20), and End of Study (Visit 8, Week 24).

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double Masked, Controlled Study Comparing the Safety and Efficacy of Suprachoroidal CLS-TA With Intravitreal Aflibercept Versus Aflibercept Alone in Subject With Diabetic Macular Edema
• Actual Study Start Date: Jul 11, 2017
• Actual Primary Completion Date: Apr 17, 2018
• Actual Study Completion Date: Apr 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA	Drug: IVT aflibercept; IVT aflibercept [2 mg/0.05 mL]; Other Names: Eylea ; Drug: SC CLS-TA; CLS-TA [4 mg/100 μL] SC injection; Other Names: Triamcinolone Acetonide
Sham Comparator: Control Treatment will consist of IVT aflibercept injection followed by a sham SC procedure	Drug: IVT aflibercept; IVT aflibercept [2 mg/0.05 mL]; Other Names: Eylea ; Drug: Sham SC; sham SC; Other Names: suprachoroidal sham

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Best Corrected Visual Acuity Letter Score [Baseline, 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. 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 Central Subfield Thickness [Baseline, 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:

• Clinical diagnosis of type 1 or type 2 DM

• DME with central involvement (> 300 µm in the central subfield on spectral-domain optical coherence tomography [SD-OCT], in the study eye

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

• Naïve to local pharmacologic treatment for DME in the study eye

Exclusion Criteria:

• IOP > 21 mmHg in the study eye at Visit 1 (Day -30 to -1); subjects are not excluded if IOP is <22 mmHg in the study eye with no more than 1 IOP lowering medication

• Any previous treatment in the study eye with an ocular corticosteroid implant

• Has significant media opacity precluding evaluation of retina and vitreous in the study eye.

• History of glaucoma or optic nerve head change consistent with glaucoma damage

• History of glaucoma surgery

• History of clinically significant IOP elevation in response to corticosteroid treatment ("steroid responder")

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retinal Consultants of Arizona and Retinal Research Institute	Phoenix	Arizona	United States	85014-2709
2	Retina Centers, PC	Tucson	Arizona	United States	85704
3	California Retina Consultants	Bakersfield	California	United States	93309
4	Retina Vitreous Medical Group Clinical Research	Beverly Hills	California	United States	90211-1841
5	Northern California Retina Vitreous Associates Medical Group, Inc.	Mountain View	California	United States	94040
6	Retina Institute of California	Palm Desert	California	United States	92260
7	Retina Consultants San Diego	Poway	California	United States	92064-2526
8	MedEye Associates	Miami	Florida	United States	33143-5188
9	Retina Specialty Institute	Pensacola	Florida	United States	32503
10	Sarasota Retina Institute	Sarasota	Florida	United States	34239
11	Center for Retina and Macular Disease	Winter Haven	Florida	United States	33880
12	Emory Eye Center	Augusta	Georgia	United States	30909-6440
13	Marietta Eye Clinic	Marietta	Georgia	United States	30060
14	Midwest Eye Institute	Indianapolis	Indiana	United States	46290
15	Retina and Vitrous Associates of Kentucky	Lexington	Kentucky	United States	40509
16	The Johns Hopkins Wilmer Eye Institute	Baltimore	Maryland	United States	21287
17	Cumberland Valley Retina Consultants	Hagerstown	Maryland	United States	21740-5940
18	Retina Associates of NJ	Teaneck	New Jersey	United States	07666
19	Western Carolina Retinal Associates	Asheville	North Carolina	United States	28803
20	Oregon Retina Institute	Medford	Oregon	United States	97504
21	Black Hills Regional Eye Institute	Rapid City	South Dakota	United States	57701-7374
22	Retina Research Institute of Texas	Abilene	Texas	United States	79606-1224
23	Texas Retina Associates-Arlington	Arlington	Texas	United States	76012-2505
24	Austin Retina Associates	Austin	Texas	United States	78705
25	Texas Retina Associates	Dallas	Texas	United States	75231
26	Valley Retina Institute, P.A.	McAllen	Texas	United States	78503
27	Valley Retina Institute	McAllen	Texas	United States	78503
28	Medical Center Ophthalmology Associates	San Antonio	Texas	United States	78240-1502
29	Retina Consultants of Houston	The Woodlands	Texas	United States	77384

Sponsors and Collaborators

• Clearside Biomedical, Inc.

Investigators

• Study Director: Thomas Ciulla, MD, Clearside Biomedical

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 19, 2018

More Information

Publications

None provided.

• Responsible Party: Clearside Biomedical, Inc.
• ClinicalTrials.gov Identifier: NCT03126786
• Other Study ID Numbers: CLS1004-201
• First Posted: Apr 24, 2017
• Last Update Posted: May 13, 2021
• Last Verified: Apr 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.: Diabetes Mellitus; Diabetic Retinopathy; Microneedle; Mircoinjection; Triamcinolone; Choroid; Choroid Injection; Aflibercept; Suprachoroidal; Triamcinolone acetonide
• Additional relevant MeSH terms: Macular Edema; Edema; Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Aflibercept; Triamcinolone diacetate

Study Results

Participant Flow

Arm/Group Title	Active	Control
Arm/Group Description	Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] SC CLS-TA: SC CLS-TA [40 mg/mL]	Treatment will consist of IVT aflibercept injection followed by a sham SC procedure IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] Sham SC: sham SC
Period Title: Overall Study
STARTED	36	35
COMPLETED	30	33
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	Active	Control	Total
Arm/Group Description	Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] SC CLS-TA: SC CLS-TA [40 mg/mL]	Treatment will consist of IVT aflibercept injection followed by a sham SC procedure IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] Sham SC: sham SC	Total of all reporting groups
Overall Participants	36	35	71
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 69.4%	23 65.7%	48 67.6%
>=65 years	11 30.6%	12 34.3%	23 32.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (10.16)	59.2 (12.89)	59.5 (11.51)
Sex: Female, Male (Count of Participants)
Female	10 27.8%	11 31.4%	21 29.6%
Male	26 72.2%	24 68.6%	50 70.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 33.3%	9 25.7%	21 29.6%
Not Hispanic or Latino	24 66.7%	26 74.3%	50 70.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.8%	0 0%	1 1.4%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 8.3%	2 5.7%	5 7%
White	31 86.1%	32 91.4%	63 88.7%
More than one race	0 0%	1 2.9%	1 1.4%
Unknown or Not Reported	1 2.8%	0 0%	1 1.4%
Region of Enrollment (participants) [Number]
United States	36 100%	35 100%	71 100%
Best corrected visual acuity (letters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [letters]	57.1 (13.00)	58.1 (11.33)	57.6 (12.13)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity Letter Score
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	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all randomized subjects who received at least 1 study treatment

Arm/Group Title	Active	Control
Arm/Group Description	Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] SC CLS-TA: SC CLS-TA [40 mg/mL]	Treatment will consist of IVT aflibercept injection followed by a sham SC procedure IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] Sham SC: sham SC
Measure Participants	36	35
Least Squares Mean (Standard Error) [letters]	11.4 (1.63)	13.8 (1.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active, Control
	Comments	The primary efficacy analysis comparing ACTIVE with CONTROL on the mean change from baseline (Visit 2, Day 0) BCVA at Week 12 was be performed using a Mixed Model for Repeated Measurements (MMRM). This model included treatment (ACTIVE or CONTROL), visit (Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12), Visit 6 (Week 16), Visit 7 (Week 20) and Visit 8 (Week 24), and the 2-way interactions of treatment and visit, and the BCVA baseline included as the covariate.
	Type of Statistical Test	Superiority
	Comments	The sample size was determined such that the difference in visual acuity between the ACTIVE treatment group and CONTROL treatment group could be estimated within +/- five ETDRS letters. Week 24 data from the Eylea prescribing information was used to estimate a pooled standard deviation of 9.17 letters. With 28 subjects per arm, a two-sided 90% confidence interval with a distance from the mean difference to the limits (half of interval width) will be less than 5 letters.
Statistical Test of Hypothesis	p-Value	0.288
	Comments	There was a single primary outcome tested at a single primary endpoint, therefore no adjustments for multiple comparisons were performed. The primary endpoint was assess with a 2-sided alpha level of 0.100.
	Method	Mixed model for repeat measures
	Comments	The covariance structure was assumed to be unstructured.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 90%; -6.2 to 1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.28
	Estimation Comments	Estimated Value calculated as Active minus Control.

2. 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	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all randomized subjects who received at least 1 study treatment

Arm/Group Title	Active	Control
Arm/Group Description	Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] SC CLS-TA: SC CLS-TA [40 mg/mL]	Treatment will consist of IVT aflibercept injection followed by a sham SC procedure IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] Sham SC: sham SC
Measure Participants	36	35
Least Squares Mean (Standard Error) [microns]	-212.1 (13.83)	-178.6 (13.61)

Adverse Events

Time Frame	Adverse events were collected over 24 weeks of follow-up.
Arm/Group Title	Active		Control
Arm/Group Description	Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] SC CLS-TA: SC CLS-TA [40 mg/mL]		Treatment will consist of IVT aflibercept injection followed by a sham SC procedure IVT aflibercept: IVT aflibercept [2 mg (0.05 mL)] Sham SC: sham SC
All Cause Mortality
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/36 (5.6%)		0/35 (0%)
Serious Adverse Events
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/36 (16.7%)		4/35 (11.4%)
Blood and lymphatic system disorders
Anaemia	1/36 (2.8%)	2	0/35 (0%)	0
Cardiac disorders
Acute left ventricular failure	0/36 (0%)	0	1/35 (2.9%)	1
Acute myocardial infarction	0/36 (0%)	0	1/35 (2.9%)	1
Cardiac arrest	1/36 (2.8%)	1	0/35 (0%)	0
Hepatobiliary disorders
Hepatorenal syndrome	1/36 (2.8%)	1	0/35 (0%)	0
Infections and infestations
Osteomyelitis	0/36 (0%)	0	1/35 (2.9%)	1
Pneumonia	2/36 (5.6%)	2	0/35 (0%)	0
Pneumonia staphylococcal	1/36 (2.8%)	1	0/35 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	1/36 (2.8%)	1	0/35 (0%)	0
Hip fracture	1/36 (2.8%)	1	0/35 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	1/36 (2.8%)	1	0/35 (0%)	0
Renal and urinary disorders
Chronic kidney disease	1/36 (2.8%)	1	0/35 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic neuropathic ulcer	0/36 (0%)	0	1/35 (2.9%)	1
Vascular disorders
Orthostatic hypotension	1/36 (2.8%)	1	0/35 (0%)	0
Other (Not Including Serious) Adverse Events
	Active		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/36 (27.8%)		11/35 (31.4%)
Eye disorders
Conjunctival haemorrhage	2/36 (5.6%)	2	1/35 (2.9%)	1
Eye pain	0/36 (0%)	0	2/35 (5.7%)	2
Intraocular pressure increased	3/36 (8.3%)	4	1/35 (2.9%)	1
Retinal exudates	0/36 (0%)	0	2/35 (5.7%)	2
Infections and infestations
Nasopharyngitis	0/36 (0%)	0	3/35 (8.6%)	5
Psychiatric disorders
Anxiety	2/36 (5.6%)	2	0/35 (0%)	0
Vascular disorders
Hypertension	3/36 (8.3%)	3	4/35 (11.4%)	4

Limitations/Caveats

[Not Specified]

More Information

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.