HULK: Suprachoroidal Injection of CLS-TA Alone or With Aflibercept in Subjects With Diabetic Macular Edema

• Sponsor: Clearside Biomedical, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02949024
• Collaborator: (none)
• Enrollment: 20
• Locations: 2
• Arms: 2
• Actual Duration (Months): 11.2
• Patients Per Site: 10
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This study is designed to demonstrate the safety and tolerability of suprachoroidal CLS-TA alone or in combination with intravitreal aflibercept in subjects with diabetic macular edema associated with diabetes mellitus.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: IVT Aflibercept; Drug: SC CLS-TA	Phase 1/Phase 2

Detailed Description

This is a Phase 1/2, multicenter, open-label study in subject with DME associated with diabetes mellitus.

Subjects will be screened and if eligible, will be assigned to study arm at the Baseline Visit (Visit 1, Day 0).

Following the Baseline Visit, subjects will participate in six monthly follow-up visits (Visit 2-7; Weeks 4-24) for safety and efficacy assessments and to determine whether additional therapy is needed based upon pre-defined criteria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label Study of the Safety and Efficacy of Suprachoroidal CLS-TA Alone or in Combination With Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema
• Actual Study Start Date: Nov 10, 2016
• Actual Primary Completion Date: Oct 17, 2017
• Actual Study Completion Date: Oct 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TX Naïve Arm Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye.	Drug: IVT Aflibercept; IVT aflibercept [2 mg (50 µL)]; Other Names: Aflibercept ; Drug: SC CLS-TA; [4 mg (100 µL)]; Other Names: Triamcinolone Acetonide
Experimental: Previous TX Arm Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA.	Drug: SC CLS-TA; [4 mg (100 µL)]; Other Names: Triamcinolone Acetonide

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events [Over 6 months of follow-up]

   Number of participants with treatment emergent adverse events and serious adverse events reported over 6 months of follow-up

Secondary Outcome Measures

1. Mean Change From Baseline in Intraocular Pressure [Baseline and 6 months]

   Baseline and change from baseline at 6 months in intraocular pressure as measured by applanation tonometry

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

   Baseline and change from baseline at 6 months in central subfield thickness. 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.

3. Best Corrected Visual Acuity [Baseline and 6 months]

   Baseline and Change from baseline at 6 months in best corrected visual acuity before and after treatment 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 as the number of letters read correctly on an ETDRS eye chart. A positive change from baseline value represents an improvement in vision.

4. CLS-TA Injections [2 to 6 months following initial treatment with study drug]

   After the initial treatment with CLS-TA, with or without intravitreal aflibercept, at Baseline, retreatment with CLS-TA was allowed in either treatment group from Month 2 through Month 6 if pre-defined retreatment criteria were met. Number of patients receiving 0, 1, 2, 3, 4 or 5 retreatments with CLS-TA.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men or women ≥ 18 years of age with type 1 or type 2 diabetes mellitus

• DME with central involvement (>320 microns in the central subfield on SD-OCT) in the study eye

• ETDRS BCVA letter score of 83 to 14, inclusive (Snellen equivalent of 20/25 to 20/500) in the study eye

Exclusion Criteria:

• Evidence of DME due to any other cause other than diabetes mellitus in the study eye

• PRP or focal laser photocoagulation in the study eye within 90 days of screening

• Intraocular pressure ≥ 22 mmHg or uncontrolled glaucoma (open angle or angle closure) in the study eye

• History of any previous ophthalmic surgeries in the study eye within 90 days of screening

• High risk PDR in the study eye, for whom enrollment into the study, in the principal investigator's opinion would put the eye at undue risk for vision loss

• Any previous treatment in the study eye with ILUVIEN implant

• Previous treatment for DME in the study eye (TX naive arm only); treatment in the study eye for DME greater than 1 year prior to screening can be considered as treatment naive, at the investigator's discretion

• Subjects previously treated for DME cannot have been treated in the study eye with an intravitreal injection of anti-VEGF or periocular corticosteroids within 90 days prior to screening (Previous TX arm only)

• Subjects previously treated for DME cannot have been treated in the study eye with intraocular corticosteroids within 6 months prior to screening (Previous TX arm only)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina Vitreous Associates Medical Group Inc	Mountain View	California	United States	94040
2	Retina Consultants of Houston, PA	The Woodlands	Texas	United States	77384

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 - Jun 23, 2017

More Information

Publications

None provided.

• Responsible Party: Clearside Biomedical, Inc.
• ClinicalTrials.gov Identifier: NCT02949024
• Other Study ID Numbers: CLS1004-101; NCT02944240
• First Posted: Oct 31, 2016
• 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; Microinjection; 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	TX Naïve Arm	Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	9
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	TX Naïve Arm	Previous TX Arm	Total
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 50%	6 60%	11 55%
>=65 years	5 50%	4 40%	9 45%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.9 (7.28)	63.1 (8.31)	62.5 (7.63)
Sex: Female, Male (Count of Participants)
Female	4 40%	4 40%	8 40%
Male	6 60%	6 60%	12 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 20%	2 20%	4 20%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 20%	2 20%	4 20%
White	6 60%	6 60%	12 60%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%
Baseline Best Corrected Visual Acuity (Letters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Letters]	67.2 (11.66)	67.2 (8.95)	67.2 (10.12)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events
Description	Number of participants with treatment emergent adverse events and serious adverse events reported over 6 months of follow-up
Time Frame	Over 6 months of follow-up

Outcome Measure Data

Analysis Population Description

The Safety population included all subjects who received study treatment.

Arm/Group Title	TX Naïve Arm	Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
Measure Participants	10	10
Number of participants with treatment emergent adverse events	8 80%	9 90%
Number of participants with serious adverse events	0 0%	0 0%

2. Secondary Outcome

Title	Mean Change From Baseline in Intraocular Pressure
Description	Baseline and change from baseline at 6 months in intraocular pressure as measured by applanation tonometry
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all subjects who received study treatment. No values were imputed for missing data.

Arm/Group Title	TX Naïve Arm	Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
Measure Participants	10	10
Baseline	14.2 (3.52)	13.3 (2.50)
Month 6	-0.3 (2.41)	2.8 (7.89)

3. Secondary Outcome

Title	Mean Change From Baseline in Central Subfield Thickness
Description	Baseline and change from baseline at 6 months in central subfield thickness. 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 and 6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all subjects who received study treatment. No values were imputed for missing data.

Arm/Group Title	Previous TX Arm	TX Naïve Arm
Arm/Group Description	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]
Measure Participants	10	10
Baseline	421.6 (94.33)	472.7 (109.46)
Month 6	-90.9 (62.48)	-119.6 (65.48)

4. Secondary Outcome

Title	Best Corrected Visual Acuity
Description	Baseline and Change from baseline at 6 months in best corrected visual acuity before and after treatment 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 as the number of letters read correctly on an ETDRS eye chart. A positive change from baseline value represents an improvement in vision.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all subjects who received study treatment.

Arm/Group Title	TX Naïve Arm	Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
Measure Participants	10	10
Baseline	67.2 (11.66)	67.2 (8.95)
Month 6	8.5 (11.96)	1.1 (11.94)

5. Secondary Outcome

Title	CLS-TA Injections
Description	After the initial treatment with CLS-TA, with or without intravitreal aflibercept, at Baseline, retreatment with CLS-TA was allowed in either treatment group from Month 2 through Month 6 if pre-defined retreatment criteria were met. Number of patients receiving 0, 1, 2, 3, 4 or 5 retreatments with CLS-TA.
Time Frame	2 to 6 months following initial treatment with study drug

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population included all subjects who received study treatment.

Arm/Group Title	TX Naïve Arm	Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]	Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
Measure Participants	10	10
0 additional injections	4 40%	1 10%
1 additional injection	2 20%	3 30%
2 additional injections	0 0%	2 20%
3 additional injections	2 20%	0 0%
4 additional injections	2 20%	4 40%

Adverse Events

Time Frame	6 months
Arm/Group Title	TX Naïve Arm		Previous TX Arm
Arm/Group Description	Treatment in the TX Naive arm will consist of one unilateral injection of IVT aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye. IVT Aflibercept: IVT aflibercept [2 mg (50 µL)] SC CLS-TA: [4 mg (100 µL)]		Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA. SC CLS-TA: [4 mg (100 µL)]
All Cause Mortality
	TX Naïve Arm		Previous TX Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	TX Naïve Arm		Previous TX Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	TX Naïve Arm		Previous TX Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		9/10 (90%)
Eye disorders
Cataract	3/10 (30%)	3	2/10 (20%)	2
Cataract	2/10 (20%)	2	0/10 (0%)	0
Conjunctival haemorrhage	3/10 (30%)	3	2/10 (20%)	2
Dry eye	0/10 (0%)	0	1/10 (10%)	1
Dry eye	0/10 (0%)	0	1/10 (10%)	1
Episcleritis	0/10 (0%)	0	1/10 (10%)	1
Eye irritation	1/10 (10%)	1	0/10 (0%)	0
Eye irritation	1/10 (10%)	1	0/10 (0%)	0
Eye pain	0/10 (0%)	0	1/10 (10%)	1
Iritis	0/10 (0%)	0	1/10 (10%)	1
Macular fibrosis	0/10 (0%)	0	1/10 (10%)	1
Ocular hypertension	0/10 (0%)	0	1/10 (10%)	1
Infections and infestations
Nasopharyngitis	1/10 (10%)	1	1/10 (10%)	1
Investigations
Intraocular pressure increased	1/10 (10%)	1	0/10 (0%)	0
Optic nerve cup/disc ratio increased	0/10 (0%)	0	1/10 (10%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia	1/10 (10%)	1	0/10 (0%)	0
Type 2 diabetes mellitus	1/10 (10%)	1	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/10 (10%)	1	0/10 (0%)	0
Pain in extremity	0/10 (0%)	0	1/10 (10%)	1
Nervous system disorders
Headache	1/10 (10%)	1	2/10 (20%)	2
Neuropathy peripheral	0/10 (0%)	0	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	0/10 (0%)	0	1/10 (10%)	1
Vascular disorders
Hypertension	0/10 (0%)	0	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The institution and investigators participating in this trial shall have no right to publish or present the results of this study without the prior written consent of Clearside Biomedical.