CIRCLE: A Study to Evaluate the Efficacy and Safety of Ocriplasmin in Inducing Total PVD in Subjects With NPDR

• Sponsor: ThromboGenics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02681809
• Collaborator: (none)
• Enrollment: 48
• Locations: 38
• Arms: 3
• Duration (Months): 47.6
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of up to 3 intravitreal injections of ocriplasmin (0.0625mg or 0.125mg), in subjects with moderate to very severe non-proliferative diabetic retinopathy (NPDR), to induce total posterior vitreous detachment (PVD) in order to reduce the risk of disease progression to proliferative diabetic retinopathy (PDR).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Retinopathy; Posterior Vitreous Detachment; Disease Progression	Drug: ocriplasmin 0.0625mg; Drug: ocriplasmin 0.125mg; Drug: Sham injection	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomised, Double Masked, Sham Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Ocriplasmin in Inducing Total Posterior Vitreous Detachment (PVD) in Subjects With Non-proliferative Diabetic Retinopathy (NPDR)
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Nov 18, 2019
• Actual Study Completion Date: Nov 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ocriplasmin 0.0625mg	Drug: ocriplasmin 0.0625mg; Up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart
Experimental: Ocriplasmin 0.125mg	Drug: ocriplasmin 0.125mg; Up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart
Sham Comparator: Sham injection	Drug: Sham injection; 3 sham injections approximately 1 month apart. No actual injections. No medication is used.

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Total PVD by the Month 3 Visit [Month 3]

   Total PVD should be confirmed on both B-scan ultrasound and spectral domain optical coherence tomography (SD-OCT), as assessed by the masked central reading centres

Secondary Outcome Measures

1. Number of Subjects With Ocular Treatment-emergent Adverse Events in the Study Eye [From first injection until the end of the study (Month 24)]

   Adverse events were identified by ophthalmic assessments (including BCVA assessment, full ophthalmic examination and ocular imaging) and by subject reporting

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female aged 18 years or older

• Best-corrected visual acuity (BCVA) of 65 letters read or greater (Snellen equivalent of 20/50 or better) in the study eye

• HbA1c ≤ 12%, as assessed by the central laboratory

• Moderate to very severe NPDR as per ETDRS Severity Scale, based on 7 standard field stereo colour fundus photograph

• Central subfield thickness of ≤ 340µm on Spectralis SD-OCT or ≤ 320µm on non-Spectralis SD OCT in the study eye, with or without mild centre-involved diabetic macular oedema

• No evidence of total PVD in the study eye

• Written informed consent obtained from the subject prior to screening procedures

Exclusion Criteria:

• History of or current ocular condition in the study eye that may interfere with the assessment of the progression to PDR

• Presence of epiretinal membrane in the study eye

• Presence of foveal ischemia in the study eye

• Presence of pre-retinal or vitreous haemorrhage in the study eye

• Presence of iris or angle neovascularisation in the study eye

• Any active ocular / intraocular infection or inflammation in either eye

• Aphakic study eye

• Uncontrolled hypertension in the opinion of the Investigator

• Pseudoexfoliation, Marfan's syndrome, phacodonesis or any other finding in the Investigator's opinion suggesting lens / zonular instability

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85021
2		Campbell	California	United States	95008
3		Irvine	California	United States	92697
4		Loma Linda	California	United States	92354
5		Santa Ana	California	United States	92705
6		Rapid City	South Dakota	United States	57701
7		McAllen	Texas	United States	78503
8		San Antonio	Texas	United States	78240
9		Charlottesville	Virginia	United States	22903
10		Brno		Czechia	625 00
11		Hradec Kralove		Czechia	500 05
12		Olomouc		Czechia	779 00
13		Pardubice		Czechia	530 02
14		Praha 10		Czechia	100 34
15		Praha 4		Czechia	140 00
16		Zlin		Czechia	760 01
17		Paris		France	75475
18		Munchen	Bayern	Germany	80336
19		Darmstadt	Hessen	Germany	64297
20		Leipzig	Sachsen	Germany	04103
21		Debrecen	Hajdú-Bihar	Hungary	4032
22		Budapest		Hungary	1062
23		Budapest		Hungary	1083
24		Budapest		Hungary	1106
25		Budapest		Hungary	1133
26		Szombathely		Hungary	9700
27		Be'er Sheva'		Israel	84101
28		Petah Tiqva		Israel	4941492
29		Rehovot		Israel	7610001
30		Tel Aviv		Israel	6423906
31		Milan		Italy	20132
32		Barcelona		Spain	08195
33		Barcelona		Spain	8025
34		Girona		Spain	17007
35		Valladolid		Spain	47012
36		Frimley	Surrey	United Kingdom	GU16 7UJ
37		London		United Kingdom	EC1V 2PD
38		London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• ThromboGenics

Investigators

• Study Director: Clinical Department, ThromboGenics

Study Documents (Full-Text)

• Study Protocol - Oct 28, 2016
• Statistical Analysis Plan - Jan 17, 2019

More Information

Publications

None provided.

• Responsible Party: ThromboGenics
• ClinicalTrials.gov Identifier: NCT02681809
• Other Study ID Numbers: TG-MV-015; 2015-002415-15
• First Posted: Feb 12, 2016
• Last Update Posted: Dec 16, 2020
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Retinal Diseases; Diabetic Retinopathy; Vitreous Detachment; Disease Progression; Fibrinolysin

Study Results

Participant Flow

Arm/Group Title	Ocriplasmin 0.0625mg	Ocriplasmin 0.125mg	Sham Injection
Arm/Group Description	Subjects received up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart	Subjects received up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart	Subjects received 3 sham injections approximately 1 month apart. No actual injections. No medication was used.
Period Title: Overall Study
STARTED	20	19	9
COMPLETED	15	15	8
NOT COMPLETED	5	4	1

Baseline Characteristics

Arm/Group Title	Ocriplasmin 0.0625mg	Ocriplasmin 0.125mg	Sham Injection	Total
Arm/Group Description	Subjects received up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart	Subjects received up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart	Subjects received 3 sham injections approximately 1 month apart. No actual injections. No medication was used.	Total of all reporting groups
Overall Participants	20	19	9	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	12 60%	14 73.7%	6 66.7%	32 66.7%
>=65 years	8 40%	5 26.3%	3 33.3%	16 33.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.7 (12.14)	55.4 (10.15)	54.3 (13.01)	56.2 (11.39)
Sex: Female, Male (Count of Participants)
Female	6 30%	5 26.3%	2 22.2%	13 27.1%
Male	14 70%	14 73.7%	7 77.8%	35 72.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 25%	4 21.1%	2 22.2%	11 22.9%
Not Hispanic or Latino	15 75%	15 78.9%	7 77.8%	37 77.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 5.3%	2 22.2%	3 6.3%
White	20 100%	18 94.7%	7 77.8%	45 93.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Total PVD by the Month 3 Visit
Description	Total PVD should be confirmed on both B-scan ultrasound and spectral domain optical coherence tomography (SD-OCT), as assessed by the masked central reading centres
Time Frame	Month 3

Outcome Measure Data

Analysis Population Description

All Treated Subjects with B-scan ultrasound and SD-OCT assessments at Month 3

Arm/Group Title	Ocriplasmin 0.0625mg	Ocriplasmin 0.125mg	Sham Injection
Arm/Group Description	Subjects received up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart	Subjects received up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart	Subjects received 3 sham injections approximately 1 month apart. No actual injections. No medication was used.
Measure Participants	20	18	8
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Number of Subjects With Ocular Treatment-emergent Adverse Events in the Study Eye
Description	Adverse events were identified by ophthalmic assessments (including BCVA assessment, full ophthalmic examination and ocular imaging) and by subject reporting
Time Frame	From first injection until the end of the study (Month 24)

Outcome Measure Data

Analysis Population Description

All Treated Subjects

Arm/Group Title	Ocriplasmin 0.0625mg	Ocriplasmin 0.125mg	Sham Injection
Arm/Group Description	Subjects received up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart	Subjects received up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart	Subjects received 3 sham injections approximately 1 month apart. No actual injections. No medication was used.
Measure Participants	20	19	9
Count of Participants [Participants]	15 75%	14 73.7%	4 44.4%

Adverse Events

Time Frame	From first injection until the end of the study (Month 24)
Adverse Event Reporting Description	Adverse events include non-ocular and ocular events (both in study eye and non-study eye)
Arm/Group Title	Ocriplasmin 0.0625mg		Ocriplasmin 0.125mg		Sham Injection
Arm/Group Description	Subjects received up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart		Subjects received up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart		Subjects received 3 sham injections approximately 1 month apart. No actual injections. No medication was used.
All Cause Mortality
	Ocriplasmin 0.0625mg		Ocriplasmin 0.125mg		Sham Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)		0/9 (0%)
Serious Adverse Events
	Ocriplasmin 0.0625mg		Ocriplasmin 0.125mg		Sham Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/20 (25%)		8/19 (42.1%)		1/9 (11.1%)
Blood and lymphatic system disorders
Anaemia	1/20 (5%)	2	0/19 (0%)	0	0/9 (0%)	0
Cardiac disorders
Cardiac Failure	1/20 (5%)	1	1/19 (5.3%)	1	0/9 (0%)	0
Cardiac Failure Congestive	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Eye disorders
Ciliary Zonular Dehiscence	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Retinal Haemorrhage	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Uveitis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Gastrointestinal disorders
Constipation	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
General disorders
Generalised Oedema	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Non-Cardiac Chest Pain	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Infections and infestations
Respiratory Tract Infection	0/20 (0%)	0	1/19 (5.3%)	2	0/9 (0%)	0
Abdominal Wall Abscess	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Catheter Site Cellulitis	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Cellulitis	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Endophthalmitis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Pneumonia	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Craniocerebral Injury	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Fibula Fracture	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Patella Fracture	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Pelvic Fracture	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	0/20 (0%)	0	1/19 (5.3%)	2	0/9 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of Colon	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Nervous system disorders
Cerebrovascular Accident	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Respiratory Failure	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Vascular disorders
Peripheral Ischaemia	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Ocriplasmin 0.0625mg		Ocriplasmin 0.125mg		Sham Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/20 (80%)		17/19 (89.5%)		7/9 (77.8%)
Cardiac disorders
Cardiac Failure	1/20 (5%)	1	1/19 (5.3%)	1	0/9 (0%)	0
Congenital, familial and genetic disorders
Colour Blindness	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Ear and labyrinth disorders
Vertigo	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Eye disorders
Eye Pain	2/20 (10%)	2	5/19 (26.3%)	7	1/9 (11.1%)	1
Diabetic Retinal Oedema	4/20 (20%)	4	1/19 (5.3%)	3	2/9 (22.2%)	3
Cataract	3/20 (15%)	4	3/19 (15.8%)	4	0/9 (0%)	0
Visual Acuity Reduced	2/20 (10%)	2	4/19 (21.1%)	4	0/9 (0%)	0
Vitreous Floaters	2/20 (10%)	2	3/19 (15.8%)	6	0/9 (0%)	0
Conjunctival Haemorrhage	4/20 (20%)	4	1/19 (5.3%)	1	0/9 (0%)	0
Macular Oedema	0/20 (0%)	0	4/19 (21.1%)	5	0/9 (0%)	0
Visual Impairment	3/20 (15%)	4	1/19 (5.3%)	1	0/9 (0%)	0
Vitreous Haemorrhage	1/20 (5%)	2	3/19 (15.8%)	3	0/9 (0%)	0
Photophobia	1/20 (5%)	1	2/19 (10.5%)	4	0/9 (0%)	0
Photopsia	1/20 (5%)	1	2/19 (10.5%)	4	0/9 (0%)	0
Diabetic Retinopathy	1/20 (5%)	2	0/19 (0%)	0	2/9 (22.2%)	2
Dry Eye	0/20 (0%)	0	2/19 (10.5%)	3	1/9 (11.1%)	1
Eye Irritation	0/20 (0%)	0	2/19 (10.5%)	3	1/9 (11.1%)	1
Macular Fibrosis	2/20 (10%)	3	1/19 (5.3%)	1	0/9 (0%)	0
Retinal Haemorrhage	2/20 (10%)	2	1/19 (5.3%)	1	0/9 (0%)	0
Vision Blurred	1/20 (5%)	1	1/19 (5.3%)	1	1/9 (11.1%)	1
Cataract Subcapsular	0/20 (0%)	0	2/19 (10.5%)	3	0/9 (0%)	0
Lacrimation Increased	0/20 (0%)	0	2/19 (10.5%)	2	0/9 (0%)	0
Punctate Keratitis	0/20 (0%)	0	1/19 (5.3%)	1	1/9 (11.1%)	1
Cataract Cortical	1/20 (5%)	2	0/19 (0%)	0	0/9 (0%)	0
Iridocyclitis	1/20 (5%)	2	0/19 (0%)	0	0/9 (0%)	0
Lenticular Opacities	0/20 (0%)	0	1/19 (5.3%)	2	0/9 (0%)	0
Ocular Hypertension	0/20 (0%)	0	1/19 (5.3%)	2	0/9 (0%)	0
Cataract Nuclear	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Corneal Oedema	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Cystoid Macular Oedema	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Eyelid Ptosis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Ocular Hyperaemia	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Optic Disc Haemorrhage	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Optic Nerve Disorder	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Retinal Aneurysm	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Retinal Cyst	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Retinal Detachment	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Retinal Exudates	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Gastrointestinal disorders
Constipation	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Diarrhoea	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Gastrooesophageal Sphincter Insufficiency	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
General disorders
Malaise	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	2
Gait Disturbance	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Injection Site Haemorrhage	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Injection Site Pain	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Infections and infestations
Viral Upper Respiratory Tract Infection	2/20 (10%)	2	3/19 (15.8%)	3	2/9 (22.2%)	2
Cellulitis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Localised Infection	0/20 (0%)	0	2/19 (10.5%)	2	0/9 (0%)	0
Nosocomial Infection	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Injury, poisoning and procedural complications
Pelvic Fracture	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Post Procedural Oedema	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Radius Fracture	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Investigations
Intraocular Pressure Increased	4/20 (20%)	6	0/19 (0%)	0	1/9 (11.1%)	2
Glycosylated Haemoglobin Increased	0/20 (0%)	0	3/19 (15.8%)	3	0/9 (0%)	0
Intraocular Pressure Decreased	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Joint Swelling	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Musculoskeletal Chest Pain	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Osteoarthritis	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Nervous system disorders
Headache	2/20 (10%)	2	2/19 (10.5%)	2	0/9 (0%)	0
Dizziness	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Loss of Consciousness	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Paralysis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Sciatica	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Psychiatric disorders
Depression	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Renal and urinary disorders
Renal Failure	1/20 (5%)	2	1/19 (5.3%)	1	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Pulmonary Hypertension	0/20 (0%)	0	0/19 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Dermatitis Herpetiformis	1/20 (5%)	1	0/19 (0%)	0	0/9 (0%)	0
Vascular disorders
Hypertension	1/20 (5%)	1	2/19 (10.5%)	3	1/9 (11.1%)	1
Deep Vein Thrombosis	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Hypertensive Crisis	0/20 (0%)	0	1/19 (5.3%)	1	0/9 (0%)	0
Peripheral Ischaemia	1/20 (5%)	2	0/19 (0%)	0	0/9 (0%)	0

Limitations/Caveats

Recruitment in the study was discontinued early due to slow recruitment rate. This led to 48 randomized subjects instead of the planned 115. By consequence, the study was not powered for its primary endpoint, which was evaluated only descriptively.

More Information

Certain Agreements

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

Sponsor has the right to the 1st publication of the Study results (multi-center publication). Following the 1st publication, PI may publish Study Results. Before submission for publication, Sponsor will be allowed 60 days for review. Sponsor may request to withhold the publication for an additional 60 days. Sponsor reserves the right to remove Confidential Information from the publication and withhold publication if this is not sufficient to protect Intellectual Property Rights.