Clinical Trials Register

Summary
EudraCT Number:	2019-003851-12
Sponsor's Protocol Code Number:	20968
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-04-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Lithuania - SMCA

A.2

EudraCT number

2019-003851-12

A.3

Full title of the trial

Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the Efficacy and Safety of High Dose Aflibercept in Patients With Neovascular Age-Related Macular Degeneration

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to gather information on safety and use of high dose aflibercept injection into the eye in patients with an age related eye disorder that causes blurred vision or a blind spot due to abnormal blood vessels that leak fluid into the light sensitive lining inside the eye

A.3.2

Name or abbreviated title of the trial where available

PULSAR

A.4.1

Sponsor's protocol code number

20968

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bayer AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bayer AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	CTP Team/Ref: 'EU CTR' /Bayer AG
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.4	Telephone number	+493030013 9003
B.5.6	E-mail	clinical-trials-contact@bayer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Aflibercept
D.3.2	Product code	BAY 86-5321
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AFLIBERCEPT
D.3.9.1	CAS number	862111-32-8
D.3.9.2	Current sponsor code	BAY 86-5321
D.3.9.3	Other descriptive name	AFLIBERCEPT
D.3.9.4	EV Substance Code	SUB26987
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	114.3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Eylea 40mg/ml solution for injection in a vial
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Aflibercept
D.3.2	Product code	BAY 86-5321
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AFLIBERCEPT
D.3.9.1	CAS number	862111-32-8
D.3.9.2	Current sponsor code	BAY 86-5321
D.3.9.3	Other descriptive name	AFLIBERCEPT
D.3.9.4	EV Substance Code	SUB26987
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Neovascular Age-Related Macular Degeneration

E.1.1.1

Medical condition in easily understood language

Neovascular AMD is an eye disease that causes blurred vision or a blind spot due to abnormal blood vessels that leak fluid or blood into the light sensitive lining inside the eye (retina).

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.0
E.1.2	Level	PT
E.1.2	Classification code	10071129
E.1.2	Term	Neovascular age-related macular degeneration
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine if treatment with aflibercept 8 mg (HD) at intervals of 12 or 16 weeks provides non-inferior BCVA change compared to aflibercept 2 mg every 8 weeks in participants with nAMD

E.2.2

Secondary objectives of the trial

- To determine the effect of HD versus 2 mg aflibercept on other visual and anatomic measures of response
- To assess the efficacy of HD compared to 2 mg aflibercept on vision related quality of life
- To evaluate the safety, pharmacokinetics (PK) and immunogenicity of aflibercept

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1. Dense Pharmacokinetic Sub-study: version 2.0 dated 14 Feb 2020
Objective is to characterize the concentrations in plasma over time, and
corresponding PK parameters for aflibercept.
2. Genomic Sub-study: version 2.0 dated 14 Feb 2020
Objective is to evaluate the clinical efficacy parameters by repertoire or
frequency of genetic alterations.

E.3

Principal inclusion criteria

1. At least 50 years of age at the time of signing the informed consent.
2. Active subfoveal CNV secondary to nAMD, including juxtafoveal lesions that affect the fovea as assessed in the study eye.
3. Total area of CNV (including both classic and occult components) must comprise greater than 50% of the total lesion area in the study eye.
4. BCVA ETDRS letter score of 78 to 24 (corresponding to a Snellen equivalent of approximately 20/32 to 20/320) in the study eye.
5. Decrease in BCVA determined to be primarily the result of nAMD in the study eye.
6. Presence of IRF and/or SRF affecting the central subfield of the study eye on OCT. The central subfield is defined as a circle with diameter 1 mm, centered on the fovea.
7. Male or female.
All randomized participants that complete Week 96 are eligible for the
extension period, as long as the following criteria apply:
1. The participant provides signed informed consent to participate in the
extension period, and no treatment for nAMD has been given in the study
eye outside of the randomized study treatment.
2. At least one BCVA value and one central subfield retinal thickness
(CST) value from measurements at one of the following visits: Visit 24
(Week 84), Visit 25 (Week 88) or Visit 26 (Week 92).
3. Participant is enrolled at a site that participates in the extension
period.

E.4

Principal exclusion criteria

1. Causes of CNV other than nAMD in the study eye.
2. Prior or concomitant conditions in the study eye:
a. Subretinal hemorrhage that is at least 50% of the total lesion area, or if the blood under the fovea is 1 or more disc areas in size in the study eye.
b. Scar or fibrosis making up more than 50% of the total lesion in the study eye.
c. Scar, fibrosis, or atrophy involving the central subfield in the study eye.
d. Presence of retinal pigment epithelial tears or rips involving the central subfield in the study eye.
e. Total lesion size >12 disc areas (30.5 mm2, including blood, scars, and neovascularization) as assessed by FA in the study eye.
f. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-glaucoma medication) in the study eye.
g. History of idiopathic or autoimmune uveitis in the study eye.
h. Vitreomacular traction or epiretinal membrane in the study eye evident on biomicroscopy or OCT that is thought to affect central vision.
i. Any history of macular hole of stage 2 and above in the study eye.
j. Structural damage to the center of the macula in the study eye that is likely to preclude improvement in BCVA following the resolution of retinal fluid including but not limited to, atrophy of the retinal pigment epithelium, subretinal fibrosis or scar or significant macular ischemia.
k. History of, or likely future need of, filtration or tube shunt surgery on the study eye.
l. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium-aluminium-garnet [YAG] posterior capsulotomy performed more than 4 weeks (28 days) before screening), in the study eye.
m. Myopia of a spherical equivalent of at least 8 diopters in the study eye prior to any refractive or cataract surgery.
n. Significant media opacities, including cataract, that interfere with BCVA assessment, fundus photography or OCT imaging in the study eye.
o. History of corneal transplant or corneal dystrophy in the study eye.
p. History of irregular astigmatism or amblyopia with chronic limitation of BCVA in the study eye.
3. Prior or concomitant conditions of the study participant:
a. History or clinical evidence of diabetic retinopathy, diabetic macular edema, or any retinal vascular disease other than nAMD in either eye.
b. Evidence of extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in either eye at the time of screening/randomization.
c. Any intraocular inflammation/infection in either eye within 12 weeks (84 days) of the screening visit.
d. Only 1 functional eye, even if that eye was otherwise eligible for the study (e.g., BCVA of counting fingers or less in the eye with worse vision).
e. Ocular conditions with poorer prognosis in the fellow eye.
4. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg).
5. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) before the screening visit.
6. Renal failure requiring dialysis, or renal transplant at screening or potentially during the study.
7. Any prior or concomitant ocular (in the study eye) or systemic treatment (with an investigational or approved, anti-VEGF or other agent) or surgery for nAMD, except dietary supplements or vitamins.
8. Prior treatment of the study eye with any of the following drugs (any route of ophthalmic administration) or procedures before baseline visit (Day 1):
a. Anti-angiogenic drugs at any time including investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies).
b. Long-acting steroids, within 16 weeks (112 days) before the screening visit, or any treatment with IVT implant, gene therapy, or cell therapy at any time.
c. Ocriplasmin (Jetrea®) at any time.
d. Vitreoretinal surgery and/or including scleral buckling at any time.
e. Any other intraocular surgery within 90 days before the screening visit.
f. Panretinal laser photocoagulation or macular laser photocoagulation within 90 days before the screening visit.
g. YAG capsulotomy in the study eye within 30 days before the screening visit.
9. Prior treatment of the fellow eye with any of the following:
a. Investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies) within 180 days before the screening visit.
b. IVT implant, gene therapy, or cell therapy at any time.
Prior treatment in the fellow eye with approved anti-VEGF therapy is allowed.
10. Participation in other clinical trials requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening, or within 30 days or 5 half-lives of administration of the previous study intervention, whichever is longer.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Week 48

E.5.1.1

Timepoint(s) of evaluation of this end point

at 48 weeks

E.5.2

Secondary end point(s)

1. Change from baseline in BCVA measured by the ETDRS letter score at Week 60
2. Proportion of participants with no intraretinal fluid (IRF) and no subretinal fluid (SRF) in central subfield at Week 16
3. Proportion of participants gaining at least 15 letters in BCVA from baseline at Week 48
4. Proportion of participants achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) at Week 48
5. Change in choroidal neovascularization (CNV) size from baseline to Week 48
6. Change in total lesion area from baseline to Week 48
7. Proportion of participants with no IRF and no SRF in the center subfield at Week 48
8. Change from baseline in central subfield retinal thickness (CST) at Week 48
9. Change from baseline in National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) total score at Week 48
10. Treatment-emergent adverse events (AEs) and serious AEs (SAEs)
through Week 48, 60, 96 and, for participants who continue in the study
extension, through Week 156
11. Systemic exposure to aflibercept as assessed by plasma concentrations of free, bound, adjusted bound and total aflibercept from baseline through Week 48
12. Assessment of immunogenicity to aflibercept by measuring the incidence of treatment-emergent anti-drug antibodies (ADA) response through end of masked study (week 96)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. at baseline and week 60
2. at week 16
3. at baseline and week 48
4. at week 48
5. at baseline and week 48
6. at baseline and week 48
7. at week 48
8. at baseline and week 48
9. at baseline and week 48
10. up to 96 / 156 weeks
11. at week 48
12. at week 96

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

108

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Colombia

Singapore

Switzerland

Ukraine

Taiwan

Australia

Belarus

Brazil

Canada

China

Georgia

Israel

Japan

Korea, Republic of

Mexico

Russian Federation

Serbia

United Kingdom

United States

Austria

Belgium

Bulgaria

Czechia

Denmark

Estonia

France

Germany

Hungary

Italy

Latvia

Lithuania

Netherlands

Portugal

Slovakia

Spain

Türkiye

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last patient last visit

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

288

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

672

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

282

F.4.2.2

In the whole clinical trial

960

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-08-07

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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