A Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration

Geographic Atrophy Clinical Trial

Official title:

A Phase 3, Multi-Center, Randomized, Double-Masked, Sham-Controlled Study to Compare the Efficacy and Safety of Intravitreal Pegcetacoplan Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (AMD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03525613
• Other study ID #: APL2-304
• Status: Completed
• Phase: Phase 3
• Start date: August 31, 2018
• Est. completion date: June 28, 2022

Study information

• Verified date: June 2023
• Source: Apellis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 24-month, Phase III, multicenter, randomized, double-masked, sham-injection controlled study to assess the efficacy and safety of multiple IVT injections of APL-2 in subjects with GA secondary to AMD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 637
• Est. completion date: June 28, 2022
• Est. primary completion date: June 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

The study eye must meet all inclusion criteria. If both eyes meet the inclusion criteria, the eye with the worst visual acuity at the screening visit will be designated as the study eye. If both eyes have the same visual acuity, the right eye will be selected as the study eye.

Ocular- specific inclusion criteria apply to the study eye only, unless otherwise specified.

• Age = 60 years.

• Normal Luminance best corrected visual acuity of 24 letters or better using Early Treatment Diabetic Retinopathy Study (ETDRS) charts (approximately 20/320 Snellen equivalent).

• Clinical diagnosis of GA of the macula secondary to AMD as determined by the Investigator and confirmed by the Reading Center.

• The GA lesion must meet the following criteria as determined by the central reading center's assessment of Fundus Autofluorescence (FAF) imaging at screening:

• Total GA area must be = 2.5 and = 17.5 mm2 (1 and 7 disk areas [DA] respectively)

• If GA is multifocal, at least one focal lesion must be = 1.25 mm2 (0.5 DA), with the overall aggregate area of GA, as specified above in 4a.

• The entire GA lesion must be completely visualized on the macula centered image and must be able to be imaged in its entirety and not contiguous with any areas of peripapillary atrophy.

• Presence of any pattern of hyperautofluorescence in the junctional zone of GA. Absence of hyperautofluorescence (i.e. pattern = none) is exclusionary.

• Adequate clarity of ocular media, adequate pupillary dilation, and fixation to permit the collection of good quality images as determined by the Investigator.

• Meets the following criteria related to microperimetry:

• Able to detect fixation target.

• Total elapsed time to complete the 10-2 68 point exam is = 30 minutes in duration.

• Reliability test ratio must be = 20%.

• Subject is willing and able to undertake microperimetry assessment in the opinion of the investigator.

• Female subjects must be:

• Women of non-child-bearing potential (WONCBP), or

• Women of child-bearing potential (WOCBP) with a negative pregnancy test at screening and must agree to use protocol defined methods of contraception for the duration of the study and refrain from breastfeeding for the duration of the study.

• Males with female partners of child-bearing potential must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study.

• Willing and able to give informed consent and to comply with the study procedures and assessments.

Exclusion Criteria:

Ocular specific exclusion criteria apply to the study eye only, unless otherwise specified.

• GA secondary to a condition other than AMD such as Stargardt disease, cone rod dystrophy or toxic maculopathies like plaquenil maculopathy in either eye.

• Spherical equivalent of the refractive error demonstrating > 6 diopters of myopia or an axial length >26 mm.

• Any history or active choroidal neovascularization (CNV), associated with AMD or any other cause, including any evidence of retinal pigment epithelium rips or evidence of neovascularization anywhere based on SD-OCT imaging and/or fluorescein angiography as assessed by the Reading Center.

• Presence of an active ocular disease that in the opinion of the Investigator compromises or confounds visual function, including but not limited to, uveitis, other macular diseases (e.g. clinically significant epiretinal membrane (ERM), full thickness macular hole or uncontrolled glaucoma/ocular hypertension. Benign conditions in the opinion of the investigator such as peripheral retina dystrophy are not exclusionary).

• Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization.

• History of laser therapy in the macular region.

• Aphakia or absence of the posterior capsule. Note: YAG laser posterior capsulotomy for posterior capsule opacification done at least 60 days prior to screening is not exclusionary.

• Any ocular condition other than GA secondary to AMD that may require surgery or medical intervention during the study period or, in the opinion of the Investigator, could compromise visual function during the study period.

• Any contraindication to IVT injection including current ocular or periocular infection.

• History of prior intravitreal injection.

• Unable to perform microperimetry reliably in the opinion of the investigator

• Prior participation in another interventional clinical study for intravitreal therapies in either eye (including subjects receiving sham).

• Prior participation in another interventional clinical study for geographic atrophy in either eye including investigational oral medication and placebo.

• Participation in any systemic experimental treatment or any other systemic investigational new drug within 6 weeks or 5 half-lives of the active ingredient (whichever is longer) prior to the start of study treatment. Note: clinical trials solely involving observation, over-the-counter vitamins, supplements, or diets are not exclusionary.

• Medical or psychiatric conditions that, in the opinion of the investigator, make consistent follow-up over the 24-month treatment period unlikely, or would make the subject an unsafe study candidate.

• Any screening laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of the Investigator is clinically significant and not suitable for study participation.

• Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to APL-2 or any of the excipients in APL-2 solution.

Related Conditions & MeSH terms

• Atrophy
• Geographic Atrophy
• Macular Degeneration

Intervention

Drug:
• APL-2
Complement (C3) Inhibitor
• APL-2
Complement (C3) Inhibitor

Other:
• Sham Procedure
Subjects will receive a Sham procedure every month
• Sham Procedure
Subjects will receive a Sham procedure every other month

Locations

Country	Name	City	State
Australia	Adelaide Eye & Retina Clinic	Adelaide	South Australia
Australia	Lions Eye Institute	Nedlands	Western Australia
Australia	Marsden Eye Specialist	Parramatta	New South Wales
Australia	Strathfield Retina Clinic	Strathfield
Australia	Save Sight Institute	Sydney	South Block
Australia	Sydney West Retina	Westmead
Brazil	UNIFESP - Federal University	São Paulo
Canada	UHN Toronto Western Hospital	Toronto	Ontario
Czechia	AXON Clinical S.R.O	Praha
Czechia	Gemini Eye Clinic	Zlín
France	CHU de Bordeaux	Bordeaux
France	CHU Dijon	Bordeaux
France	Centre Hospitalier Intercommunal de Créteil	Créteil
France	Clinique du Val d'Ouest	Écully
France	Centre Ophtalmologique d'Imagerie et Laser	Paris
France	CHNO des Quinze-Vingts	Paris
France	Hopital Lariboisière	Paris
France	CHU de Strasbourg Hopital Civil	Strasbourg
Germany	Universitäts-Augenklinik Bonn	Bonn
Germany	University Opthalmology Clinic	Freiburg im Breisgau
Germany	Universitätsmedizin Göttingen Georg-August-Universität	Göttingen
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck
Germany	Augenklinik der LMU München	München
Germany	Augenzentrum am St. Franziskus-Hospital	Münster
Germany	Universitäts-Augenklinik	Münster
Germany	STZ Eyetrial	Tübingen
Israel	Carmel Medical Center	Haifa
Israel	Rambam Medical Centre	Haifa
Israel	Hadassah Medical Center	Jerusalem
Italy	Luigi Sacco Hospital	Milano
Italy	Ospedale San Raffaele	Milano
Italy	IRCCS Fondazione G.B. Bietti	Roma
Netherlands	Academisch Medisch Centrum	Amsterdam
Netherlands	Radboud University Medical Center Oogheelkunde	Nijmegen
New Zealand	Southern Eye Specialists	Christchurch
Poland	Oculomedica Eye Centre	Bydgoszcz
Poland	Oftalmika Eye Hospital	Bydgoszcz
Poland	Eye Surgery Center Professor Zagorski	Rzeszów
Spain	Centro de Oftalmologia Barraquer	Barcelona
Spain	Centro Médico Teknon	Barcelona
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrir
United Kingdom	The Royal Victoria Hospital	Belfast
United Kingdom	Liverpool University Hospitals NHS Foundation Trust	Liverpool
United Kingdom	Sunderland Eye Infirmary	Sunderland
United Kingdom	York Teaching Hospital NHS Foundation Trust	York
United States	Retina Research Institute of Texas	Abilene	Texas
United States	Vision Research Center Eye Associates of NM	Albuquerque	New Mexico
United States	Michigan Medicine Kellogg Eye Center	Ann Arbor	Michigan
United States	Southeast Retina Center, PC	Augusta	Georgia
United States	California Retina Consultants	Bakersfield	California
United States	The Retina Care Center	Baltimore	Maryland
United States	Mid Atlantic Retina	Bethlehem	Pennsylvania
United States	Retina Vitreous Associates Medical Group	Beverly Hills	California
United States	Retina Center of NJ, LLC	Bloomfield	New Jersey
United States	Gailey Eye Clinic Retina Center	Bloomington	Illinois
United States	Tufts Medical Center	Boston	Massachusetts
United States	Retinal Diagnostic Center	Campbell	California
United States	The Retina Group of Washington	Chevy Chase	Maryland
United States	Northwestern Feinberg School of Medicine	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Blue Ocean Clinical Research / The Macula Center	Clearwater	Florida
United States	Texas Retina Associates	Dallas	Texas
United States	Southwest Retina Research Center, LLC	Durango	Colorado
United States	Duke University, Duke Eye Center	Durham	North Carolina
United States	Research - Retina Vitreous Center	Edmond	Oklahoma
United States	Oregon Retina, LLP	Eugene	Oregon
United States	Emerson Clinical Research Institute	Falls Church	Virginia
United States	National Ophthalmic Research Institute (Retina Consultants of Southwest Florida)	Fort Myers	Florida
United States	Retina Consultants of Orange County	Fullerton	California
United States	Charles Retina Institute	Germantown	Tennessee
United States	Colorado Retina Associates	Golden	Colorado
United States	Associated Retinal Consultants, P.C	Grand Rapids	Michigan
United States	Cumberland Valley Retina Center	Hagerstown	Maryland
United States	Mid Atlantic Retina Specialists	Hagerstown	Maryland
United States	Houston Eye Associates	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Atlantis Eyecare	Huntington Beach	California
United States	Midwest Eye Institute	Indianapolis	Indiana
United States	University of California, San Diego, Jacobs Retina	La Jolla	California
United States	Retina and Vitreous Associates of Kentucky, PSC dba Retina Associates of Kentucky	Lexington	Kentucky
United States	Ophthalmic Consultants of Long Island	Lynbrook	New York
United States	University of Wisconsin	Madison	Wisconsin
United States	Retina Associates New Orleans	Metairie	Louisiana
United States	Bascom Palmer Eye Institute	Miami	Florida
United States	VitreoRetinal Surgery PA	Minneapolis	Minnesota
United States	Retina Vitreous Consultants	Monroeville	Pennsylvania
United States	Bascom Palmer Eye Institute of Naples	Naples	Florida
United States	Tennessee Retina, PC	Nashville	Tennessee
United States	New York Eye and Ear Infirmary of Mount Sinai	New York	New York
United States	Vitreous Retina Macula Consultants of NY	New York	New York
United States	Byers Eye Institute at Stanford, Stanford School of Medicine	Palo Alto	California
United States	Doheny Eye Center UCLA	Pasadena	California
United States	Retina Specialty Institute	Pensacola	Florida
United States	Mid Atlantic Retina, Wills Eye Hospital	Philadelphia	Pennsylvania
United States	Arizona Retina & Vitreous Consultants	Phoenix	Arizona
United States	Retina Consultants San Diego	Poway	California
United States	Sierra Eye Associates	Reno	Nevada
United States	Retinal Consultants Med Group, Inc.	Sacramento	California
United States	University of Utah - John A. Moran Center	Salt Lake City	Utah
United States	Brown Retina Institute	San Antonio	Texas
United States	Medical Center Ophthalmology Associates	San Antonio	Texas
United States	Retina Associates of South Texas	San Antonio	Texas
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	San Antonia Eye Center	San Antonio	Texas
United States	Orange County Retina Medical Group	Santa Ana	California
United States	California Retina Consultants	Santa Barbara	California
United States	New England Retina Consultants	Springfield	Massachusetts
United States	NJ Retina	Toms River	New Jersey
United States	Retina Group of New England	Waterford	Connecticut
United States	AIO Visionary Eye Care	West Mifflin	Pennsylvania
United States	Strategic Clinical Research Group	Willow Park	Texas
United States	Center for Retina and Macular Disease	Winter Haven	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Apellis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Czechia,  France,  Germany,  Israel,  Italy,  Netherlands,  New Zealand,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Least Squares (LS) Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 12	The GA lesion area was measured by a quantified central reading center based on FAF images. LS mean was calculated using a mixed effect model for repeated measure (MMRM) model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 12
Secondary	LS Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 24	The GA lesion area was measured by a quantified central reading center based on FAF images. LS mean was calculated using a mixed effect model for repeated measure model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 24
Secondary	Mean Change in Total Area of GA Lesions in the Study Eye Through Month 24	The mean change in GA lesion area through Month 24 was measured by assuming a piecewise linear trend in time with knots by FAF images at Months 6, 12, 18, and 24 and was calculated using a MMRM model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	From Baseline (screening) through Month 24
Secondary	LS Mean Change From Baseline in Mean Threshold Sensitivity of All Points of the Study Eye at Month 24	Mean threshold sensitivity of all points was determined from the mesopic microperimetry as an assessment of the macular functional response. Microperimetry offers the option to test retinal light sensitivity while directly observing the fundus and allows for monitoring of macular function loss associated with GA progression. The microperimetry reading center overlaid the baseline FAF images with GA lesions traced by the imaging reading center and the corresponding macular integrity assessment microperimetry baseline scanning laser ophthalmoscope image and identified perilesional (within 500 microns outside the atrophy border), paralesional (beyond 500 microns outside the atrophy border), and extralesional (outside the atrophy border) loci on the microperimetry grid to determine the mean threshold sensitivity for these 3 areas. LS mean was calculated using a MMRM model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 24
Secondary	LS Mean Change From Baseline in Monocular Maximum Reading Speed of the Study Eye at Month 24	The maximum reading speed of the study eye was calculated per Minnesota Low-Vision Reading Test (MNREAD) or Radner Reading Charts user manuals, with no adjustment for reading inaccuracy. An additional step to cap resulting reading speed values at a maximum of 300 words per minute (wpm) was implemented. Maximum reading speed was calculated as the mean of the 3 highest non-zero reading speeds (or 2, or 1 value, as available), except when all wpm were calculated as 0 then the maximum reading speed was calculated as 0. LS mean was calculated using a MMRM model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 24
Secondary	LS Mean Change From Baseline in Mean Functional Reading Independence (FRI) Index Score at Month 24	The FRI was an interviewer-administered questionnaire with 7 items on functional reading activities most relevant to GA AMD subjects. It had 1 total index score. For each FRI Index reading activity performed in the past 7 days, subjects were asked about the extent to which they required assistance beyond eyeglasses/contact lenses, including the use of low-vision aids, adjustments in the activity, or help from another subject. Mean FRI Index scores ranged from 1 (unable to do independently) to 4 (totally independent), with higher scores indicating higher functional reading independence. A negative change from baseline indicated a decrease in the FRI; disease worsening. LS mean was calculated using a MMRM model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 24
Secondary	LS Mean Change From Baseline in Normal-Luminance Best-Corrected Visual Acuity (NL-BCVA) Score of the Study Eye at Month 24	The NL-BCVA was assessed by early treatment diabetic retinopathy study (ETDRS) chart prior to dilating the eyes at a starting distance of 4 meters and ranged from 0 (least score) to 100 (best score). If the 4-meter score was >19 letters read correctly, the visual acuity score was the sum of total letters correctly read at 4 meters plus the addition of 30. If the 4-meter score was =19 letters read correctly, the visual acuity score was the sum of total letters read correctly at 4 meters and total letters read correctly at the 1-meter distance. If no letters were read correctly at either the 4-meter distance or the 1-meter distance, the visual acuity score was 0. A positive change in the value indicated improvement in visual acuity. LS mean was calculated using a MMRM model. Baseline was defined as the last available, non-missing observation prior to first study drug administration.	Baseline (screening) and Month 24