A Phase 3 Safety and Efficacy Study of Intravitreal Administration of Zimura (Complement C5 Inhibitor)

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ClinicalTrials.gov Identifier: NCT04435366

Recruitment Status : Completed

First Posted : June 17, 2020

Results First Posted : December 28, 2023

Last Update Posted : February 23, 2024

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Sponsor:

Information provided by (Responsible Party):

Astellas Pharma Inc ( IVERIC bio, Inc. )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
Conditions	Geographic Atrophy Macular Degeneration
Interventions	Drug: Avacincaptad Pegol Drug: Sham
Enrollment	448

Participant Flow

Recruitment Details
Pre-assignment Details	Study participants are planned to receive 24 monthly intravitreal injections of avacincaptad pegol and/or sham in a single designated study eye. The study eye is designated by the Investigator prior to first administration of study drug and does not change throughout the duration of study participation.


Arm/Group Title	Avacincaptad Pegol Treatment Group	Sham Treatment Group
Arm/Group Description	Monthly avacincaptad pegol 2mg intr...	Monthly sham administration through...
Arm/Group Description	Monthly avacincaptad pegol 2mg intravitreal injections through Month 11 (Year 1) NOTE: At Month 12, participants are re-randomized to receive either monthly injections or every other month injections (alternating with sham) from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis	Monthly sham administration through Month 11 (Year 1) NOTE: At Month 12, participants continue to receive monthly sham administration from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis
Period Title: Overall Study
Started	225	222 ^[1]
Month 12	200	205
Completed ^[2]	200	205
Not Completed	25	17
Reason Not Completed
Adverse Event	3	2
Death	2	1
Lost to Follow-up	2	1
Withdrawal by Subject	17	13
Patient non-compliance	1	0
[1] 223 participants were randomized to the Sham Treatment Group, but 1 participant was never treated [2] Completed up to Month 12 (Year 1); Month 24 (Year 2) data availability pending Year 2 Clinical Study Report finalization and submission (anticipated no later than August 22, 2024)

Baseline Characteristics

Arm/Group Title		Avacincaptad Pegol Treatment Group	Sham Treatment Group	Total
Arm/Group Description		Monthly avacincaptad pegol 2mg intr...	Monthly sham administration through...	Total of all reporting groups
Arm/Group Description		Monthly avacincaptad pegol 2mg intravitreal injections through Month 11 (Year 1) NOTE: At Month 12, participants are re-randomized to receive either monthly injections or every other month injections (alternating with sham) from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis	Monthly sham administration through Month 11 (Year 1) NOTE: At Month 12, participants continue to receive monthly sham administration from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis	Total of all reporting groups
Overall Number of Baseline Participants		225	222	447
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	225 participants	222 participants	447 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	19 8.4%	20 9.0%	39 8.7%
	>=65 years	206 91.6%	202 91.0%	408 91.3%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	225 participants	222 participants	447 participants
	Female	154 68.4%	156 70.3%	310 69.4%
	Male	71 31.6%	66 29.7%	137 30.6%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	225 participants	222 participants	447 participants
	Hispanic or Latino	27 12.0%	23 10.4%	50 11.2%
	Not Hispanic or Latino	168 74.7%	178 80.2%	346 77.4%
	Unknown or Not Reported	30 13.3%	21 9.5%	51 11.4%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	225 participants	222 participants	447 participants
	American Indian or Alaska Native	1 0.4%	0 0.0%	1 0.2%
	Asian	1 0.4%	1 0.5%	2 0.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	1 0.5%	1 0.2%
	White	182 80.9%	186 83.8%	368 82.3%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	41 18.2%	34 15.3%	75 16.8%

Outcome Measures

1.Primary Outcome


Title	Mean Rate of Change in GA Over 12 Months (Measured at Three Time Points: Baseline, Month 6, and Month 12)
Description	The least squares mean rate of growth (slope) estimated based on geogr...
Description	The least squares mean rate of growth (slope) estimated based on geographic atrophy (GA) area measured by fundus autofluorescence (FAF) in at least 3 timepoints: Baseline, Month 6, and Month 12 was used to determine mean rate of change (slope) in GA from Baseline to Month 12. The square root of the GA area was used in the analysis.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Avacincaptad Pegol Treatment Group	Sham Treatment Group
Arm/Group Description:	Monthly avacincaptad pegol 2mg intr...	Monthly sham administration through...
Arm/Group Description:	Monthly avacincaptad pegol 2mg intravitreal injections through Month 11 (Year 1) NOTE: At Month 12, participants are re-randomized to receive either monthly injections or every other month injections (alternating with sham) from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis	Monthly sham administration through Month 11 (Year 1) NOTE: At Month 12, participants continue to receive monthly sham administration from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis
Overall Number of Participants Analyzed	225	222
Least Squares Mean (Standard Error) Unit of Measure: millimeters (mm) per year
	0.336 (0.032)	0.392 (0.033)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Avacincaptad Pegol Treatment Group, Sham Treatment Group
	Comments	Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol).
	Type of Statistical Test	Other
	Comments	Model for repeated measures (MRM) was used to compare the treatment groups.

Statistical Test of Hypothesis	P-Value	0.0064
	Comments	[Not Specified]
	Method	Model for Repeated Measures (MRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.056
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events were recorded starting at Day 1 after the first dose of study drug and continuing until 30 days after the last dose or until the last follow-up visit required by the protocol, whichever comes later (for the primary analysis, adverse events up to approximately 12 months from first dose are reported here).
Adverse Event Reporting Description	The analysis population for all-cause mortality, serious adverse events (SAEs), and non-serious adverse events (NSAEs) consisted of all participants who received at least one dose of study treatment. Participants who received an injection of avacincaptad pegol during this study were analyzed in the avacincaptad pegol treatment group according to the actual injections received.

Arm/Group Title	Avacincaptad Pegol Treatment Group	Sham Treatment Group
Arm/Group Description	Monthly avacincaptad pegol 2mg intr...	Monthly sham administration through...
Arm/Group Description	Monthly avacincaptad pegol 2mg intravitreal injections through Month 11 (Year 1) NOTE: At Month 12, participants are re-randomized to receive either monthly injections or every other month injections (alternating with sham) from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis	Monthly sham administration through Month 11 (Year 1) NOTE: At Month 12, participants continue to receive monthly sham administration from Month 12 to Month 23 (Year 2) - Year 2 is not included in the primary analysis
All-Cause Mortality
	Avacincaptad Pegol Treatment Group	Sham Treatment Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/225 (0.89%)	1/222 (0.45%)
Serious Adverse Events Serious Adverse Events
	Avacincaptad Pegol Treatment Group	Sham Treatment Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	30/225 (13.33%)	37/222 (16.67%)
Cardiac disorders
Atrial fibrillation ^† 1	2/225 (0.89%)	1/222 (0.45%)
Cardiac failure congestive ^† 1	1/225 (0.44%)	1/222 (0.45%)
Angina pectoris ^† 1	0/225 (0.00%)	1/222 (0.45%)
Atrial flutter ^† 1	1/225 (0.44%)	0/222 (0.00%)
Cardiac failure chronic ^† 1	0/225 (0.00%)	1/222 (0.45%)
Coronary artery disease ^† 1	1/225 (0.44%)	0/222 (0.00%)
Coronary artery insufficiency ^† 1	1/225 (0.44%)	0/222 (0.00%)
Myocardial ischaemia ^† 1	0/225 (0.00%)	1/222 (0.45%)
Sinus arrest ^† 1	0/225 (0.00%)	1/222 (0.45%)
Congenital, familial and genetic disorders
Mobile caecum syndrome ^† 1	0/225 (0.00%)	1/222 (0.45%)
Eye disorders
Choroidal neovascularisation ^† 1 [1]	2/225 (0.89%)	1/222 (0.45%)
Visual acuity reduced ^† 1 [1]	0/225 (0.00%)	1/222 (0.45%)
Visual acuity reduced transiently ^† 1 [1]	0/225 (0.00%)	1/222 (0.45%)
Gastrointestinal disorders
Enterovesical fistula ^† 1	0/225 (0.00%)	1/222 (0.45%)
Haemorrhoidal haemorrhage ^† 1	0/225 (0.00%)	1/222 (0.45%)
Inguinal hernia ^† 1	1/225 (0.44%)	0/222 (0.00%)
Large intestine polyp ^† 1	0/225 (0.00%)	1/222 (0.45%)
Pancreatitis chronic ^† 1	1/225 (0.44%)	0/222 (0.00%)
Rectal haemorrhage ^† 1	0/225 (0.00%)	1/222 (0.45%)
Small intestinal obstruction ^† 1	0/225 (0.00%)	1/222 (0.45%)
Upper gastrointestinal haemorrhage ^† 1	1/225 (0.44%)	0/222 (0.00%)
Vomiting ^† 1	1/225 (0.44%)	0/222 (0.00%)
Hepatobiliary disorders
Cholecystitis acute ^† 1	1/225 (0.44%)	0/222 (0.00%)
Hepatic cirrhosis ^† 1	1/225 (0.44%)	0/222 (0.00%)
Infections and infestations
Pneumonia ^† 1	3/225 (1.33%)	2/222 (0.90%)
COVID-19 ^† 1	1/225 (0.44%)	2/222 (0.90%)
Urosepsis ^† 1	0/225 (0.00%)	2/222 (0.90%)
COVID-19 pneumonia ^† 1	1/225 (0.44%)	0/222 (0.00%)
Clostridium difficile infection ^† 1	1/225 (0.44%)	0/222 (0.00%)
Diverticulitis ^† 1	0/225 (0.00%)	1/222 (0.45%)
Herpes zoster ^† 1	1/225 (0.44%)	0/222 (0.00%)
Listeria sepsis ^† 1	0/225 (0.00%)	1/222 (0.45%)
Injury, poisoning and procedural complications
Exposure to toxic agent ^† 1	1/225 (0.44%)	0/222 (0.00%)
Facial bones fracture ^† 1	0/225 (0.00%)	1/222 (0.45%)
Fall ^† 1	1/225 (0.44%)	0/222 (0.00%)
Humerus fracture ^† 1	0/225 (0.00%)	1/222 (0.45%)
Lumbar vertebral fracture ^† 1	1/225 (0.44%)	0/222 (0.00%)
Multiple fractures ^† 1	1/225 (0.44%)	0/222 (0.00%)
Multiple injuries ^† 1	0/225 (0.00%)	1/222 (0.45%)
Procedural intestinal perforation ^† 1	1/225 (0.44%)	0/222 (0.00%)
Radius fracture ^† 1	0/225 (0.00%)	1/222 (0.45%)
Rib fracture ^† 1	0/225 (0.00%)	1/222 (0.45%)
Spinal compression fracture ^† 1	1/225 (0.44%)	0/222 (0.00%)
Tibia fracture ^† 1	0/225 (0.00%)	1/222 (0.45%)
Traumatic intracranial haemorrhage ^† 1	0/225 (0.00%)	1/222 (0.45%)
Wrist fracture ^† 1	1/225 (0.44%)	0/222 (0.00%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis ^† 1	0/225 (0.00%)	1/222 (0.45%)
Tenosynovitis ^† 1	1/225 (0.44%)	0/222 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia ^† 1	1/225 (0.44%)	0/222 (0.00%)
Colon cancer ^† 1	0/225 (0.00%)	1/222 (0.45%)
Non-small cell lung cancer stage IIIA ^† 1	0/225 (0.00%)	1/222 (0.45%)
Squamous cell carcinoma of lung ^† 1	1/225 (0.44%)	0/222 (0.00%)
Nervous system disorders
Transient ischaemic attack ^† 1	0/225 (0.00%)	2/222 (0.90%)
Cerebral haemorrhage ^† 1	0/225 (0.00%)	1/222 (0.45%)
Cerebrovascular accident ^† 1	0/225 (0.00%)	1/222 (0.45%)
Metabolic encephalopathy ^† 1	0/225 (0.00%)	1/222 (0.45%)
Product Issues
Device lead damage ^† 1	0/225 (0.00%)	1/222 (0.45%)
Reproductive system and breast disorders
Prostatitis ^† 1	0/225 (0.00%)	1/222 (0.45%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^† 1	2/225 (0.89%)	1/222 (0.45%)
Pleural effusion ^† 1	1/225 (0.44%)	1/222 (0.45%)
Acute respiratory failure ^† 1	1/225 (0.44%)	0/222 (0.00%)
Chronic obstructive pulmonary disease ^† 1	0/225 (0.00%)	1/222 (0.45%)
Emphysema ^† 1	0/225 (0.00%)	1/222 (0.45%)
Pneumothorax ^† 1	1/225 (0.44%)	0/222 (0.00%)
Vascular disorders
Hypertension ^† 1	1/225 (0.44%)	2/222 (0.90%)
Aortic aneurysm ^† 1	1/225 (0.44%)	0/222 (0.00%)
Aortic stenosis ^† 1	0/225 (0.00%)	1/222 (0.45%)
Circulatory collapse ^† 1	1/225 (0.44%)	0/222 (0.00%)
Neurogenic shock ^† 1	1/225 (0.44%)	0/222 (0.00%)
Peripheral arterial occlusive disease ^† 1	0/225 (0.00%)	1/222 (0.45%)
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment [1] included study and fellow eye events
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Avacincaptad Pegol Treatment Group	Sham Treatment Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	77/225 (34.22%)	62/222 (27.93%)
Eye disorders
Conjunctival haemorrhage ^† 1 [1]	28/225 (12.44%)	17/222 (7.66%)
Conjunctival hyperaemia ^† 1 [1]	12/225 (5.33%)	13/222 (5.86%)
Punctate keratitis ^† 1 [1]	11/225 (4.89%)	14/222 (6.31%)
Choroidal neovascularisation ^† 1 [1]	12/225 (5.33%)	9/222 (4.05%)
Infections and infestations
Urinary tract infection ^† 1	13/225 (5.78%)	12/222 (5.41%)
Injury, poisoning and procedural complications
Fall ^† 1	13/225 (5.78%)	18/222 (8.11%)
Investigations
Intraocular pressure increased ^† 1	21/225 (9.33%)	3/222 (1.35%)
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment [1] included study and fellow eye events

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

No individual site or investigator may publish or present any results from the trial until a joint, multi-center publication of the trial results is made by Sponsor in conjunction with various participating investigators and appropriate sites contributing data and comments. Subsequently, individual investigators may request to publish or present results from the trial; however approval will be at the sole discretion of the Sponsor.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Information
Organization:	IVERIC Bio, Inc.
Phone:	800-707-4479
EMail:	medicalinformation@ivericbio.com

Layout table for additonal information

Responsible Party:	Astellas Pharma Inc ( IVERIC bio, Inc. )
ClinicalTrials.gov Identifier:	NCT04435366
Other Study ID Numbers:	ISEE2008
First Submitted:	May 12, 2020
First Posted:	June 17, 2020
Results First Submitted:	November 1, 2023
Results First Posted:	December 28, 2023
Last Update Posted:	February 23, 2024

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