Study to Collect Safety and ECG Data on Brolucizumab 6 mg Intravitreal Treatment in Patients With Wet AMD

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03954626
• Collaborator: (none)
• Enrollment: 14
• Locations: 3
• Arm: 1
• Actual Duration (Months): 1.8
• Patients Per Site: 4.7
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

The purpose of this study was to collect ECG data after a single IVT injection of brolucizumab 6 mg in patients with neovascular age-related macular degeneration (nAMD).

Condition or Disease	Intervention/Treatment	Phase
Age-Related Macular Degeneration; Macular Degeneration; Wet Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases	Biological: brolucuzumab 6 mg IVT	Phase 3

Detailed Description

This is a single-arm, open-label, multicenter study that collected ECG data after a single IVT injection of brolucizumab 6 mg in patients with nAMD. Triplicate 12-lead ECG recording was performed at screening to determine eligibility. A second triplicate 12-lead ECG recording was collected approximately 2h prior to the brolucizumab IVT injection on Day 1. Holter ECG recording started approximately 1 h prior to the brolucizumab IVT injection and ended approximately 48h after the IVT injection. A third triplicate 12-lead ECG recording was performed after the conclusion of Holter monitoring on Day 3.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single arm, multicenterSingle arm, multicenter
• Masking: None (Open Label)
• Masking Description: Open label study
• Primary Purpose: Treatment
• Official Title: A Single-Arm, Open-Label, Multicenter, Phase IIIb Study to Collect Safety and Electrocardiogram Data on Brolucizumab 6 mg Intravitreal Treatment in Patients With Neovascular Age-Related Macular Degeneration
• Actual Study Start Date: Jun 7, 2019
• Actual Primary Completion Date: Jul 9, 2019
• Actual Study Completion Date: Jul 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RTH258 Intravitreal injection	Biological: brolucuzumab 6 mg IVT; Single intravitreal injection (IVT) of brolucizumab 6 mg; Other Names: RTH258

Outcome Measures

Primary Outcome Measures

1. Frequency of Clinically Relevant Treatment Emergent ECG Changes After Intravitreal Injection of Brolucizumab 6 mg in Patients With nAMD [Baseline, Hour 20, Hour 22, Hour 24]

   Incidence between 20 and 24 h post-injection of clinically relevant treatment emergent changes in heart rate (HR), pulse rate (PR), QRS, and QTc (heart rate corrected QT using Fridericia's formula, QTcF) interval (ms). This is a composite endpoint capturing all 4 parameters and 3 time-points in one Outcome Measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent MUST be obtained prior to participation in the study

• Study eye is diagnosed with nAMD and deemed to be eligible for intravitreal injection at the discretion of the Investigator

Exclusion Criteria:

• Concomitant conditions or ocular disorders in the study eye at screening which may cause safety concerns on the judgement of the investigator

• Any active intraocular or periocular or systemic infection or active intraocular inflammation at Baseline

• Treatment with any ocular intravitreal injection in the study eye within the past 7 half lives prior to Baseline

• Intraocular surgery, prior long-acting therapeutic agent, or ocular drug release device implantation (approved or investigational) in the study eye any time during the past 3 months prior to Baseline

• Diagnosis of ECG abnormalities including:

• Clinically significant cardiac arrhythmias, e.g., atrial fibrillation, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker

• Familial long QT syndrome or known family history of Torsades de Pointes

• Resting heart rate < 50 or > 90 bpm at screening

• Resting QTcF ≥ 450 ms (male) or ≥ 460 ms (female) at screening

• Use of concomitant medications that are classified as known risk, conditional risk or possible risk to prolong QT/QTc interval within 7 half-lives prior to Baseline

• History of stroke (including transient ischemic attack, reversible ischemic neurological deficit, prolonged reversible ischemic neurological deficit) or myocardial infarction (ST or non-ST elevation myocardial infarction) at any time prior to baseline

• Chronic kidney disease as determined as a CrCL at screening of < 60 ml/min/1.73 m2 as determined by the MDRD formula

• Uncontrolled high blood pressure defined as a systolic value ≥ 140 mmHg or diastolic value ≥ 90 mmHg at screening or baseline

• Systemic anti-VEGF therapy during the 6-month period prior to baseline

• Electrolyte disturbances determined as out of normal range sodium, potassium or calcium serum concentrations at screening

• Concomitant intake of long-acting muscarinic antagonist (LAMA)/ long-acting beta adrenergic (LABA) combination therapy

• History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar classes as assessed by the investigator

• Use of systemic or ocular (including intravitreal) investigational drugs within 7 half-lives of baseline, (or within 30 days/until the expected pharmacodynamic effect has returned to baseline), whichever is longer or longer if required by local regulations (observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary)

• Pregnant or nursing (lactating) women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Phoenix	Arizona	United States	85014
2	Novartis Investigative Site	Abilene	Texas	United States	79606
3	Novartis Investigative Site	Arecibo		Puerto Rico	00612

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Nadia Zakaria, MD, Novartis Institutes for BioMedical Research

Study Documents (Full-Text)

• Study Protocol - Mar 13, 2019
• Statistical Analysis Plan - May 29, 2019

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03954626
• Other Study ID Numbers: CRTH258A2309
• First Posted: May 17, 2019
• Last Update Posted: Jan 5, 2021
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: AMD, nAMD, wet AMD, RTH258, brolucizumab, ECG, open-label
• Additional relevant MeSH terms: Macular Degeneration; Eye Diseases; Retinal Diseases; Retinal Degeneration; Wet Macular Degeneration

Study Results

Participant Flow

Recruitment Details	The study enrolled patients from 3 centers from the United States.14 patients were enrolled and analyzed in the study.

Arm/Group Title	RTH258
Arm/Group Description	Intravitreal injection
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RTH258
Arm/Group Description	Intravitreal injection
Overall Participants	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75.7 (6.57)
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 85.7%
Not Hispanic or Latino	2 14.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	14 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Frequency of Clinically Relevant Treatment Emergent ECG Changes After Intravitreal Injection of Brolucizumab 6 mg in Patients With nAMD
Description	Incidence between 20 and 24 h post-injection of clinically relevant treatment emergent changes in heart rate (HR), pulse rate (PR), QRS, and QTc (heart rate corrected QT using Fridericia's formula, QTcF) interval (ms). This is a composite endpoint capturing all 4 parameters and 3 time-points in one Outcome Measure.
Time Frame	Baseline, Hour 20, Hour 22, Hour 24

Outcome Measure Data

Analysis Population Description

The safety analysis, which included all patients who received one intravitreal injection of brolucizumab 6 mg.

Arm/Group Title	RTH258
Arm/Group Description	Intravitreal injection
Measure Participants	14
Number [Number of events]	0

Adverse Events

Time Frame	Adverse events were collected from date of written informed consent until the end of study visit (Day 8)
Arm/Group Title	RTH258
Arm/Group Description	Intravitreal injection
All Cause Mortality
	RTH258
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	RTH258
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Other (Not Including Serious) Adverse Events
	RTH258
	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)
Investigations
Intraocular pressure increased	1/14 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.