Systemic Vascular Endothelial Growth Factor (VEGF) Protein Dynamics Following Intravitreal Injections of Ranibizumab Versus Aflibercept in Patients With Neovascular Age-related Macular Degeneration (TIDE AMD)

A Randomized, Single-blinded, Multicenter, Phase IV Study to Compare Systemic VEGF Protein Dynamics Following Monthly Intravitreal Injections of 0.5 mg Ranibizumab Versus 2 mg Aflibercept Until Study Week 12 in Patients With Neovascular (Wet) Age-related Macular Degeneration

The purpose of the study was to compare the effect of intravitreal injections of ranibizumab and aflibercept on systemic VEGF protein levels in treatment naïve wet neovascular Age-related Macular Degeneration (wAMD) patients in a detailed time course.

Study Overview

• Status: Completed
• Conditions: Wet Age-Related Macular Degeneration
• Intervention / Treatment: Drug: Ranibizumab 0.5 mg; Drug: Aflibercept 2 mg

Detailed Description

A planned study visit schedule was established at the time of baseline visit (day 1) for all patients. Study assessments for patients were performed at screening visit, baseline (day 1), day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day 169 at biweekly visits.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Koeln, Germany, 50924
    • Novartis Investigative Site
  • Marburg, Germany, 35039
    • Novartis Investigative Site
  • München, Germany, 81675
    • Novartis Investigative Site
  • München, Germany, 80336
    • Novartis Investigative Site
  • Osnabrück, Germany, 49076
    • Novartis Investigative Site
  • Regensburg, Germany, 93042
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Visual impairment predominantly due to neovascular AMD.
• Active, newly diagnosed, untreated, angiographically documented, CNV lesion (i.e. leakage on fluorescein angiography plus intraretinal, subretinal or sub-RPE fluid on OCT) secondary to neovascular AMD in line with SmPC of ranibizumab and aflibercept

Exclusion Criteria:

• Stroke or myocardial infarction less than 3 months prior to screening.
• Presence of uncontrolled systolic blood pressure or diastolic blood pressure
• Type 1 or Type 2 diabetes mellitus
• Use of any systemic anti-VEGF drugs
• Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3 months prior to screening.
• Women who are pregnant or breast feeding or who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception

For either eye:

• Any active periocular or ocular infection or inflammation
• Uncontrolled glaucoma
• Neovascularization of the iris or neovascular glaucoma
• History of treatment with any anti-angiogenic drugs

For study eye:

• Atrophy or fibrosis involving the center of the fovea at the time of screening or baseline.
• Cataract (if causing significant visual impairment), planned cataract surgery during the study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization of any other cause than wAMD
• Irreversible structural damage within 0.5 disc diameter of the center of the macula
• Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months following baseline.
• Use of intravitreal or topical ocular corticosteroids administered for at least 30 consecutive days within 3 months prior to screening.

For fellow eye

- Retinal or choroidal neovascularization or macula edema of any cause

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 6 monthly intravitreal injections of 0.5 mg ranibizumab	Drug: Ranibizumab 0.5 mg; Administered as an intravitreal injection; Other Names: Lucentis
Experimental: Group 2; 3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab	Drug: Ranibizumab 0.5 mg; Administered as an intravitreal injection; Other Names: Lucentis; Drug: Aflibercept 2 mg; Administered as an intravitreal injection; Other Names: Eylea

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase	The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.	Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic VEGF-A Protein Levels From Study Week 12 to 24	Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)	From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169)
Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)	Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab	From study week 12 to 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2015
• Primary Completion (Actual): March 20, 2017
• Study Completion (Actual): June 8, 2017

Study Registration Dates

• First Submitted: October 2, 2014
• First Submitted That Met QC Criteria: October 2, 2014
• First Posted (Estimate): October 6, 2014

Study Record Updates

• Last Update Posted (Actual): May 7, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab; Aflibercept
• Other Study ID Numbers: CRFB002ADE27

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No