A Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients (RIVAL)

Development of New Geographic Atrophy in Patients With Neovascular (Wet) Age-related Macular Degeneration: a Comparison of Ranibizumab and Aflibercept

The purpose of this study was to compare the development of new geographic atrophy in patients with wet Age-related Macular Degeneration (AMD) when treated with either ranibizumab or aflibercept over 24 months. Geographic atrophy is an advanced form of AMD that can result in the progressive and irreversible loss of visual function over time.

Study Overview

• Status: Completed
• Conditions: Age-Related Macular Degeneration
• Intervention / Treatment: Drug: Ranibizumab 0.5 mg; Drug: Aflibercept 2.0 mg

Detailed Description

In each arm, patients underwent three monthly loading doses (at Baseline, Week 4, and Week 8). From Week 8, after the patient had received their third injection of study treatment, the visit intervals were determined by the patient's disease activity. If any of the protocol-specified signs of disease activity were present in the study eye, the subsequent injection visit interval was kept at 4 weeks. If none of the signs were present, the subsequent injection interval was extended by 2-week increments up until a maximum of 12-weekly intervals was reached. If there were any signs of disease activity in the study eye, the treatment interval was reduced as specified in the protocol. The planned individual duration of study participation was 24 months.

• Study Type: Interventional
• Enrollment (Actual): 281
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Novartis Investigative Site
    • Brookvale, New South Wales, Australia, 2100
      • Novartis Investigative Site
    • Chatswood, New South Wales, Australia, 2067
      • Novartis Investigative Site
    • Hurtsville, New South Wales, Australia, 2220
      • Novartis Investigative Site
    • Mona Vale, New South Wales, Australia
      • Novartis Investigative Site
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Strathfield, New South Wales, Australia, 2135
      • Novartis Investigative Site
    • Strathfield, New South Wales, Australia, 2035
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, Australia
      • Novartis Investigative Site
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Queensland
    • Caboolture, Queensland, Australia, 4510
      • Novartis Investigative Site
    • Redcliffe, Queensland, Australia, 4020
      • Novartis Investigative Site
    • South Brisbane, Queensland, Australia, 4101
      • Novartis Investigative Site
    • Southport, Queensland, Australia, 4215
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Tasmania
    • South Launceston, Tasmania, Australia, 7249
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
    • Malvern, Victoria, Australia, 3144
      • Novartis Investigative Site
    • Parkville,, Victoria, Australia, 3065
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
    • Subiaco, Western Australia, Australia, 6008
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

- Written informed consent.

Inclusion criteria specific to the study eye:

• Diagnosis of active subfoveal Choroidal Neovascularisation (CNV) secondary to wet Age-related Macular Degeneration (AMD);
• Best Corrected Visual Acuity (BCVA) score of 23 letters or more as measured by 3-metre Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts.

Exclusion criteria:

• Pregnant, nursing, or at risk of becoming pregnant during the study;
• Inability to comply with the study or follow-up procedures;
• Recent (3 months) stroke or myocardial infarction; uncontrolled hypertension; hypersensitivity to the study treatments or to fluorescein;
• In either eye: active periocular or ocular infection or inflammation; iris neovascularisation; uncontrolled or neovascular glaucoma; or one or more patch of geographic atrophy (GA) as specified in the protocol.

Exclusion criteria specific to the study eye:

• Prior or current treatment with anti-angiogenic drugs or corticosteroids;
• Other eye conditions as specified in the protocol;
• Any intraocular procedure carried out within 2 months before baseline or anticipated within 6 months following baseline.

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: Ranibizumab 0.5 mg; 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	Drug: Ranibizumab 0.5 mg; Administered as an intravitreal injection; Other Names: Lucentis
Active Comparator: Aflibercept 2.0 mg; 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	Drug: Aflibercept 2.0 mg; Administered as an intravitreal injection; Other Names: Eylea

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.	Baseline, Month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.	Baseline, Month 12
Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center. A patient was considered to have developed new GA if they did not have any GA at the start of the study period and were subsequently diagnosed with GA during the study period (diagnosis of GA change from "No" to "Yes)." The analysis of new GA development was restricted to only those subjects without GA reported at baseline. One eye (study eye) contributed to the analysis.	Baseline, Month 12, Month 24
Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24	The number of intravitreal injections was calculated. One eye (study eye) contributed to the analysis.	Baseline, Month 12, Month 24
Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. BCVA change was defined as a change in letters correctly identified from the baseline assessment. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis	Baseline, Month 12, Month 24
Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24	CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis	Baseline, Month 12, Month 24
Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF)	Intraretinal fluid and subretinal fluid was assessed using Optical Coherence Tomography (OCT) and recorded as Present/Absent. One eye (study eye) contributed to the analysis.	Month 2, Month 12, Month 24
Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Month 12, Month 24
Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Month 12, Month 24
Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months	The number of times the patient returned to a monthly injection interval (from an extended interval) at least once during the 24-month study was calculated. One eye (study eye) contributed to the analysis.	Month 24
Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment	Blood for VEGF plasma concentration analysis was collected at Baseline and again at 7 days after the injection at Week 4 and 7 days after the injection at Week 8.	Baseline, Week 5, Week 9
Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24	Retinal nerve fibre thickness was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change in value (i.e. thinner nerve fibre) indicates nerve damage. One eye (study eye) contributed to the analysis.	Baseline, Month 12, Month 24
Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells	Anterior cell grade was assessed by the Investigator during slit lamp examination and graded on a 5-point scale: Grade 0=0 cells; Grade 1=1 to 10 cells; Grade 2=11 to 20 cells; Grade 3=21 to 50 cells; Grade 4=>50 cells. The presence of blood cells (red and white) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. One eye (study eye) contributed to the analysis.	Baseline, Week 9
Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare	Anterior chamber flare was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. The presence of flare (increased protein levels) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. Proportion of patients is reported as a percentage. One eye (study eye) contributed to the analysis.	Baseline, Week 9

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2020 May 5;5(5):CD012208. doi: 10.1002/14651858.CD012208.pub2.
• Gillies MC, Hunyor AP, Arnold JJ, Guymer RH, Wolf S, Ng P, Pecheur FL, McAllister IL. Effect of Ranibizumab and Aflibercept on Best-Corrected Visual Acuity in Treat-and-Extend for Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial. JAMA Ophthalmol. 2019 Apr 1;137(4):372-379. doi: 10.1001/jamaophthalmol.2018.6776.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2014
• Primary Completion (Actual): November 15, 2017
• Study Completion (Actual): November 15, 2017

Study Registration Dates

• First Submitted: March 27, 2014
• First Submitted That Met QC Criteria: April 30, 2014
• First Posted (Estimate): May 2, 2014

Study Record Updates

• Last Update Posted (Actual): June 5, 2019
• Last Update Submitted That Met QC Criteria: February 28, 2019
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: AMD; Age-related macular degeneration; ranibizumab; aflibercept; wet AMD; geographic atrophy; inject and extend
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Pathological Conditions, Anatomical; Macular Degeneration; Geographic Atrophy; Atrophy; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab; Aflibercept
• Other Study ID Numbers: CRFB002AAU17

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