Safety and Efficacy of Switching From Aflibercept to Ranibizumab in Patients With nAMD (SAFARI)

A Phase IV, Prospective, Open-label, Uncontrolled, European Study in Patients With Neovascular Age-related Macular Degeneration (nAMD), Evaluating the Efficacy and Safety of Switching From Intravitreal Aflibercept to Ranibizumab 0.5mg.

AMD (Age Related Macular Degeneration) is the leading cause of severe visual loss and blindness registration in the UK . It is a disease which affects the retina (the nerve and blood vessel network at the back of the eye responsible for vision). Patients can suffer with severe visual loss and have difficulties with every day tasks such as recognising faces, reading & driving.

There are two variations of the disease, a 'dry' type & a 'wet' type also known as neovascular AMD (nAMD). In wet/nAMD new vessels grow from the blood supply underneath the retina, in part due to higher than normal levels of a protein called Vascular Endothelial Growth Factor (VEGF). Since the introduction of drugs which block VEGF, visual outcomes for patients with wAMD have dramatically improved.

There are 2 widely used treatments; ranibizumab and aflibercept. Whilst the majority of patients have a successful outcome with treatment, many patients experience suboptimal response. This study evaluated if these patients experience a benefit from a switch to a different antiVEGF drug treatment.

In this study nAMD patients who are showing no or poor to response to treatment with aflibercept were switched to ranibizumab to assess if there is any benefit in terms of treatment outcomes.

Patients visited the hospital clinic 8 times over the 7 - 8 month study period. Monthly ranibizumab injections were given for the first 3 months, then monthly as required for the next 3 months.

Study Overview

• Status: Completed
• Conditions: Neovascular Age-related Macular Degeneration
• Intervention / Treatment: Drug: Ranibizumab

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53127
    • Novartis Investigative Site
  • Karlsruhe, Germany, 76135
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Mühlheim, Germany, 45468
    • Novartis Investigative Site
  • München, Germany, 80336
    • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Novartis Investigative Site
  • East Kilbride, United Kingdom, G75 8RG
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 OYN
    • Novartis Investigative Site
  • Great Yarmouth, United Kingdom, NR31 6LA
    • Novartis Investigative Site
  • Harrogate, United Kingdom, HG2 7SX
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • London, United Kingdom, EC1V 2PD
    • Novartis Investigative Site
  • London, United Kingdom, NW1 5QH
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 9DU
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Sunderland, United Kingdom, SR2 9HP
    • Novartis Investigative Site
  • Uxbridge, United Kingdom, UB8 3NN
    • Novartis Investigative Site
  • York, United Kingdom, YO31 8HE
    • Novartis Investigative Site
  • Durham
    • Darlington, Durham, United Kingdom, DL3 6HX
      • Novartis Investigative Site
  • Essex
    • Harlow, Essex, United Kingdom, CM20 1QX
      • Novartis Investigative Site
  • Kent
    • Canterbury, Kent, United Kingdom, CT1 3NG
      • Novartis Investigative Site
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Novartis Investigative Site
  • Suffolk
    • Ipswich, Suffolk, United Kingdom, IP4 5PD
      • Novartis Investigative Site
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • Novartis Investigative Site
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom, BD9 6RJ
      • 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:

• Best corrected visual acuity (BCVA) ≥23 ETDRS letters in study eye
• Evidence of active choroidal neovascularisation (CNV) involving the center of the fovea in study eye Patient subgroup specific inclusion criteria: - Group 1. Primary treatment failure
• Initiated treatment with aflibercept <130 days prior to the Screening Visit.
• No increase in BCVA (≥5 letters) since commencing treatment with aflibercept.
• Disease activity has never been controlled in the study eye after initiating aflibercept as defined by at least one of the following: evidence of unchanged or increasing retinal or subretinal fluid; new PED; unchanged or increasing size of preexisting PED.

Group 2. Suboptimal treatment response

• Aflibercept commenced ≥6 months prior to the Screening Visit.
• Received ≥3 aflibercept injections into the study eye within 6 months of the Screening Visit.
• Evidence of previous reduced disease activity (as defined by reduction of ≥50μm in Central Subfield Retinal Thickness on OCT) noted in the study eye after initiating aflibercept.
• At Screening Visit, disease activity has worsened (as defined by increasing retinal* or subretinal fluid, or new or increasing size of PED) in the study eye compared to prior visits.

Exclusion Criteria:

• History of cerebrovascular accident, transient ischemic attack or myocardial infarction within 3 months of the Screening visit.
• Uncontrolled blood pressure
• Evidence of bilateral active CNV during the Screening Period or at Baseline requiring bilateral antiVEGF injections.
• Prior intravitreal injection of ranibizumab or bevacizumab into the study eye and/or prior intravitreal injection of bevacizumab into the fellow eye.
• Cataract (if causing significant visual impairment), aphakia, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization of any other cause than wet AMD (e.g. ocular histoplasmosis, pathologic myopia (≥8 dioptres)) at the time of Screening and Baseline.
• Irreversible structural damage involving the center of the fovea (e.g. advanced fibrosis or geographic atrophy) which in the opinion of the Investigator is sufficient to irreversibly impair visual acuity.
• Polypoidal choroidal vasculopathy (PCV), RPE tear, central serous retinopathy (CSR), or significant vitreomacular traction identified during Screening period or within 4 months of Baseline visit.
• Unable to obtain at Screening OCT images of sufficient quality to be analyzed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ranibizumab; All patients received 3 monthly intraveal injections of 0.5mg ranibizumab followed by monthly injections of ranibizumab 0.5mg for a further 3 months on a prn (as required) basis, as determined by the study doctor.	Drug: Ranibizumab; Intraveal injections of 0.5mg ranibizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Central Subfield Retinal Thickness (CSRT) From Baseline to Day 90.	Measurement of the change in CSRT, determined by high definition optical coherence tomography (HD-OCT) after 3 monthly injections of ranibizumab. OCT is a non-invasive technique which can determine and measure thickness of the retina. A negative change from Baseline indicates an improvement (less retinal fluid and lower disease activity). Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Subfoveal Retinal Thickness (SRT) From Baseline to Day 180	Measurement of change in SRT from Baseline to Day 180 as determined by high definition optical coherence tomography (HD-OCT). A reduction indicates an improvement in overall disease activity. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Central Subfield Retinal Thickness (CSRT) From Baseline to Day 180	Measurement of change in CSRT from Baseline to Day 180 as determined by high definition optical coherence tomography (HD-OCT). A reduction indicates an improvement in overall disease activity. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Central Subfield Retinal Volume (CSRV) From Baseline to Day 180	Measurement of change in CSRV from Baseline to Day 180 as determined by high definition optical coherence tomography (HD-OCT). A reduction indicates an improvement in overall disease activity. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Number of Patients With Intraretinal Fluid Assessed at Baseline and Day 180	Presence or absence of qualitative OCT parameter Intraretinal Fluid. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Number of Patients With Subretinal Fluid Assessed at Baseline and Day 180	Presence or absence of qualitative OCT parameter Subretinal Fluid. Data collected on the study eye were used for the evaluation of efficacy.	Baseline to Day 180
Number of Patients With Intraretinal/Subretinal Fluid Within the Central Subfield Fluid Assessed at Baseline and Day 180	Presence or absence of qualitative OCT parameter Intraretinal/Subretinal Fluid Within the Central Subfield. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Number of Patients With Pigment Epithelial Detachments Assessed at Baseline and Day 180	Presence or absence of qualitative OCT parameter Pigment Epithelial Detachments. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Number of Patients With Dry Retina Assessed at Baseline and Day 180	Presence or absence of qualitative OCT parameter Dry Retina. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Maximum PED Height From Baseline to Day 180	Change from Baseline to Day 180 in Maximum Pigment Epithelial Detachment (PED) Height. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Maximum PED Diameter From Baseline to Day 180	Change from Baseline to Day 180 in Maximum Pigment Epithelial Detachment (PED) Diameter. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Maximum IRC Height From Baseline to Day 180	Change from Baseline to Day 180 in Maximum Intraretinal Cyst (IRC) Height. Data collected on the study eye were used for the evaluation of efficacy.	Baseline and Day 180
Change in Best Corrected Visual Acuity (BCVA) in the Study Eye	BCVA was assessed as letters read and measured in a sitting position using subjective refraction and Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at an initial testing distance of 4 meters.	Baseline, Day 90 and Day 180
Change in ETDRS Letters for Study Eye From Baseline to Day 180	Number of patients gaining at least 15 letters from Baseline to Day 180	Baseline and Day 180
Incidence of Ocular TEAEs in the Study Eye Reported by ≥2% Patients From Baseline to Day 180	Incidence of ocular Treatment Emergent Adverse Events (TEAEs) in the study eye reported by ≥2% patients by preferred term.	Baseline to Day 180

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Gale RP, Pearce I, Eter N, Ghanchi F, Holz FG, Schmitz-Valckenberg S, Balaskas K, Burton BJL, Downes SM, Eleftheriadis H, George S, Gilmour D, Hamilton R, Lotery AJ, Patel N, Prakash P, Santiago C, Thomas S, Varma D, Walters G, Williams M, Wolf A, Zakri RH, Igwe F, Ayan F. Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study. Br J Ophthalmol. 2020 Apr;104(4):493-499. doi: 10.1136/bjophthalmol-2019-314251. Epub 2019 Aug 5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 28, 2014
• Primary Completion (ACTUAL): September 14, 2017
• Study Completion (ACTUAL): September 14, 2017

Study Registration Dates

• First Submitted: June 10, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (ESTIMATE): June 11, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 15, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: AMD; Macular degeneration; vision loss; wet macular degeneration; age-related macular degeneration (ARMD); macula damage; retina damage; dry macular degeneration
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Wet Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002AGB17; 2014-001085-10 (EUDRACT_NUMBER)

Drug and device information, study documents

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