Ranibizumab Intravitreal Injections in Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion (CRYSTAL)

A 24-month, Phase IIIb, Open-label, Single Arm, Multicenter Study Assessing the Efficacy and Safety of an Individualized, Stabilization-criteria-driven PRN Dosing Regimen With 0.5-mg Ranibizumab Intravitreal Injections Applied as Monotherapy in Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal

The present study provided additional efficacy and safety data for 0.5-mg ranibizumab using as needed (PRN) dosing over 24 months in patients with visual impairment due to macular edema secondary to Central Retinal Vein Occlusion (CRVO). Spectral domain high-definition optical coherence tomography (OCT) images was analyzed to gain insights into predictive factors for disease progression and the possibility of reduced monitoring was assessed in Year 2. The results of this open-label study provided long-term safety and efficacy data to further guide recommendations on the use of ranibizumab in this indication.

Study Overview

• Status: Completed
• Conditions: Central Retinal Vein Occlusion; Macular Edema
• Intervention / Treatment: Drug: Ranibizumab 0.5 mg/0.05 ml

• Study Type: Interventional
• Enrollment (Actual): 357
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Linz, Austria, 4021
    • Novartis Investigative Site
  • Wien, Austria, 1090
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2H0C8
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Novartis Investigative Site
    • Victoria, British Columbia, Canada, V8V 4X3
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • Novartis Investigative Site
  • Quebec
    • Boisbriand, Quebec, Canada, J7H 1S6
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
• Czech Republic
  • Olomouc, Czech Republic, 775 20
    • Novartis Investigative Site
  • Praha 10, Czech Republic, 100 34
    • Novartis Investigative Site
• Denmark
  • Glostrup, Denmark, DK-2600
    • Novartis Investigative Site
• Greece
  • Patras, Greece, 26504
    • Novartis Investigative Site
  • Thessaloniki, Greece, GR 54636
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 124 62
      • Novartis Investigative Site
    • Heraklion Crete, GR, Greece, 711 10
      • Novartis Investigative Site
    • Larissa, GR, Greece, 411 10
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 546 29
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
  • Budapest, Hungary, 1133
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland
    • Novartis Investigative Site
  • Dublin 7, Ireland
    • Novartis Investigative Site
• Italy
  • Udine, Italy, 33100
    • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00144
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10122
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081
    • Novartis Investigative Site
  • Leiden 2333 ZA, Netherlands, 2333
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6525 GA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3011 BH
    • Novartis Investigative Site
  • Tilburg, Netherlands, 5022 GC
    • Novartis Investigative Site
• Poland
  • Bielsko-Biala, Poland, 43-300
    • Novartis Investigative Site
  • Gdansk, Poland, 80-809
    • Novartis Investigative Site
  • Kraków, Poland, 31-501
    • Novartis Investigative Site
  • Lublin, Poland, 20-079
    • Novartis Investigative Site
  • Warszawa, Poland, 02-005
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-556
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000-354
    • Novartis Investigative Site
  • Coimbra, Portugal, 3030-163
    • Novartis Investigative Site
  • Lisboa, Portugal, 1349-019
    • Novartis Investigative Site
  • Lisboa, Portugal, 1050-085
    • Novartis Investigative Site
  • Porto, Portugal, 4099-001
    • Novartis Investigative Site
  • Porto, Portugal, 4200-319
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • Novartis Investigative Site
  • Bratislava, Slovakia, 826 06
    • Novartis Investigative Site
  • Slovak Republic
    • Zilina, Slovak Republic, Slovakia, 010 01
      • Novartis Investigative Site
• Spain
  • Castilla y Leon
    • Valladolid, Castilla y Leon, Spain, 47011
      • Novartis Investigative Site
  • Cataluña
    • Barcelona, Cataluña, Spain
      • Novartis Investigative Site
    • Barcelona, Cataluña, Spain, 08022
      • Novartis Investigative Site
    • L´Hospitalet de Llobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03016
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46015
      • Novartis Investigative Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
  • Pais Vasco
    • Bilbao, Pais Vasco, Spain, 48006
      • Novartis Investigative Site
• Sweden
  • Örebro, Sweden, 701 85
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3012
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1007
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8063
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Novartis Investigative Site
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Bristol, United Kingdom, BS1 2LX
    • Novartis Investigative Site
  • Hull, United Kingdom, HU3 2JZ
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L69 3GA
    • Novartis Investigative Site
  • London, United Kingdom, EC1V 2PD
    • Novartis Investigative Site
  • London, United Kingdom, NW1 5QH
    • Novartis Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • Plymouth, United Kingdom, PL4 6PL
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • 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:

• Male or female patients ≥ 18 years of age
• Diagnosis of visual impairment exclusively due to ME secondary to CRVO
• BCVA score at Screening and Baseline between 73 and 19 letters Early Treatment Diabetic Retinopathy Study (ETDRS), inclusively (approximate Snellen chart equivalent of 20/40 and 20/400)

Exclusion Criteria:

• Uncontrolled blood pressure defined as systolic value of > 160 mm Hg or diastolic value of > 100 mm Hg at Screening or Baseline.
• Any active periocular or ocular infection or inflammation at Screening or Baseline in either eye
• Uncontrolled glaucoma at Screening or Baseline or diagnosed within 6 months before Baseline in either eye
• Use of any systemic antivascular endothelial growth factor (anti-VEGF) drugs within 6 months before Baseline (eg, sorafenib [Nexavar®], sunitinib [Sutent®], bevacizumab [Avastin®])

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ranibizumab arm; Intravitreal injection with standard dose of 0.5 mg/0.05mL PRN

Drug: Ranibizumab 0.5 mg/0.05 ml; Patients will receive the first dose at Baseline, as an intravitreal injection with a standard dose of 0.5 mg/0.05 ml. Patients will receive at least 3 study treatments at monthly intervals (Day 1, Month 1 and Month 2). The last mandatory dose during treatment initiation will be administered approximately 60 days after the first study treatment. If there is no improvement in VA over the course of the first 3 injections, continued treatment is not recommended and the patient may receive alternative treatment at the investigator's discretion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Best Corrected Visual Acuity (BCVA) at Month 12 Compared to Baseline	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement	Baseline to month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Best Corrected Visual Acuity (BCVA) at Month 24 Compared to Baseline	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement	Baseline to Month 24
Mean Average Change in Best Corrected Visual Acuity (BCVA From Baseline Month 12 and Month 24	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Mean Average Change: for each patient, first average change is calculated as the average of the changes from baseline to Month 1 over Month 12 (or Month 24). Then, mean average change is calculated as the average of average changes across all patients.	Baseline and Month 1 to 12 or Month 24
Mean Average Change in BCVA From First Treatment Interruption (Due to BCVA Stabilization) to Month 12 and Month 24	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Stability in visual acuity after treatment interruption indicates longer duration of the drug efficacy	Month 12 and Month 24
Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye	BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters of visual acuity at month 12 as compared with baseline	Month 12 and Month 24
Number of Patients With a BCVA Value of ≥ 73 Letters (Approximate 20/40 Snellen Chart Equivalent) at Month 12 and Month 24	Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at month 12 and month 24 indicates a positive outcome.	Month 12 and Month 24
Mean Change in Central Reading Center (CRC)-Assessed Central Subfield Thickness (CSFT) From Month 12 and Month 24 Compared to Baseline	Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation	Baseline, Month 12 and Month 24
Mean Change in Patient-reported Outcomes in NEI-VFQ-25 Composite and Subscale Scores at Month 12 and Month 24 Compared to Baseline	The survey consists of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranges from 0 (worst) to 100 which indicates the best possible response. The composite score and score of each of each construct also range from 0 to 100 as they are calculated as total scores divided by the number of questions. The higher the values of total scores represent better outcome. Scores per visit and of the change descriptively by visit.	Month 12 and Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Pawloff M, Bogunovic H, Gruber A, Michl M, Riedl S, Schmidt-Erfurth U. SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES. Retina. 2022 May 1;42(5):831-841. doi: 10.1097/IAE.0000000000003385.
• Larsen M, Waldstein SM, Priglinger S, Hykin P, Barnes E, Gekkieva M, Das Gupta A, Wenzel A, Mones J; CRYSTAL Study Group. Sustained Benefits from Ranibizumab for Central Retinal Vein Occlusion with Macular Edema: 24-Month Results of the CRYSTAL Study. Ophthalmol Retina. 2018 Feb;2(2):134-142. doi: 10.1016/j.oret.2017.05.016. Epub 2017 Sep 9.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: February 14, 2012
• First Submitted That Met QC Criteria: February 16, 2012
• First Posted (Estimate): February 17, 2012

Study Record Updates

• Last Update Posted (Estimate): October 27, 2016
• Last Update Submitted That Met QC Criteria: September 21, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Ranibizumab; Central Retinal Vein Occlusion; Ophthalmology
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Degeneration; Retinal Diseases; Embolism and Thrombosis; Venous Thrombosis; Thrombosis; Macular Degeneration; Sensation Disorders; Macular Edema; Retinal Vein Occlusion; Edema; Vision, Low; Vision Disorders; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002E2401; 2011-002350-31 (EudraCT Number)