Efficacy and Safety of Ranibizumab in Two "Treat and Extend" Treatment Algorithms Versus Ranibizumab As Needed in Patients With Macular Edema and Visual Impairment Secondary to Diabetes Mellitus (RETAIN)

A 2 Year Randomized, Single-masked, Multicenter, Controlled Phase IIIb Trial Assessing the Efficacy and Safety of 0.5 mg Ranibizumab in Two "Treat and Extend" Treatment Algorithms vs. 0.5 mg Ranibizumab As Needed in Patients With Macular Edema and Visual Impairment Secondary to Diabetes Mellitus

The purpose of this study is to demonstrate that two investigational treatment regimens have the potential to result in a superior visual acuity improvement as compared to a ranibizumab pro re nata (PRN=as needed) treatment regimen.

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: Ranibizumab

• Study Type: Interventional
• Enrollment (Actual): 373
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Kortrijk, Belgium, 8500
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Czech Republic
  • Hradec Kralove, Czech Republic, 505 05
    • Novartis Investigative Site
  • Olomouc, Czech Republic, 775 20
    • Novartis Investigative Site
  • Plzen, Czech Republic, 301 00
    • Novartis Investigative Site
  • Prague 2, Czech Republic, 128 08
    • Novartis Investigative Site
  • Praha 6, Czech Republic, 169 02
    • Novartis Investigative Site
• France
  • Bordeaux, France, 33 000
    • Novartis Investigative Site
  • Dijon, France, 21034
    • Novartis Investigative Site
  • Lille, France, 59 037
    • Novartis Investigative Site
  • Limoges Cedex, France, 87042
    • Novartis Investigative Site
  • Lyon, France, 69003
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Nice, France, 6 000
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Paris cedex 10, France, 75475
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 152 31
    • Novartis Investigative Site
  • Thessaloniki, Greece, 546 36
    • Novartis Investigative Site
  • Crete
    • Heraklion Crete, Crete, Greece, GR-71110
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1083
    • Novartis Investigative Site
  • Budapest, Hungary, 1133
    • Novartis Investigative Site
  • Debrecen, Hungary, 4012
    • Novartis Investigative Site
  • Gyor, Hungary, 9024
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland
    • Novartis Investigative Site
  • Dublin 7, Ireland
    • Novartis Investigative Site
  • Kilkenny, Ireland
    • Novartis Investigative Site
  • Limerick, Ireland
    • Novartis Investigative Site
• Italy
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
    • Milano, MI, Italy, 20157
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
    • Roma, RM, Italy, 00198
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Leiden 2333 ZA, Netherlands, 2333
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6525 EX
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3011 BH
    • Novartis Investigative Site
• Poland
  • Bielsko-Biala, Poland, 43-300
    • Novartis Investigative Site
  • Lublin, Poland, 20-954
    • Novartis Investigative Site
  • Warszawa, Poland, 00-416
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-367
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000-354
    • Novartis Investigative Site
  • Lisboa, Portugal, 1150-199
    • Novartis Investigative Site
  • Porto, Portugal, 4099-001
    • Novartis Investigative Site
• Spain
  • Las Palmas de Gran Canaria, Spain, 35016
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Andalucia
    • Málaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
  • Castilla y Leon
    • Valladolid, Castilla y Leon, Spain, 47011
      • Novartis Investigative Site
  • Cataluña
    • L'Hospitalet de Llobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03016
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46015
      • Novartis Investigative Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15705
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Novartis Investigative Site
  • Bern, Switzerland, 3012
    • Novartis Investigative Site
  • Binningen, Switzerland, 4102
    • Novartis Investigative Site
  • Zürich, Switzerland, 8063
    • Novartis Investigative Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Novartis Investigative Site
  • Bristol, United Kingdom, BS1 2LX
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • Sheffield, United Kingdom, S10 2JF
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Sunderland, United Kingdom, SR2 9HP
    • Novartis Investigative Site
  • Wolverhampton, United Kingdom, WV10 0QP
    • 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:

Patient

• Patients with Type 1 or Type 2 diabetes mellitus (according to American Diabetes Association or World Health Organization [WHO] guidelines) with glycosylated hemoglobin (HbA1c) ≤ 12.0% at screening (Visit 1). Patients should be on diet, exercise, and/or pharmacological treatment for diabetes. Treatment for diabetes must have been stable for at least 3 month.

Ocular

• Patients with visual impairment due to DME in at least one eye who are eligible for laser treatment in the opinion of the investigator. If both eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected by the investigator as the study eye.
• BCVA ≥ 39 and ≤78 letters in the study eye and, inclusively, using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/160) at screening.
• Concomitant conditions in the study eye are only permitted if, in the opinion of the investigator, they do not prevent improvement of visual acuity on study treatment.

Exclusion Criteria:

Patient Compliance/ Administrative

• Pregnant or nursing (lactating) women.

Ocular medical history

• Active intraocular inflammation (grade trace or above) in either eye at enrollment.
• Any active infection (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) in either eye at the time of enrollment.
• History of uveitis in either eye at any time.
• Structural damage within 0.5 disc diameter of the center of the macular in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema.
• Uncontrolled glaucoma in either eye at screening.

Prior Ocular treatments

• Panretinal laser photocoagulation in the study eye within 6 months prior to randomization.
• Focal/grid laser photocoagulation in the study eye within 3 months prior to randomization.
• Treatment with anti-angiogenic drugs in either eye.

Systemic conditions or treatments

• History of stroke within 6 months prior to enrollment.
• Renal failure requiring dialysis.
• Untreated diabetes mellitus.
• Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TE Ranibizumab 0.5 mg and Laser; On Day 1, all patients received an intravitreal injection with 0.5 mg ranibizumab and subsequently entered Phase A which comprised of monthly injections. Laser therapy was applied at Day 1. It could then be re-administered according to ETDRS criteria at any visit with 0.5 mg ranibizumab treatment if deemed necessary by the Treating Investigator with a minimal treatment interval between laser treatments of 3 months. Laser therapy was administered ≥ 30 minutes prior to the ranibizumab injection.	Drug: Ranibizumab; Ranibizumab (Lucentis®) was supplied in vials containing a dose of 0.5 mg/0.05 mL in an aqueous solution (pH 5.5) with histidine, trehalose, and polysorbate 20.
Experimental: TE Ranibizumab 0.5 mg alone; Patients received ranibizumab intravitreal injection therapy only.	Drug: Ranibizumab; Ranibizumab (Lucentis®) was supplied in vials containing a dose of 0.5 mg/0.05 mL in an aqueous solution (pH 5.5) with histidine, trehalose, and polysorbate 20.
Active Comparator: PRN Ranibizumab 0.5 mg; Patients received ranibizumab intravitreal injection therapy as needed according to signs and symptoms of disease.	Drug: Ranibizumab; Ranibizumab (Lucentis®) was supplied in vials containing a dose of 0.5 mg/0.05 mL in an aqueous solution (pH 5.5) with histidine, trehalose, and polysorbate 20.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Acuity of the Study Eye: Average Change From Baseline to Month 1 Through Month 12	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Acuity of the Study Eye: Average Change From Baseline to Month 1 Through Month 24	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline to Month 24
Visual Acuity of the Study Eye: Change From Baseline at Month 12	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline and Month 12
Visual Acuity of the Study Eye: Change From Baseline at Month 24	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline and Month 24
Visual Acuity of the Study Eye: Categorized Change From Baseline at Month 12	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline, Month 12
Visual Acuity of the Study Eye: Categorized Change From Baseline at Month 24	Visual acuity was assessed at every study visit for the study eye using best correction determined from protocol refraction. The BCVA measurements were taken in a sitting position using ETDRS-like VA testing charts at a starting distance of 4 meters.	Baseline, 24 month
Central Subfield Thickness of the Study Eye: Percent Change From Baseline at Month 12	High Resolution OCT was performed at every study visit by Spectral Domain OCT (if not available Time Domain OCT was acceptable) and the images were transferred to a digital video disc. These assessments were performed by trained and adequately qualified experts at the sites and prior to any study drug administration. CSFT is the average retinal thickness of the circular area with 1 mm diameter around the foveal center.	Baseline, Month 12
Central Subfield Thickness of the Study Eye: Percent Change From Baseline at Month 24	High Resolution OCT was performed at every study visit by Spectral Domain OCT (if not available Time Domain OCT was acceptable) and the images were transferred to a digital video disc. These assessments were performed by trained and adequately qualified experts at the sites and prior to any study drug administration. CSFT is the average retinal thickness of the circular area with 1 mm diameter around the foveal center.	Baseline and 24 month
Visual Functioning Questionnaire (VFQ-25) Change From Baseline in Total Score at Month 12 and Month 24	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure the influence of visual disability and symptoms on general health. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. For each, the patient was asked to rate their condition on a scale of 1-5 or 1-6, where a low number reflects a better outcome. Each response was recoded per the scoring rules outlined in the National Eye Institute (NEI) VFQ-25 Scoring Algorithm. Under this scoring algorithm , the recoded values range between 0 and 100 and a high score means a better functioning	Baseline, Month 12 and Month 24
EuroQoL (EQ-5D) Thermometer Score: Change From Baseline at Month 12 and Month 24	The Euro Quality of Life Questionnaire (EQ-5D) is an indirect utility questionnaire. It is a standardized instrument was utilized to measure health outcomes related to 5 dimensions, namely: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The possible range for each dimension was 1 to 3, where 1= "no problems", 2="some problems" and 3="extreme problems" . A composite health index was then defined by combining the levels for each dimension. Overall, 243 health states are possible. For each health state, the EuroQol group has assigned a utility value typically between 0 and 1 with lower scores representing a higher level of dysfunction	Baseline, Month 12 and Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Prunte C, Fajnkuchen F, Mahmood S, Ricci F, Hatz K, Studnicka J, Bezlyak V, Parikh S, Stubbings WJ, Wenzel A, Figueira J; RETAIN Study Group. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. 2016 Jun;100(6):787-95. doi: 10.1136/bjophthalmol-2015-307249. Epub 2015 Oct 9.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: July 27, 2010
• First Submitted That Met QC Criteria: July 27, 2010
• First Posted (Estimate): July 29, 2010

Study Record Updates

• Last Update Posted (Estimate): September 15, 2014
• Last Update Submitted That Met QC Criteria: September 10, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: ranibizumab; DME; RETAIN; Diabetic macula edema
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Endocrine System Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Sensation Disorders; Diabetes Mellitus; Macular Edema; 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: CRFB002D2304; 2010-019795-74 (EudraCT Number)