Table 3

Ranibizumab trials

StudyParticipants and baseline valuesInterventionOutcome (change from baseline at study end)
READ-2 Study (Nguyen et al)28 47 USA
Multicenter
Design: 3-arm RCT
Follow-up: 6 months, 2-year extension (no relevant outcomes as IVR received by all groups by that time, no safety outcomes for 2-year data)
N: 126 eyes of 126 patients
Inclusion criteria: ≥18 years, type 1 or 2 DM, DMO, BCVA 20/40-20/320, CMT ≥250 µm, HbA1c ≥6% within 12 months before randomisation; expectation that scatter laser photocoagulation not required for 6 months
Exclusion criteria: contributing causes to reduced BCVA other than DMO, focal/grid laser within 3 months, intraocular steroid within 3 months, intraocular VEGF antagonist within 2 months
Age: 62 years
Sex: 52–69% female
Diabetes type: not reported
HbA1c: 7.39–7.77%
Baseline VA: ETDRS letter score 24.85–28.35
Baseline CMT: excess foveal thickness 198.75–262.52 µm
Comorbidities: not reported
Group 1 (IVR, n=42 eyes): IV injections of 0.5 mg ranibizumab at baseline, 1, 3 and 5 months
Group 2 (L, n=42 eyes): focal/grid laser at baseline and 3 months if CMT ≥250 µm
Group 3 (IVRL, n=42 eyes): IV injections of 0.5 mg ranibizumab at baseline and 3 months, followed by focal/grid laser treatment 1 week later
Regimen for all groups: after 6 months, patients could receive IV injections of ranibizumab no more than every 2 months or focal/grid laser no more than every 3 months if CMT ≥250 µm
Laser Modified ETDRS protocol was used
At 6 months
BCVA (ETDRS):
BCVA (letters)p Value
IVR+7.240.0003 vs L
L−0.43
IVRL+3.80NS vs IVR or
L
Plus3 lines
IVR22%<0.05 vs L
L0
IVRL8%
CMT (OCT):
CMT (µm)p Value
IVR−106.3All <0.01 vs baseline, NS for elimination of ≥50% excess foveal thickness between groups
L−82.8
IVRL−117.2
READ-3 Study (Do et al) USA50
Design: phase 2, 2-arm RCT
Follow-up: 6 months
N: 152 eyes
Inclusion criteria: NR
Exclusion criteria: NR
Age: NR
Sex: NR
Diabetes type: NR
HbA1c: NR
Baseline VA: Mean BCVA Snellen equivalent 20/63 in the 2.0 mg group and 20/80 in the 0.5 mg group
Baseline CST (central subfield thickness): 432 µm in the 2.0 mg group and 441 µm in the 0.5 mg group
Comorbidities: NR
Group 1 (IVR2.0, n=NR): monthly injections
Group 2 (IVR0.5, n=NR): monthly injections
After month 6, eyes evaluated and additional ranibizumab injections given on an as needed basis if DMO still present on OCT.
At 6 months:
BCVA
 Mean BCVA letters gainp Value
IVR2.0+7.46NR
IVR0.5+8.69NR
CSTCST reduction
IVR2.0−163.86 µmNR
IVR0.5−169.27 µmNR
RESOLVE Study (Massin et al)36
Multicenter international
Design: 3-arm placebo-controlled RCT
Follow-up: 12 months
N: 151 eyes of 151 patients
Inclusion criteria: >18 years, type 1 or 2 DM, clinically significant DMO, BCVA 20/40–20/160, HbA1c <12%, decreased vision attributed to foveal thickening from DMO, laser photocoagulation could be safely withheld in the study eye for at least 3 months after randomisation
Exclusion criteria: unstable medical status, panretinal laser photocoagulation performed within 6 months before study entry, previous grid/laser photocoagulation except patients with only mild laser burns at least 1000 µm from the centre of the fovea performed >6 months previously
Age: 63–65 (range 32–85) years
Sex: 43.1–49% female
Diabetes type: 96.1–98% type 2 DM
HbA1c: 7.3–7.6 (range 5.3–11.1) %
Baseline VA: ETDRS letter score 59.2–61.2 SD9.0–10.2
Baseline CMT: 448.9–459.5 SD102.8–120.1 µm
Comorbidities: not reported
Group 1 (IVR0.3, n=51 eyes): 0.3 mg (0.05 ml) IV ranibizumab, 3 monthly injections (dose up to 0.6 mg, see below) Group 2 (IVR0.5, n=51 eyes): 0.5 mg IV (0.05 ml) ranibizumab, 3 monthly injections (dose up to 1.0 mg, see below)
Group 3 (C, n=49 eyes): sham treatment, 3 monthly injections
Regimen for all groups: after month 1, the injection dose could be doubled if CMT remained >300 µm or was >225 µm and reduction in retinal oedema from previous assessment was <50 µm; once injection volume was 0.1 ml it remained that for subsequent injections; if treatment had been withheld for >45 days, subsequent injections restarted at 0.05 ml; 68.6% of dose doubling with ranibizumab, 91.8% with sham; 34.7% of rescue laser photocoagulation in sham group, 4.9% in ranibizumab group
At 12 months
BCVA (ETDRS):
 BCVA (letters)p Value
IVR0.3+11.8 SD6.6<0.0001 vs C
IVR0.5+8.8 SD11.0<0.0001 vs C
C−1.4 SD14.2
Change10 letters
IVR0.3Gain 72.5%
loss 0
<0.0001 vs C
IVR0.5Gain 49%
loss 9.8%
0.001 vs C
CGain 18.4%
loss 24.5%
CMT (OCT):
CMT (µm)p Value
IVR0.3−200.7 SD122.2<0.0001 vs C
IVR0.5−187.6 SD147.8<0.0001 vs C
C−48.4 SD153.4
RESTORE Study (Mitchell et al)24 49
Multicenter international
Design: 3-arm RCT
Follow-up: 12 months
N: 345 eyes of 345 patients
Inclusion criteria: ≥18 years, type 1 or 2 DM, HbA1c ≤10%, visual impairment due to DMO (eligible for laser treatment), stable medication for management of diabetes, BCVA ETDRS letter score 39–78
Exclusion criteria: concomitant eye conditions that could affect VA, active intraocular inflammation or infection, uncontrolled glaucoma in either eye, panretinal laser photocoagulation within 6 months or focal/grid laser photocoagulation within 3 months prior to study entry, history of stroke, hypertension
Age: 62.9–64.0 SD8.15–9.29 years
Sex: 37.1–47.7% female
Diabetes type: 86.4–88.8% type 2 DM
HbA1c: not reported
Baseline VA: ETDRS letter score 62.4–64.8 SD9.99–11.11
Baseline CMT: 412.4–426.6 SD118.01–123.95
Comorbidities: not reported
Group 1 (IVR, n=116 eyes): 0.5 mg IV ranibizumab plus sham laser (median injections 7 (range 1–12), median sham laser treatments 2 (range 1–5))
Group 2 (IVRL, n=118 eyes): 0.5 mg IV ranibizumab plus active laser (median injections 7 (range 2–12), median laser treatments 1 (range 1–5))
Group 3 (L, n=111 eyes): laser treatment plus sham injections (median sham injections 7 (range 1–12), median laser treatments 2 (range 1–4))
Regimen for all groups: 3 initial monthly injections, followed by retreatment schedule; 1 injection per month if stable VA not reached;
Laser retreatments in accordance with ETDRS guidelines at intervals no shorter than 3 months from previous treatment
At 12 months
BCVA (ETDRS):
 BCVA (letters)p Value
IVR+6.1 SD6.43<0.0001 vs L
IVRL+5.9 SD7.92<0.0001 vs L
L+0.8 SD8.56
BCVA change categories
IVRPlus ≥10: 37.4%
Loss ≥10: 3.5%
<0.0001 vs L
IVRLPlus ≥10: 43.2%
Loss ≥10: 4.2%
<0.0001 vs L
LPlus ≥10: 15.5%
Loss ≥10: 12.7%
CMT (OCT):
CMT (µm)p Value
IVR−118.7 SD115.070.0002 vs L
IVRL−128.3 SD114.34<0.0001 vs L
L−61.3 SD132.29
REVEAL Study (Ohji and Ishibashi )48
Japan Multicenter
Design: phase III double-masked RCT
Follow-up: 12 months
N: 396 patients
Inclusion criteria: NR
Exclusion criteria: NR
Age: 61.1 years
Sex: NR
Diabetes type: 98.7% with type 2 diabetes
HbA1c: 7.5%
Baseline VA: 58.6 letters
Baseline CMT: 421.9 µm
Comorbidities: NR
Group 1 (IVR 0.5 + sham laser, n=133): day 1, month 1, 2 and pro-renata thereafter based on BCVA
Group 2 (IVR 0.5+ active laser, n=132): day 1, month 1, 2 and pro-renata thereafter based on BCVA
Group 3 (sham injection + active laser, n=131): day 1, month 1, 2 and pro-renata thereafter based on BCVA
Active/sham laser photocoagulation performed according to ETDRS guidelines at ≥3 month intervals
At 12 months
BCVA:
 Mean average change from baseline to months 1–12p Value
IVR+sham laser+5.9vs laser <0.0001
IVR+laser+5.7vs laser <0.0001
Laser+sham+1.4
Mean change from baseline to month12 in BCVA and CRT
IVR+sham laser+6.6; −148.0 µmvs C <0.0001
IVR+laser+6.4; −163.8 µmvs C <0.0001
Laser+sham+1.8; −57.1 µm
RISE Study (Brown et al/Nguyen et al)38 139
USA
Multicenter
Design: 3-arm double-blind sham-controlled RCT
Follow-up: 24 months
N: 377 eyes of 377 patients
Inclusion criteria: ≥18 years, type 1 or 2 diabetes, BCVA 20/40–20/320, DMO CMT ≥275 µm
Exclusion criteria: prior vitreoretinal surgery, recent history (within 3 months of screening) of panretinal or macular laser in the study eye, intraocular corticosteroids or antiangiogenic drugs, those with uncontrolled hypertension, uncontrolled diabetes (HbA1c >12%), recent (within 3 months) cerebrovascular accident or myocardial infarction
Age: 61.7–62.8 SD8.9–10.0 (range 21–87) years
Sex: 41.6–48% female
Diabetes type: type 1 or 2
HbA1c: 7.7% SD 1.4–1.5; ≤8% (65–68.3%); >8% (31.7%–35%)
Baseline VA: Mean ETDRS letter score 54.7–57.2; ≤20/200 (7.9–13.6%); >20/200 but <20/40 (72.4–72.8%); ≥20/40 (13.6–19.7%)
Baseline CMT: 463.8–474.5 µm
Comorbidities: History of smoking 46.4–51.2%
Group 1 (IVR0.3, n=125 eyes): 0.3 mg IV ranibizumab
Group 2 (IVR0.5, n=125 eyes): 0.5 mg IV ranibizumab
Group 3 (C, n=127 eyes): sham injection
Regimen for all groups: monthly injections; need for macular rescue laser assessed monthly starting at month 3
At 24 months
BCVA:  
 Plus15 lettersp Value
IVR0.344.8%<0.0001 vs C
IVR0.539.2%=0.0002 vs C
C18.1% 
Loss of <15 letters 
IVR0.397.6%=0.0086 vs C
IVR0.597.6%=0.0126 vs C
C89.8% 
Snellen equivalent of 20/40 or better 
IVR0.360%<0.0001 vs C
IVR0.563.2%<0.0001 vs C
C37.8% 
Mean BCVA gain (letters) 
IVR0.3+12.5 SD14.1<0.0001 vs C
IVR0.5+11.9 SD12.1<0.0001 vs C
C+2.6 SD13.9
CFT:
Mean change from baselinep Value
IVR0.3−250.6 SD212.2<0.0001 vs C
IVR0.5−253.1 SD183.7<0.0001 vs C
C−133.4 SD209.0
RIDE study (Boyer et al/Nguyen et al)38 140
USA
Multicentre
Design: 3-arm double-blind sham-controlled RCT
Follow-up: 24 months
N: 382 eyes
Inclusion criteria: ≥18 years, type 1 or 2 diabetes, BCVA 20/40–20/320 and DMO CMT ≥275 µm
Exclusion criteria: prior vitreoretinal surgery, recent history (within 3 months of screening) of panretinal or macular laser in the study eye, intraocular corticosteroids or antiangiogenic drugs, those with uncontrolled hypertension, uncontrolled diabetes (HbA1c >12%), recent (within 3 months) cerebrovascular accident or myocardial infarction
Age: 61.8–63.5 (range 22–91) years
Sex: 37–49.1% female
Diabetes type: type 1 or 2
HbA1c: 7.6 SD1.3–1.5; ≤8% (65.8–67.5%); >8% (32.5–34.2%)
Baseline VA: Mean ETDRS letter score 56.9–57.5
Baseline CMT: 447.4–482.6 µm
Comorbidities: history of smoking 33.6–51.6%
Group 1 (IVR0.3, n=125 eyes): 0.3 mg IV ranibizumab
Group 2 (IVR0.5, n=127 eyes): 0.5 mg IV ranibizumab
Group 3 (C, n=130 eyes): sham injection
Regimen for all groups: Patients were eligible for rescue macular laser starting at month 3
At 24 months
BCVA:
 More than 15 lettersp Value
IVR0.333.6%<0.0001 vs C
IVR0.545.7%<0.0001 vs C
C12.3%
Less than 15 letters
IVR0.31.6%>0.05 vs C
IVR0.53.9%<0.05 vs C
C8.5%
Snellen equivalent of 20/40 or better
IVR0.354.4%=0.0002 vs C
IVR0.562.2%<0.0001 vs C
C34.6%
Mean BCVA gain (letters)
IVR0.3+10.9 SD10.4<0.0001vs C
IVR0.5+12.0 SD14.9<0.0001 vs C
C+2.3 SD14.2
CMT:
Mean change from baselinep Value
IVR0.3−259.8 SD169.3<0.0001 vs C
IVR0.5−270.7 SD201.6<0.0001 vs C
C−125.8 SD198.3
  • Injections are intravitreal unless otherwise noted.

    BCVA, best corrected visual acuity; C, control; CMT, central macular thickness; CSME, clinically significant macular oedema; DDS, dexamethasone; DIL, dexamethasone followed by laser; DM, diabetes mellitus; DMO, diabetic macular oedema; DP, diastolic pressure; DR, diabetic retinopathy; HR QoL, health-related quality of life; IOP, intraocular pressure; IV, intravitreal; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; IVR, intravitreal ranibizumab; IVT, intravitreal triamcinolone; IVTL, intravitreal triamcinolone plus laser; IVVTE, intravitreal VEGF Trap Eye; L, laser; MLT/MPC, macular laser therapy/macular photocoagulation; NEI VFQ-25, National Eye Institute Visual Function Questionnaire-25; NPDR, non-proliferative diabetic retinopathy; NR, not reported; OCT, optical coherence tomography; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; RCT, randomised controlled trial; SOC, standard of care; SP, systolic pressure; SRFA, fluocinolone; VA, visual acuity; VEGF, vascular endothelia growth factor.