Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE
2012 · paper · Clinical trials
Two randomized, sham-controlled trials (RISE and RIDE) of monthly ranibizumab injections in about 760 patients with diabetic macular edema. At 24 months, significantly more treated patients gained 15 or more letters of vision than sham patients, with low rates of eye and systemic harm.
1 finding
Substance Table 2, RIDE 0.5 mg (n = 127), '>20/200 but <20/40, n (%)' printed as "91 (71.1)"; 91/127 = 71.7%.
- p. 4 Table 2, row '>20/200 but <20/40, n (%)', RIDE 0.5 mg column (n = 127)
91 (71.1)
Judge's note: Page image shows 91 (71.1). The column's three counts 11+91+25 add up to 127, and the other two percentages (8.7, 19.7) match n = 127. The Table 2 footnote changes n to 126 only for the CSME-duration row, and 91/126 = 72.2% would not match either. Other cells with the same count are correct (91/125 = 72.8; RIDE 0.3 mg 92/125 = 73.6).
Second check: another model agreed
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8 minor (typos and the like; most checked by the judge only)
Wording Results text says Snellen ≥20/40 at month 24 had "P<0.0001 for each ranibizumab group vs sham; Table 5; Fig 3", but Fig 3F prints P = 0.0002 for RIDE 0.3 mg vs sham.
- p. 5 Results, Visual Acuity Outcomes
P<0.0001 for each ranibizumab group vs sham; Table 5; Fig 3
- p. 6 Figure 3F (RIDE, Snellen equivalent of 20/40 or better), sham vs 0.3 mg bracket
P = 0.0002
- p. 1 Abstract, Results
39.2% of 0.5-mg ranibizumab patients (P<0.001;
Judge's note: Page 5 text (Visual Acuity Outcomes) and Fig 3F on p.6 are the same endpoint, population and timepoint. The caption says the P values come from the stratified CMH test, the procedure the methods name for binary endpoints. The text cites Fig 3, which shows P = 0.0002 for sham vs 0.3 mg in RIDE, and that is not <0.0001. The result stays significant, so this is a wording-level misstatement. Table 5 (online) is not in the files. The second reviewer's point (abstract P<0.001 for the RISE 0.5-mg primary endpoint vs Fig 3A P = 0.0002) is consistent and is not a defect.
Second check: another model agreed
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Wording Discussion: "this was accomplished in two 12-month controlled studies,9,10 which demonstrated that ranibizumab … is superior to laser alone with respect to VA outcomes over ≤2 years". The time frame of the two cited 12-month studies does not clearly match the claim of up to 2 years, and ref 11 (the 2-year follow-up) is not cited here.
- p. 11 Discussion, para 2 (end)
was accomplished in two 12-month controlled studies,9,10
- p. 11 Discussion, para 2 (end)
laser alone with respect to VA outcomes over ≤2 years
- p. 11 Discussion, penultimate paragraph
two 12-month controlled studies,9,10
- p. 11 Discussion, same sentence
is superior to laser alone with respect to VA outcomes over 2 years
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: whether ref 10 (Protocol I, Ophthalmology 2010) itself reports any 2-year data. The page image (main-p011.png, crop C017-a) prints "over ≤2 years". The text layer dropped the "≤", so the reviewer readings of a flat "over 2 years" are an extraction artefact. The "≤" hedges the claim. Still, calling refs 9,10 "12-month controlled studies" while crediting them with results over up to 2 years is unclear. The 2-year Protocol I report is ref 11 ("Expanded 2-year follow-up…"), which is not cited in this sentence. The Introduction (p.2) cites superiority to laser "at 6 months and … at 12 months" (refs 9,10,19,20). This is minor wording/citation ambiguity for the authors to clarify.
Second check: another model agreed
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Wording Results text says more RISE 0.3-mg patients "had a BCVA <20/200", but the Table 2 category it cites is "≤20/200".
- p. 5 Results, first paragraph
group had a BCVA <20/200
- p. 4 Table 2 row label
≤20/200, n (%)
Judge's note: Page 5 image shows '<20/200' in the text. Page 4 Table 2 has only a '≤20/200, n (%)' row (17 [13.6] in RISE 0.3 mg) and no strict '<20/200' category.
Second check: another model agreed
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Wording Discussion says "deaths and CVAs were numerically higher in ranibizumab groups (CVAs, 1.6% of sham and 0.8%–4.0% of ranibizumab patients…)", but in Table 13 RISE 0.3 mg had fewer CVAs than sham (1 [0.8%] vs 2 [1.6%]) and RIDE 0.3 mg had the same number (2 [1.6%] vs 2 [1.6%]).
- p. 10 Discussion, para 3 (below Table 13)
Although deaths and CVAs were numeri-cally higher in ranibizumab groups (CVAs, 1.6% of sham and 0.8%–4.0% of ranibizumab patients
- p. 10 Table 13, 'CVA, overall' row
CVA, overall
Judge's note: Checked Table 13 on p.10 (main-p010.png). CVA, overall: RISE sham 2 (1.6), 0.3 mg 1 (0.8), 0.5 mg 5 (4.0); RIDE sham 2 (1.6), 0.3 mg 2 (1.6), 0.5 mg 3 (2.4). So CVAs were higher only in the two 0.5-mg groups. Pooled across all ranibizumab groups the rate (11/499, about 2.2%) is above sham (4/250, 1.6%), and the sentence itself prints the range 0.8%–4.0%, so a reader can see the facts. The deaths figures (0.8%/1.6% sham vs 2.4%–4.8% ranibizumab) match the table. This is wording that overstates the CVA pattern, not a wrong number.
Second check: another model agreed
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Typo Table 4, RISE 0.3 mg, difference vs sham in proportion receiving macular laser: "−35.0 (−46.4 to −23.7%)" has a stray % sign that the other difference cells do not have.
- p. 4 Table 4, RISE 0.3 mg, difference vs sham in proportion receiving laser
−35.0 (−46.4 to −23.7%)
- p. 4 Table 4 (page image)
(−46.4 to −23.7%)
Judge's note: Page image p.4 shows the % sign after −23.7 in this cell only; the cells −39.3 (−50.7 to −28.0) etc. have none. The second reviewer's claim that the bounds are reversed comes from the text layer losing the minus signs: the image shows −46.4 to −23.7, which is correctly ordered.
Second check: code check
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Typo Figure 3 caption: "are in Table 2, Vertical bars are 95% confidence intervals" has a comma where a full stop should end the sentence.
- p. 6 Figure 3 caption
are in Table 2, Vertical bars are 95% confidence intervals
- p. 6 Figure 3 caption
are in Table 2, Vertical bars
Judge's note: The crop of the caption on p.6 shows the comma, followed by the capitalised 'Vertical', which starts a new sentence.
Second check: none (judge only)
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Typo Figure 4B y-axis label reads "Meanchange in CFT, µm" with no space between 'Mean' and 'change'.
- p. 7 Figure 4B y-axis label
Meanchange in CFT, µm
Judge's note: In the p.7 page image, panel B's axis label appears run together as 'Meanchange', while panel A reads 'Mean change in visual acuity'. This is cosmetic.
Second check: none (judge only)
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Typo Discussion prints "endophthalmitis rates (4/10; 584 injections)", where a semicolon has replaced the thousands space in 10 584.
- p. 9 Discussion, paragraph on ocular safety
endophthalmitis rates (4/10; 584 injections)
- p. 7 Results, Ocular Harm
out of 10 584 intravitreal injections
Judge's note: The p.9 crop shows the semicolon. Results on p.7 gives '10 584 intravitreal injections', and Table 9 has 1+1+2 = 4 endophthalmitis cases, so the intended figure is 4/10 584.
Second check: none (judge only)