Macugen 2005

Methods	Parallel group RCT One eye per person, chosen by participant and physician. In 81% of cases the eye with the worse VA was chosen
Participants	Country: USA Number of people randomised: 172 (172 eyes) Average age: 62 years (range 27 to 89) Sex: 49% women Inclusion criteria: 18 years or older diabetes (study eyes) macular oedema involving the centre of the macula demonstrated on OCT with corresponding leakage from microaneurysms, retinal telangiectasis, or both on fluorescein angiography an area of retinal thickening of at least half a disc area involving the central macula as confirmed by graders at an independent fundus photograph and angiogram reading center (University of Wisconsin, Madison, Wisconsin) clear ocular media and adequate pupillary dilation to permit good stereoscopic fundus photographs (participants) BCVA letter scores between 68‐25 inclusive (approximate Snellen equivalent, 20/50–20/320) in the study eye and at least 35 (20/100 or better) in the fellow eye IOP ≤ 23 mmHg assessment by the treating ophthalmologist that focal photocoagulation could be deferred safely for 16 weeks an electrocardiogram that demonstrated no abnormalities judged to be clinically relevant and serological test results that suggested no clinically meaningful haematological, liver, or renal abnormalities women enrolling in the study were required to be postmenopausal for 12 months before the study, surgically sterile, or not pregnant and on 2 forms of effective contraception Exclusion criteria: history of PRP or focal photocoagulation neodymium:yttrium–aluminum–garnet laser or peripheral retinal cryoablation within the previous 6 months any abnormality thought likely to confound VA assessments or fundus photography, including cataract; vitreoretinal traction within 1 disc diameter of the fovea confirmed either clinically or on OCT vitreous incarceration in a previous wound or incision any retinal vein occlusion involving the macula; and atrophy/scarring/fibrosis or hard exudates involving the centre of the macula that would preclude improvement in VA a history of any intraocular surgery within the previous 12 months, myopia of ≥ 8 dioptres, axial length of ≥ 25 mm, and the likelihood of requiring either scatter (panretinal) photocoagulation within the ensuing 9 months or cataract surgery within 12 months active ocular or periocular infection previous therapeutic radiation to the eye, head, or neck any treatment with an investigational agent for any condition in the 60 days before enrolment. Known serious allergies to fluorescein dye glycosylated haemoglobin (GHb) levels of ≥ 13% 3 episodes of severe hypoglycaemia within 3 months of study entry 2 episodes of ketoacidosis within 1 year of baseline any episode of ketoacidosis within 3 months of baseline evidence of severe cardiac disease clinically significant peripheral vascular disease (previous surgery, amputation, or symptoms of claudication) uncontrolled hypertension (treated systolic BP 155 or diastolic BP 95), or stroke within the preceding 12 months
Interventions	Intervention: pegaptanib (0.3 mg, 1 mg, or 3 mg) n = 130 (130 eyes) Comparator: sham injection n = 42 (42 eyes) "Intravitreous pegaptanib or sham injections were administered at entry, week 6, and week 12, for a minimum of 3 injections. Thereafter, additional injections were administered every 6 weeks at the discretion of investigators if judged indicated, to a maximum of 6 injections up to week 30. [...] Pegaptanib was formulated for intravitreous injection at 0.3 mg/90 µl, 1 mg/90 µl, and 3 mg/90 µl concentrations in preservative‐free phosphate‐buffered saline (pH 5–7). Pegaptanib was packaged in sterile, single‐use, United States Pharmacopeia type 1 graduated glass 1‐ml syringes with preattached 27‐gauge needles" Page 1748
Outcomes	Outcomes: BCVA (measured using ETDRS chart) CRT on OCT change in retinal thickness derived by comparing measurements at baseline with those at week 36 or final examination if before week 36 focal photocoagulation applied at week 12 or later size of the area of retinal thickness measured by photography macular capillary leakage and cystoid spaces adverse events laboratory test abnormalities Follow‐up: 36 weeks
Notes	Dates participants enrolled: not reported, study published 2005 Funding:"The study was sponsored by Eyetech Pharmaceuticals, Inc., New York, New York, and Pfizer Inc., New York, New York." Page 1747 Conflict of interest: not reported Trial registration: NCT00040313
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were allocated [...] by a dynamic minimization procedure using a stochastic treatment allocation algorithm based on the variance method. Randomization was stratified by study site, size of the thickened retina area [...] and baseline VA [...]". Page 1748
Allocation concealment (selection bias)	Low risk	"An independent fundus photograph and angiogram reading center confirmed eligibility and appropriate retinal thickness classification both for study entry and for randomization and stratification using baseline fluorescein angiography and OCT." Page 1748
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Study subjects receiving sham or study medication were treated identically in all regards, including ocular antisepsis procedures and subconjunctival anesthetic, except that subjects receiving active treatment had pegaptanib injected into the vitreous, whereas those receiving sham had a needleless syringe pressed against the conjunctiva and sclera. The injection procedure prevented subjects from seeing the syringe and needle, to minimize the risk of unmasking. In all but 3 subjects, injection was administered by a staff member other than the study ophthalmologist responsible for all other aspects of the protocol, to maintain investigator masking." Page 1748
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Study subjects receiving sham or study medication were treated identically in all regards, including ocular antisepsis procedures and subconjunctival anesthetic, except that subjects receiving active treatment had pegaptanib injected into the vitreous, whereas those receiving sham had a needleless syringe pressed against the conjunctiva and sclera. The injection procedure prevented subjects from seeing the syringe and needle, to minimize the risk of unmasking. In all but 3 subjects, injection was administered by a staff member other than the study ophthalmologist responsible for all other aspects of the protocol, to maintain investigator masking. Visual acuity was determined by a separate VA examiner masked to treatment." Page 1748 "At baseline and at each study visit thereafter, refraction and VA were determined and OCT was performed by certified examiners masked both to randomization and to findings of the previous measurement." Page 1749
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nine participants were discontinued from the study before week 36. None in pegaptanib groups 0.3 mg and 1 mg, 3 in pegaptanib 3 mg group (3 mg subgroup: 2 participants by request at weeks 12 and 16 and 1 by other reason at week 1), 6 in sham group (5 participants by request at weeks 6, 11, 18, 30, and 33 and 1 due to death at week 8)
Selective reporting (reporting bias)	Low risk	The study protocol is available and all (primary and secondary) outcomes that are of interest in the study have been reported in the pre‐specified way
Other bias	Low risk	No other source of bias identified
Overall risk of bias	Low risk	Low risk of bias for all items