Pradhan.

Study characteristics
Methods	Study design: parallel‐group RCT Unit of randomization and analysis: individual Number randomized: Total: 40 (35 included in the analysis) Per group: 18 to enalapril; 17 to multivitamin Sample size calculation: not reported
Participants	Country: USA Study period: April 1997 through June 1998 Type of diabetes: type 2 Participants’ status at baseline: Age, years, mean (SD): 49.3 (2.7) in enalapril group; 53.4 (3.4) in multivitamin group Gender, % women: 50% in enalapril group, 58.8% in placebo group Race/ethnicity: not reported Duration of diabetes, years, mean (SD): 12.9 (1.8) enalapril, 9.1 (1.2) multivitamin Smokers, % current: not reported Blood pressure, mean (SD): all had BP < 140/90 mmHg; mean arterial pressures were 91.3 (1.6) in enalapril group, 89.1 (2.1) in multivitamin group Hypertension, %: 0% ("normotensives"; BP < 140/90) Glycated hemoglobin, mean (SD): 10.6 (0.6) for both groups BMI, mean (SD): 28.0 (1.7) enalapril, 25.8 (1.0) multivitamin Retinopathy status: all had moderate or severe NPDR (ETDRS grade 40 to 50) Medical history: Myocardial infarction, %: not reported Stroke, %: not reported Equivalence of groups at baseline: fairly well balanced, considering small sample size Inclusion criteria: type 2 diabetes, normotensive (< 140/90 mmHg), not on any ACEi or antihypertensive agent, moderate or severe NPDR identified and graded as ETDRS 40 to 50 Exclusion criteria: abnormal serum creatinine, visual acuity < 20/50, dipstick proteinuria more than trace, treatment with ACEi or other antihypertensive medications
Interventions	Intervention 1: 5 mg enalapril daily Intervention 2: multivitamin placebo daily Length of follow‐up: Planned: 2 years Actual: 7.1 months mean (0.59 years) (range: 3 to 15 months)
Outcomes	Primary outcome, as specified for this review: none Secondary outcomes, as specified for this review: progression to PDR or macular edema requiring laser treatment based on slit‐lamp examination; PDR when detected ophthalmoscopically and documented by 7‐field photos; visual acuity measured but not reported Other diabetic retinopathy outcomes: none mentioned Retinopathy diagnosis and monitoring: if a slit‐lamp examination by the masked ophthalmologist showed either PDR or CSME, photographs were taken to confirm the diagnosis Intervals at which outcomes were assessed: all participants scheduled to have retinal photographs taken at 1 and 2 years; slit‐lamp assessment every 3 months Participants (eyes) examined for outcome: 35 Cost of interventions: not reported Quality of life: not reported Adverse outcomes: not mentioned Other outcomes reported: proteinuria
Notes	Source of funding: government agency Declaration of interest: not reported Class(es) of antihypertensive agents assigned: ACEi only Length of run‐in period: none Degree of blood pressure control achieved: "mean arterial pressures were similar at last visit"; 90.4 (1.4) mmHg in enalapril group, 93.6 (2.0) mmHg in multivitamin group, and did not differ from each other Trial registration: not reported and not found Other: terminated with mean follow‐up less than 1 year for “unlikelihood” of demonstrating a significant difference between ACEi and placebo in the study cohort
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“After randomization to either a multivitamin (MVI) placebo or an ACE‐I ...”; details of sequence generation not reported
Allocation concealment (selection bias)	Unclear risk	No information reported.
Masking (performance bias and detection bias) Secondary outcomes	Unclear risk	PDR and CSME reported at 3‐month intervals based on slit‐lamp examination by ophthalmologist for whom masking was not mentioned.
Incomplete outcome data (attrition bias) Secondary outcomes	Unclear risk	Visual acuity was measured but not reported. "One woman had an allergic reaction and was dropped from the study. Four patients did not return for the 3‐month evaluation and were also dropped from the study since they could not be contacted." Dropouts not specified for treatment arm. Also, study terminated early for futility.
Selective reporting (reporting bias)	Unclear risk	Unclear from available information, but visual acuity measured at 3‐month intervals and not reported
Other bias	High risk	Terminated prematurely for futility; less than 1‐year follow‐up inadequate to assess diabetic retinopathy outcomes in so few participants.