DCCT 1993a.

Methods	A total of 1441 participants with insulin‐dependent diabetes mellitus (726 with no retinopathy at baseline (the primary‐prevention cohort) and 715 with mild retinopathy (the secondary‐intervention cohort)) were randomly assigned to intensive therapy administered either with an external insulin pump or by 3 or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with 1 or 2 daily insulin injections. The participants were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. 1436 received baseline neuropathy assessment (primary cohort: 346 intensive, 376 conventional; secondary cohort: 362 intensive, 353 conventional).
Participants	The major criteria for eligibility included insulin dependence, as evidenced by deficient C‐peptide secretion; an age of 13 to 39 years; and the absence of hypertension, hypercholesterolemia, and severe diabetic complications or medical conditions. To be eligible for the primary‐prevention cohort, participants were required to have had IDDM for 1 to 5 years, to have no retinopathy as detected by 7‐field stereoscopic fundus photography, and to have urinary albumin excretion of less than 40 mg per 24 hours. To be eligible for the secondary‐intervention cohort, the participants were required to have had IDDM for 1 to 15 years, to have very mild to moderate non‐proliferative retinopathy, and to have urinary albumin excretion of less than 200 mg per 24 hours.
Interventions	Conventional therapy consisted of 1 or 2 daily injections of insulin, including mixed intermediate and rapid‐acting insulins, daily self‐ monitoring of urine or blood glucose, and education about diet and exercise. Intensive therapy included the administration of insulin 3 or more times daily by injection or an external pump. The dosage was adjusted according to the results of self monitoring of blood glucose performed at least 4 times per day, dietary intake, and anticipated exercise. The goals of intensive therapy included preprandial blood glucose concentrations between 70 and 120 mg per dL (3.9 and 6.7 mmol per L), postprandial concentrations of less than 180 mg per dL (10 mmol/L), a weekly 3 a.m. measurement greater than 65 mg/dL (3.6 mmol/L), and hemoglobin A1c (glycated hemoglobin), measured monthly, within the normal range (less than 6.05%).
Outcomes	Definite clinical neuropathy was defined as the presence of abnormalities consistent with diabetic neuropathy in at least 2 of the following: physical symptoms, peripheral sensation, or decreased or absent reflexes. A single abnormality was labeled “possible” neuropathy. “Confirmed” definite clinical neuropathy also required the finding of unequivocal abnormality on nerve conduction studies or autonomic nervous system (ANS) testing. Nerve conduction evaluations were performed at baseline, at 5 years, and at study end. Nerve conduction evaluations included the dominant median (motor and sensory), peroneal (motor), and sural nerves.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomization was stratified according to the primary‐prevention and secondary‐intervention cohorts at each center. However, the process of randomization was not stated in the methods.
Allocation concealment (selection bias)	Unclear risk	Neither the investigators nor the participants were aware of the outcome data unless predetermined criteria, such as the development of severe retinopathy requiring laser therapy, were met. However, there is no mention of allocation concealment.
Blinding (performance bias and detection bias) All outcomes	Low risk	All responses were recorded and available for independent review
Incomplete outcome data (attrition bias) All outcomes	Low risk	1441 randomized, 1290 at least 4.5 years, 1243 had nerve conduction studies at baseline and at 5 years
Selective reporting (reporting bias)	Low risk	Authors report on all measures
Other bias	Low risk	None