Barbosa 1994

Methods	Study design: prospective RCT Study duration: 1978 to 1992 Study follow‐up period: 5 years
Participants	Country: USA Setting: single centre; University of Minnesota Hospital and Clinic and Hennepin County Medical Center, Minneapolis. Referral population from all 50 USA states, although approximately 90% came from the upper Midwest and all were white Inclusion criteria: patients with T1DM who had received a kidney allograft as treatment for end‐stage diabetic nephropathy Number: treatment group (52); control group (47) Mean age ± SD (years): treatment group (35 ± 6); control group (36 ± 8) Sex: (M/F): treatment group (41/11); control group (34/13) Exclusion criteria: not reported
Interventions	Treatment group Intensive insulin therapy Aiming for HbA1 levels within normal limits (i.e. 0.051 to 0.071) Study nurses contacted patients 2 to 3 times/week, and study dietitian contacted the patient frequently Home BGL 4 to 6 times/d, allowing frequent readjustment of the insulin dose Diet and exercise to meet the study goals Various forms of insulin used; continuous SC infusions, multi‐dose injections commonly consisting of a mixture of beef/pork isophane insulin and crystalline regular insulin before breakfast, crystalline regular insulin before supper and isophane insulin at bedtime. Some also took crystalline regular insulin at lunch and a few were treated with extended insulin zinc once or twice a day and crystalline regular insulin at the 3 main meals. During the last 5 years of the study, many people used human insulin Control group Less intensive insulin therapy Aimed to alleviate hyperglycaemic symptoms or reduce HbA1 levels to ≤ 0.12 Study nurses contacted patients every 2 to 4 months (more often if subjects had concerns such as symptomatic hyperglycaemia HbA1 > 0.12 or hypoglycaemic episodes) and study dietitian contacted patient once annually Home BGL 1 to 4 times/d Exercise was recommended to participants in general terms Patients received 1 daily injection of a mixture of isophane insulin and crystalline regular insulin (beef/pork) 30 minutes before breakfast. About a third of patients had 2 injections of a mixture of isophane insulin and crystalline regular insulin daily but attempts were made to return to 1 injection/d Baseline immunosuppression AZA and prednisolone, CSA and prednisolone, or CSA and AZA and prednisolone Co‐interventions None
Outcomes	Primary outcomes Transplant or graft survival: reported graft losses and chronic rejections HbA1c: reported HbA1 not HbA1c FBG: not reported Kidney function markers including creatinine, eGFR, albuminuria: not reported Systolic and diastolic BP Lipids (HDL, LDL, triglyceride): not reported Body weight: not reported Secondary outcomes All‐cause mortality Macrovascular events (cardiovascular death, non‐fatal MI, non‐fatal stroke) Microvascular events (new or worsening kidney disease, or retinopathy): not reported Safety/adverse events (including hypoglycaemia)
Notes	Comparison groups were well matched for age, sex and duration of diabetes Conflict of interest: none declared Contact with authors: corresponding author contacted but data requested was not supplied by the time the review was finalised
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible due to the nature of the treatment
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	A large number of patients did not complete the study, however, all the withdrawals and losses to follow‐up were described. Although dropout rate was high, the authors wrote that there was no significant difference in dropout rates between groups, and no obvious source of bias that would affect conclusions, regarding maximised versus standard glycaemic control. However, with regard to the breakdown of causes of drop‐out, the intensive insulin therapy group had a higher rate of voluntary withdrawals 9/27 or 33.33% (i.e. people who could not tolerate the intensive insulin therapy) compared with the less intensive insulin therapy group 4/24 or 16.67%. This could lead to attrition bias, given that the authors did a per protocol analysis for outcomes show
Selective reporting (reporting bias)	Low risk	The prespecified primary outcome of glomerular mesangial expansion as determined by electron microscopy was reported
Other bias	High risk	There was an additional risk of selection bias because there was a change in the randomisation method ‐ initially investigators randomised 2:1 in favour of the intensive group as investigators hypothesised that this group would have more withdrawals from the study than the standard group. As this was not the case, in the seventh year of recruiting, they randomised 2:1 in favour of the standard group Funding source: Grants from the National Institute of Health and the National Centre for Research Resources. Also funding from Eli Lilly and Boehringer Mannheim Diagnostics, Minnesota Medical Foundation and the American Diabetes Association