Ferguson 2001.

Methods	Cross‐over randomised controlled clinical trial
Participants	Inclusion criteria: participants with type 1 diabetes for > 5 years; reported reduction in hypoglycaemia warnings symptoms for ≥ 2 years; experienced ≥ 2 episodes of severe hypoglycaemia in the 2 years preceding participation, HbA1c of less than double the local non‐diabetic reference range (HbA1c: 5.0‐6.6%); aged 19‐65 years Exclusion criteria: systemic, renal or hepatic disease; pregnant participants; active, proliferative retinopathy (untreated) Diagnostic criteria: WHOa
Interventions	Number of study centres: 1 Treatment before study: either twice‐daily free‐mixed insulin or multiple injection regimen Titration period: 12‐months (2 treatment periods each lasting 24 weeks) Insulin lispro vs. RHI (see Appendix 2)
Outcomes	Outcomes reported in abstract of publication: HbA1c, 8‐point blood glucose profile, frequency and severity of hypoglycaemic episodes and quality of life Primary outcome(s): frequency of severe hypoglycaemic episodesb Secondary outcome(s): ‐ Other outcome(s): treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire), aspects of quality of life (Hypoglycaemia Fear Survey), hypoglycaemia (mild, severe nocturnal)
Study details	Run‐in period: 4 weeks Study terminated before regular end: no
Publication details	Language of publication: English Funding: commercial (Eli Lilly) Publication status: peer‐reviewed journal/full article
Stated aim for study	Quote from publication: "The aim of this study was to compare treatment with insulin lispro and regular human insulin in a cohort of patients with type 1 diabetes who had impaired awareness of hypoglycaemia and a history of frequent severe hypoglycaemia. The two insulins were compared with respect to the frequency of mild and severe hypoglycaemia, glycaemic control, and quality of life measures"
Notes	aAccording to the study protocol, but no year given (information obtained from IQWIG report) bThe quality of glycaemic control was described as a primary outcome in Ferguson 2001, but not in the original study report
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Participants were randomised to receive treatment either with insulin lispro and human NPH [neutral protamine Hagedorn] insulin, or alternatively with regular human insulin and NPH insulin" Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Objective outcomes	High risk	Quote: "open‐label" Comment: no blinding
Blinding of participants and personnel (performance bias) Subjective outcomes	High risk	Quote: "open‐label" Comment: no blinding
Blinding of outcome assessment (detection bias) Objective outcomes	Unclear risk	Comment: study diaries were validated against data stored in participants' blood glucose meters
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Comment: not described, but considered unlikely
Incomplete outcome data (attrition bias) Objective outcomes	Unclear risk	Comment: participants dropped out before treatment or were excluded for data validity reasons ‐ no drop‐outs from ITT population. Unclear whether there were missing values and how they were addressed
Incomplete outcome data (attrition bias) Subjective outcomes	Unclear risk	Comment: participants dropped out before treatment or were excluded for data validity reasons ‐ no drop‐outs from ITT population. Unclear whether there were missing values and how they were addressed
Selective reporting (reporting bias)	High risk	Comment: primary outcomes were differently defined in publication and study report; incomplete reporting on health‐related quality of life results, baseline data only provided for overall participant population
Other bias	Unclear risk	Comment: not enough information to judge