Rosenstock 2008

Methods	RANDOMISED CONTROLLED CLINICAL TRIAL (RCT): Yes. RANDOMISATION RATIO: 1:1. NON‐INFERIORITY DESIGN: Yes. EQUIVALENCE DESIGN: No. PARALLEL / CROSSOVER / FACTORIAL RCT: Parallel. CONTROLLED CLINICAL TRIAL (CCT): Yes.
Participants	WHO PARTCIPATED: SEX (female% / male%): 245 (42.1%) / 337 (57.9%). AGE (mean years (SD)): Insulin detemir: 58.4 (10.2); Insulin glargine: 59.4 (9.6). ETHNIC GROUPS (%): Insulin detemir: 22 (7.6%) black, 250 (85.9%) white, 7 (2.4%) Asian‐Pacific islander, 12 (4.1%) other; Insulin glargine: 12 (4.1%) black, 263 (90.4%) white, 7 (2.4%) Asian‐Pacific islander, 9 (3.1%) other.  DURATION OF DISEASE (mean years (SD)): Insulin detemir: 9.1 (6.1); Insulin glargine: 9.1 (6.4). INCLUSION CRITERIA: Insulin‐naive men and women with type 2 diabetes, ≥ 18 years old, ≥ 12 months disease duration, BMI ≤ 40.0 kg/m2, HbA1c between 7.5% and 10.0% and 1 or 2 OGLDs (metformin, insulin secretagogues, α‐glucosidase inhibitors) for ≥ 4 months on at least half the maximum recommended dose. EXCLUSION CRITERIA: Treatment with thiazolidinediones, use of > 2 OGLDs within 6 months, hypoglycaemic unawareness or other medical conditions likely to interfere with trial conduct. Novo Nordisk A/S web site: Current or previous treatment with thiazolidinediones within last 6 months, OGLD treatment with combination of ≥ 3 OGLDs within last 6 months, proliferative retinopathy or maculopathy or known hypoglycaemia unawareness. DIAGNOSTIC CRITERIA: Not specified. CO‐MORBIDITIES: Not reported. CO‐MEDICATIONS: Insulin detemir: 32 (11.0%) metformin monotherapy, 41 (14.1%) insulin secretagogue monotherapy, 212 (72.9%) metformin + insulin secretagogue, 3 (1.0%) metformin + α‐glucosidase inhibitor, 3 (1.0%) insulin secretagogue + α‐glucosidase inhibitor; Insulin glargine: 33 (11.3%) metformin monotherapy, 37 (12.7%) insulin secretagogue monotherapy, 215 (73.9%) metformin + insulin secretagogue, 1 metformin + α‐glucosidase inhibitor (0.3%), 4 insulin secretagogue + α‐glucosidase inhibitor (1.4%), 1 (0.3%) insulin secretagogue + insulin secretagogue.
Interventions	NUMBER OF STUDY CENTRES: 80. COUNTRY/ LOCATION: Europe (Austria, Belgium, France, Germany, Ireland, UK) and United States. SETTING: Not reported. INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin detemir: Initiated once‐daily in the evening at a dose of 12 units/day, titrated according to structured algorithm to FPG ≤ 6.0 mmol/L in the absence of hypoglycaemia and (if needed) to pre‐dinner PG ≤ 6.0 mmol/L, additional morning insulin dose if pre‐dinner PG > 7.0 mmol/L, but only if FPG < 7.0 mmol/L or nocturnal hypoglycaemia precluded achievement of the FPG target. Pen‐injector (Flexpen), 1 hour before to 1 hour after dinner and (if needed) within 30 minutes of breakfast. CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin glargine: Initiated once‐daily in the evening at a dose of 12 units/day, titrated according to a structured algorithm to FPG ≤ 6.0 mmol/L in the absence of hypoglycaemia. Pen‐injector in Europe (OptiPen Pro 1) and syringes and vials in United States, at bedtime. TREATMENT BEFORE STUDY: Insulin‐naive, 1 or 2 OGLDs (metformin, insulin secretagogues, α‐glucosidase inhibitors) ≥ 4 months on at least half the maximum recommended dose, according to local guidelines. Insulin added to OGLDs, OGLDs were recommended to remain stable during the study. TITRATION PERIOD: 52 weeks, 16 clinical visits and 9 telephone contacts. Dose adjustments were to be based on the average of 3 self‐measurements, during the first 12 weeks weekly investigator contact. Titration algorithm is given. Titration committee.
Outcomes	PRIMARY OUTCOME(S) (as stated in the publication): Baseline‐adjusted HbA1c at end of treatment. SECONDARY OUTCOMES (as stated in the publication): Clinic FPG, within‐subject variation in PG, 10‐point self‐measured PG profiles, proportion of subjects achieving HbA1c ≤ 7.0% with and without hypoglycaemia, change in body weight, incidence of hypoglycaemia, adverse events and standard safety parameters. Major hypoglycaemia = if assistance of another person was required; Minor hypoglycaemia = confirmed by PG < 3.1 mmol/L; Symptoms only = if PG ≥ 3.1 mmol/L or no measurement was made. ADDITIONAL OUTCOMES: Novo Nordisk A/S web site: Primary outcome: HbA1c after 52 weeks; Secondary outcomes: Insulin antibodies, incidence of hypoglycaemic episodes and adverse events, plasma glucose profiles and change in body weight.
Study details	DURATION OF INTERVENTION: 52 weeks. DURATION OF FOLLOW‐UP: 52 weeks. RUN‐IN PERIOD: Not specified.
Publication details	LANGUAGE OF PUBLICATION: English. COMMERCIAL FUNDING: Yes: "The study was funded and monitored by Novo Nordisk". NON‐COMMERCIAL FUNDING: No. PUBLICATION STATUS (PEER REVIEW JOURNAL): Yes. PUBLICATION STATUS (JOURNAL SUPPLEMENT): Yes: American Diabetes Association Scientific Sessions 2004 + American Diabetes Association Scientific Sessions 2006. PUBLICATION STATUS (ABSTRACT): No.
Stated aim of study	Quote: "The objective of the current study was to compare treatment with insulin detemir and insulin glargine in line with their licensed indications as add‐on therapy to oral glucose‐lowering agents in insulin‐naive patients with type 2 diabetes".
Notes	Trialnumbers: NN304‐1373 and NCT00283751. Contact information: Julio Rosenstock (juliorosenstock@dallasdiabetes.com).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Concealed randomisation was carried out by an automatic telephone system and was stratified according to OGLD monotherapy or combination therapy at study entry". Comment: Probably done, as the "automatic telephone system" probably used a computer random number generator.
Allocation concealment (selection bias)	Low risk	Quote: "Concealed randomisation was carried out by an automatic telephone system and was stratified according to OGLD monotherapy or combination therapy at study entry". Comment: Done, as central allocation (by means of telephone) was used.
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "An open‐label design was required to allow twice daily‐daily administration of insulin detemir if needed" and "To reduce potential bias, HbA1c results were only disclosed to investigators at randomisation and at trial end". Comment: Neither study participants nor study personnel were blinded and this may have influenced outcome measurements.
Incomplete outcome data (attrition bias) All outcomes	High risk	Safety analysis: no missing data in either intervention group (291/291 analysed). Primary analysis: 23/291 (=7.9%) excluded from intervention group as no post‐baseline information and 16/291 (=5.5%) excluded from control group as no post‐baseline information. Thus, no imbalance in number of missing data. Primary weight analysis: 60/291 (=20.6%) excluded from intervention group and 39/291 (=13.4%) excluded from control group. Imbalance in numbers and reasons for missing data across intervention groups.
Selective reporting (reporting bias)	Low risk	Probably, as all of the study's pre‐specified outcomes (as listed on www.ClinicalTrials.gov) are reported (except for insulin antibodies, which was a pre‐specified secondary outcome).
Other bias	High risk	Quote: "In line with its license, people allocated to insulin detemir were allowed to receive an additional morning insulin dose if" and "Glargine was given once‐daily". Also, all patients randomised to insulin detemir used a pen‐injector, whereas United States patients randomised to insulin glargine used syringes and vials. Comment: The study has a potential source of bias related to the specific study design used, i.e. different frequency of injection and different injection devices across treatments.