| Outcome Measures: |
Primary: Clinically significant hypoglycaemia (Double dose): Clinically significant hypoglycaemia (Plasma glucose [PG] less than 3.0 mmol/L [54 mg/dL]) after 2 times the individualised optimal basal dose of insulin, Yes/No Blood sugar lower than 3.0 mmol/L (54 mg/dL) after receiving a double dose of basal insulin Number of subjects experiencing an event is to be reported, From start of hypoglycaemia induction after 2 times the individualised optimal basal dose of insulin (day 17 for insulin 287, day 4 for insulin glargine) until termination of the clamp the following day | Secondary: PG (nadir) - PG concentration at nadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in mmol/L Minimum blood sugar level achieved after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|t (decline, PG 5.5 mmol/L - PG 3.0 mmol/L) - Time from start of hypoglycaemia induction until a PG concentration of 3.0 mmol/L (54 mg/dL) is reached after 2 and 3 times the individualised optimal basal dose of insulin, Measured in hours Time from when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until blood sugar is 3.0 mmol/L (54 mg/dL) after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|t (decline, PG 5.5 mmol/L - PG nadir) - Time from start of hypoglycaemia induction until PGnadir is reached after 2 and 3 times the individualised optimal basal dose of insulin, Measured in hours Time from when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|t (recovery, PG nadir - PG 5.5 mmol/L) - Time to increase from PGnadir to a PG concentration of 5.5 mmol/L (100 mg/dL) after 2 and 3 times the individualised optimal basal dose of insulin, Measured in hours Time from when blood sugar is at a minimum level until blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] during recovery from low blood sugar after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|C (glucagon, PG nadir) - Plasma glucagon concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in pg/mL Blood level of the glucagon hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|C (adrenaline, PG nadir) - Plasma adrenaline concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in pg/mL Blood level of the adrenaline hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|C (noradrenaline, PG nadir) - Plasma noradrenaline concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in pg/mL Blood level of the noradrenaline hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|C (growth hormone [GH], PG nadir) - Serum growth hormone concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in ng/mL Blood level of GH at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|C (cortisol, PG nadir) - Serum cortisol concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in ng/mL Blood level of the cortisol hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Pulse (PG 5.5 mmol/L - PG nadir) - Change in pulse rate from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in beats/min Change in pulse from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Diastolic blood pressure (DBP) (PG 5.5 mmol/L - PG nadir) - Change in diastolic blood pressure from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in mmHg Change in DBP from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Systolic blood pressure (SBP) (PG 5.5 mmol/L - PG nadir) - Change in systolic blood pressure from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in mmHg Change in SBP from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Digit Symbol Substitution Test (DSST) (PG 5.5 mmol/L - PG nadir) - Change in DSST score from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Number of correct responses Change in performance in the DSST (a cognitive ability test) from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Four-Choice Reaction Time (4CRT) (reaction 4CRT) (PG 5.5 mmol/L - PG nadir) - Change in 4CRT performance from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in msec Change in reaction time in the 4CRT test (a cognitive ability test) from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|4CRT (% correct answers) (PG 5.5 mmol/L - PG nadir) - Change in 4CRT performance (% correct answers) from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in %-points Change in the percentage correct answers in the 4CRT test (a cognitive ability test) from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Trail Making B test (TMB) (PG 5.5 mmol/L - PG nadir) - Change in TMB from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Measured in sec Change in performance in the TMB (a cognitive ability test) from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Hypoglycaemic symptoms score (HSS) (PG 5.5 mmol/L - PG nadir) - Change in HSS from a PG concentration of 5.5 mmol/L (100 mg/dL) to PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Test score (arbitrary units) Change in symptoms of low blood sugar from the time point when blood sugar is normal \[5.5 mmol/L (100 mg/dL)\] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Hypoglycaemia awareness (HA) (PG nadir) - HA at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin, Yes/No Number of subjects with a feeling of low blood sugar at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|AUC (GIR, recovery, PG nadir -PG 5.5 mmol/L) - Area under the glucose infusion rate-time profile during recovery from PGnadir to a PG concentration of 5.5 mmol/L (100 mg/dL) after 2 and 3 times the individualised optimal basal dose of insulin, Measured in mg/kg Amount of glucose needed to be infused to increase blood sugar from a minimum level to a normal level \[5.5 mmol/L (100 mg/dL)\] during recovery from low blood sugar after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|AUC (GIR, recovery, PG 5.5 mmol/L, 0-6h)-Area under the glucose infusion rate-time profile during 6 hours at a PG concentration of 5.5 mmol/L (100 mg/dL) after recovery from hypoglycaemia after 2 & 3 times the individualised optimal basal dose of insulin, Measured in mg/kg Amount of glucose needed to be infused to keep blood sugar at a normal level \[5.5 mmol/L (100 mg/dL)\] for 6 hours after recovery from low blood sugar after receiving a double or triple dose of basal insulin, From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day|Clinically significant hypoglycaemia (Triple dose) - Clinically significant hypoglycaemia [PG less than 3.0 mmol/L (54 mg/dL)], after 3 times the individualised optimal basal dose of insulin, Yes/No Blood sugar lower than 3.0 mmol/L (54 mg/dL) after receiving a triple dose of basal insulin Number of subjects experiencing an event is to be reported, From start of hypoglycaemia induction after 3 times the individualised optimal basal dose of insulin (day 38 for insulin 287, day 11 for insulin glargine) until termination of the clamp the following day
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