14 CLINICAL STUDIES

The safety and efficacy of APIDRA were studied in adult patients with type 1 and type 2 diabetes (n=1833) and in pediatric patients (4 to 17 years) with type 1 diabetes (n=572). The primary efficacy parameter in these trials was glycemic control, assessed using glycated hemoglobin (GHb reported as HbA1c equivalent).

14.1 Type 1 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA (n=339) compared to insulin lispro (n=333) when administered subcutaneously within 15 minutes before a meal. Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4-week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients were Caucasian (97%). Fifty-eight percent of the patients were men. The mean age was 39 years (range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and the total daily doses of APIDRA and insulin lispro were similar in the two treatment groups (see Table 7).

Table 7: Type 1 Diabetes Mellitus–Adult
Treatment duration Treatment in combination with:	26 weeks Insulin glargine
	APIDRA	Insulin Lispro
* GHb reported as HbA1c equivalent
Glycated hemoglobin (GHb)* (%) Number of patients	331	322
Baseline mean	7.6	7.6
Adjusted mean change from baseline	-0.1	-0.1
Treatment difference: APIDRA – Insulin Lispro	0.0
95% CI for treatment difference	(-0.1; 0.1)
Basal insulin dose (Units/day)
Baseline mean	24	24
Adjusted mean change from baseline	0	2
Short-acting insulin dose (Units/day)
Baseline mean	30	31
Adjusted mean change from baseline	-1	-1
Mean number of short-acting insulin injections per day	3	3
Body weight (kg)
Baseline mean	73.9	74.1
Mean change from baseline	0.6	0.3

14.2 Type 2 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in insulin-treated patients with type 2 diabetes to assess the safety and efficacy of APIDRA (n=435) given within 15 minutes before a meal compared to regular human insulin (n=441) administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the basal insulin. All patients participated in a 4-week run-in period with regular human insulin and NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6 kg/m2. At randomization, 58% of the patients were taking an oral antidiabetic agent. These patients were instructed to continue use of their oral antidiabetic agent at the same dose throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH human insulin immediately prior to injection. The reductions from baseline in GHb were similar between the 2 treatment groups (see Table 8). No differences between APIDRA and regular human insulin groups were seen in the number of daily short-acting insulin injections or basal or short-acting insulin doses (see Table 8).

Table 8: Type 2 Diabetes Mellitus–Adult
Treatment duration Treatment in combination with:	26 weeks NPH human insulin
	APIDRA	Regular Human Insulin
* GHb reported as HbA1c equivalent
Glycated hemoglobin (GHb)* (%) Number of patients	404	403
Baseline mean	7.6	7.5
Adjusted mean change from baseline	-0.5	-0.3
Treatment difference: APIDRA – Regular Human Insulin	-0.2
95% CI for treatment difference	(-0.3; -0.1)
Basal insulin dose (Units/day)
Baseline mean	59	57
Adjusted mean change from baseline	6	6
Short-acting insulin dose (Units/day)
Baseline mean	32	31
Adjusted mean change from baseline	4	5
Mean number of short-acting insulin injections per day	2	2
Body weight (kg)
Baseline mean	100.5	99.2
Mean change from baseline	1.8	2.0

14.3 Type 1 Diabetes-Adults: Pre and Postmeal Administration

A 12-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA administered at different times with respect to a meal. APIDRA was administered subcutaneously either within 15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human insulin (n=278) was administered subcutaneously 30 to 45 minutes prior to a meal. Insulin glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in period with regular human insulin and insulin glargine followed by randomization. Most patients were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control (see Table 9) was comparable for the 3 treatment regimens. No changes from baseline between the treatments were seen in the total daily number of short-acting insulin injections (see Table 9).

Table 9: Pre and Postmeal Administration in Type 1 Diabetes Mellitus–Adult
Treatment duration Treatment in combination with:	12 weeks insulin glargine	12 weeks insulin glargine	12 weeks insulin glargine
	APIDRA pre meal	APIDRA post meal	Regular Human Insulin
* GHb reported as HbA1c equivalent † Adjusted mean change from baseline treatment difference (98.33% CI for treatment difference): APIDRA pre meal vs Regular Human Insulin -0.1 (-0.3; 0.0) APIDRA post meal vs Regular Human Insulin 0.0 (-0.1; 0.2) APIDRA post meal vs pre meal 0.2 (0.0; 0.3)
Glycated hemoglobin (GHb)* (%) Number of patients	268	276	257
Baseline mean	7.7	7.7	7.6
Adjusted mean change from baseline†	-0.3	-0.1	-0.1
Basal insulin dose (Units/day)
Baseline mean	29	29	28
Adjusted mean change from baseline	1	0	1
Short-acting insulin dose (Units/day)
Baseline mean	29	29	27
Adjusted mean change from baseline	-1	-1	2
Mean number of short-acting insulin injections per day	3	3	3
Body weight (kg)
Baseline mean	79.2	80.3	78.9
Mean change from baseline	0.3	-0.3	0.3

14.4 Type 1 Diabetes-Pediatric Patients

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the safety and efficacy of APIDRA (n=277) compared to insulin lispro (n=295) when administered subcutaneously within 15 minutes before a meal. Patients also received insulin glargine (administered once daily in the evening) or NPH insulin (administered once in the morning and once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m2. Glycemic control (see Table 10) was comparable for the two treatment regimens.

Table 10: Results from a 26-Week Study in Pediatric Patients with Type 1 Diabetes Mellitus
	APIDRA	Insulin Lispro
* GHb reported as HbA1c equivalent
Number of patients	271	291
Basal Insulin	NPH or insulin glargine	NPH or insulin glargine
Glycated hemoglobin (GHb)* (%)
Baseline mean	8.2	8.2
Adjusted mean change from baseline	0.1	0.2
Treatment Difference: Mean (95% confidence interval)	-0.1 (-0.2, 0.1)
Basal insulin dose (Units/kg/day)
Baseline mean	0.5	0.5
Mean change from baseline	0.0	0.0
Short-acting insulin dose (Units/kg/day)
Baseline mean	0.5	0.5
Mean change from baseline	0.0	0.0
Mean number of short-acting insulin injections per day	3	3
Baseline mean body weight (kg) Mean weight change from baseline (kg)	51.5 2.2	50.8 2.2

14.5 Type 1 Diabetes-Adults: Continuous Subcutaneous Insulin Infusion

A 12-week randomized, active control study (APIDRA versus insulin aspart) conducted in adults with type 1 diabetes (APIDRA n=29, insulin aspart n=30) evaluated the use of APIDRA in an external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was 46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both treatment groups (from 6.8% to 7.0% for APIDRA; from 7.1% to 7.2% for insulin aspart).