14 CLINICAL STUDIES

14.1 Clinical Studies in Adult Patients with Type 1 and Type 2 Diabetes

In a three-month, open-label trial, adult patients with type 1 (n=104) or type 2 (n=187) diabetes mellitus were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30 or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 4).

For patients with type 1 diabetes mellitus (T1DM) the mean age was 43 years old, 64% were male, 100% were White, the mean body mass index (BMI) was 26.1 kg/m2, and mean duration of diabetes mellitus was 15 years. For patients with type 2 diabetes mellitus (T2DM), the mean age was 63 years old, 54% were male, 100% were White, the BMI 28.1 kg/m2, and the mean duration of diabetes mellitus was 15 years.

Table 4: Glycemic Parameters at the End of Treatment [Mean ± SD (n subjects)]

	NOVOLOG MIX 70/30	Novolin 70/30
Type 1, n=104
Fasting Blood Glucose (mg/dL)	174 ± 64 (48)	142 ± 59 (44)
1.5 Hour Post Breakfast (mg/dL)	187 ± 82 (48)	200 ± 82 (42)
1.5 Hour Post Dinner (mg/dL)	162 ± 77 (47)	171 ± 66 (41)
HbA1c (%) Baseline	8.4 ± 1.2 (51)	8.5 ± 1.1 (46)
HbA1c (%) Week 12	8.4 ± 1.1 (51)	8.3 ± 1.0 (47)
Type 2, n=187
Fasting Blood Glucose (mg/dL)	153 ± 40 (76)	152 ± 69 (93)
1.5 Hour Post Breakfast (mg/dL)	182 ± 65 (75)	200 ± 80 (92)
1.5 Hour Post Dinner (mg/dL)	168 ± 51 (75)	191 ± 65 (93)
HbA1c (%) Baseline	8.1 ± 1.2 (82)	8.2 ± 1.3 (98)
HbA1c (%) Week 12	7.9 ± 1.0 (81)	8.1 ± 1.1 (96)

The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.

14.2 Clinical Studies in Adult Patients with Type 2 Diabetes with Insulin and Oral Antidiabetic Agents

Trial 1:

In a 34-week, open-label trial (Trial 1), insulin-naïve patients with type 2 diabetes mellitus currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. The mean age of the trial population was 53 years and mean duration of diabetes was 9.2 years. Forty-six percent were male. Eighty-five percent were White, 12% were Black and 3% were Asian. The mean BMI was approximately 32.4 kg/m2. During an 8-week optimization period metformin and pioglitazone were increased to 2,500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, patients were randomized to receive either NOVOLOG MIX 70/30 twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. NOVOLOG MIX 70/30 was started at a dose of 6 international units twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 international units.

Table 5: Combination Therapy with Metformin and Pioglitazone in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 1)

Treatment duration 24-weeks	NOVOLOG MIX 70/30 + Metformin + Pioglitazone	Metformin + Pioglitazone
HbA1c
Baseline mean ± SD (n)	8.1 ± 1.0 (102)	8.1 ± 1.0 (98)
End-of-study mean ± SD (n) - LOCF	6.6 ± 1.0 (93)	7.8 ± 1.2 (87)
Adjusted Mean change from baseline ± SE (n)*	-1.6 ± 0.1 (93)	-0.3 ± 0.1 (87)
Treatment difference mean ± SE* 95% CI*	-1.3 ± 0.1 (-1.6, -1.0)
Percentage of subjects reaching HbA1c <7.0%	76%	24%
Percentage of subjects reaching HbA1c ≤6.5%	59%	12%
Fasting Blood Glucose (mg/dL)
Baseline Mean ± SD (n)	173 ± 39.8 (93)	163 ± 35.4 (88)
End of Study Mean ± SD (n) - LOCF	130 ± 50.0 (90)	162 ± 40.8 (84)
Adjusted Mean change from baseline ± SE (n)*	-43.0 ± 5.3 (90)	-3.9 ± 5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
2 Hour Post Breakfast	138 ± 42.8 (86)	188 ± 57.7 (74)
2 Hour Post Lunch	150 ± 41.5 (86)	176 ± 56.5 (74)
2 Hour Post Dinner	141 ± 57.8 (86)	195 ± 60.1 (74)

: *Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.
: Trial 2:
: In a 28-week, open-label trial (Trial 2), insulin-naïve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy were randomized to receive either NOVOLOG MIX 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6). NOVOLOG MIX 70/30 was started at an average dose of 5-6 international units (0.07 ± 0.03 international units/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 international units (0.13 ± 0.03 international units/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL. The metformin dose was adjusted to 2,550 mg/day. Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients were White (53%), and the mean initial weight was 90 kg.
: The mean age of the trial population was 53 years old and mean duration of diabetes was 9.5 years. Fifty three percent were male. Fifty-five percent were White, 15% Black, 27% were Hispanic, 2% were Asian and 2% were Other. The mean BMI was approximately 31.5 kg/m2.

Table 6:Combination Therapy with Metformin ± Pioglitazone and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 2)

Treatment duration 28-weeks	NOVOLOG MIX 70/30 + Metformin ± Pioglitazone	Insulin Glargine + Metformin ± Pioglitazone
Number of patients	117	116
HbA1c
Baseline mean (%)	9.7 ± 1.5 (117)	9.8 ± 1.4 (114)
End-of-study mean (± SD)	6.9 ± 1.2 (108)	7.4 ± 1.2 (114)
Mean change from baseline	-2.7 ± 1.6 (108)	-2.4 ± 1.5 (114)
Percentage of subjects reaching HbA1c <7.0%	66%	40%