Levemir (Page 6 of 8)

14.2 Type 1 Diabetes — Pediatric

Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6 to 17 years of age. The other study was 52 weeks in duration and enrolled patients 2 to 16 years of age. In both studies, LEVEMIR and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of NPH insulin (Table 9). In the 52-week study, the randomization was stratified by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 9).

Table 9: Type 1 Diabetes Mellitus – Pediatric

Study D

Study I

Treatment duration

26 weeks

52 weeks

Treatment in combination with

NovoLog

(insulin aspart)

NovoLog

(insulin aspart)

Once- or Twice Daily LEVEMIR

Once- or Twice Daily NPH

Once- or Twice Daily LEVEMIR

Once- or Twice Daily NPH

Number of subjects treated

232

115

177

170

HbA1c (%)

Baseline HbA1c

8.8

8.8

8.4

8.4

Adj. mean change from baseline

-0.7*

-0.8*

0.3**

0.2**

LEVEMIR – NPH

95% CI for Treatment

difference

0.1

-0.1; 0.3

0.1

-0.1; 0.4

Fasting blood glucose (mg/dL)

Baseline mean

181

181

135

141

Adj. mean change from baseline

-39

-21

-10**

0**

*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).

**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).

14.3 Type 1 Diabetes — Pregnancy

In an open-label clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of 152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the study (Total pregnant women = 310). Approximately one half of the study participants in each arm were randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first 8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c ) was

<7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient (n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically significant.

14.4 Type 2 Diabetes — Adult

In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast and evening) as part of a regimen of stable combination therapy with one or two of the following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin similarly lowered HbA1c from baseline (Table 10).

In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes, LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.

Table 10: Type 2 Diabetes Mellitus – Adult

Study E

Study F

Treatment duration

24 weeks

22 weeks

Treatment in combination with

oral agents

insulin aspart

Twice-daily

LEVEMIR

Twice-daily

NPH

Once- or Twice Daily LEVEMIR

Once- or Twice Daily

NPH

Number of subjects treated

237

239

195

200

HbA1c (%)

Baseline HbA1c

8.6

8.5

8.2

8.1

Adj. mean change from baseline

-2.0*

-2.1*

-0.6**

-0.6**

LEVEMIR – NPH

95% CI for Treatment difference

0.1

(-0.0, 0.3)

-0.1

(-0.2, 0.1)

Fasting blood glucose1 (mg/dL)

Baseline mean

179

173

Adj. mean change from baseline

-69*

-74*

1 Study F — Fasting blood glucose data not collected

*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.

**From an ANCOVA model adjusted for baseline value and country.

Combination Therapy with Metformin and Liraglutide

This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions. The remaining 323 patients with HbA1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with LEVEMIR.

Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg + metformin alone (Table 11). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8 mg + metformin alone.

Table 11: Results of a 26-week Open-label Trial of LEVEMIR as Add-on to Liraglutide + Metformin Compared to Continued Treatment with Liraglutide + Metformin Alone in Patients Not Achieving HbA1c < 7% After 12 Weeks of Metformin and Liraglutide

Study H

LEVEMIR + Liraglutide +Metformin

Liraglutide+

Metformin

Intent-to-Treat Population (N)a

162

157

HbA1c (%) (Mean)

Baseline (week 0)

7.6

7.6

Adjusted mean change from baseline

-0.5*

0*

Difference from liraglutide + metformin arm

(LS mean)b

95% Confidence Interval

-0.5***

(-0.7, -0.4)

Percentage of patients achieving A1c <7%

43**

17**

Fasting Plasma Glucose (mg/dL) (Mean)

Baseline (week 0)

166

159

Adjusted mean change from baseline

-38*

-7*

Difference from liraglutide + metformin arm

(LS mean)b

95% Confidence Interval

-31***

(-39, -23)

a Intent-to-treat population using last observation on study

b Least squares mean adjusted for baseline value

*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.

**From a logistic regression model adjusted for baseline HbA1c.

***p-value <0.0001

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