Levemir (Page 5 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.

In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.

14 CLINICAL STUDIES

The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2 diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials that also administered LEVEMIR in the morning. In general, the reduction in HbA1c with LEVEMIR was similar to that with NPH insulin or insulin glargine.

14.1 Type 1 Diabetes — Adult

In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 8). Differences in timing of LEVEMIR administration had no effect on HbA1c , fasting plasma glucose (FPG), or body weight.

In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine (administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.

In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on HbA1c.

Table 8: Type 1 Diabetes Mellitus – Adult

Study A

Study B

Study C

Treatment duration

16 weeks

26 weeks

24 weeks

Treatment in combination with

NovoLog

(insulin aspart)

NovoLog

(insulin aspart)

Human Soluble Insulin

(regular insulin)

Twice-daily

LEVEMIR

Twice-daily

NPH

Twice-daily LEVEMIR

Once-daily insulin glargine

Once-daily LEVEMIR

Once-daily NPH

Number of patients treated

276

133

161

159

492

257

HbA1c (%)

Baseline HbA1c

8.6

8.5

8.9

8.8

8.4

8.3

Adj. mean change from

baseline

-0.8*

-0.7*

-0.6**

-0.5**

-0.1*

0.0*

LEVEMIR – NPH

95% CI for Treatment

difference

-0.2

(-0.3, -0.0)

-0.0

(-0.2, 0.2)

-0.1

(-0.3, 0.0)

Fasting blood glucose (mg/dL)

Baseline mean

209

220

153

150

213

206

Adj. mean change from

baseline

-44*

-9*

-38**

-41**

-30*

-9*

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

**From an ANCOVA model adjusted for baseline value and study site.

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