NN1250-3995

Novo Nordisk A/S

Novo Allé, Bagsvaerd, Denmark, 2880

Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

No

No

No

Final

03 Jun 2016

Yes

12 Jan 2016

Yes

12 Jan 2016

No

To compare the rates of severe or BG (blood glucose) confirmed symptomatic hypoglycaemia of IDeg once daily (OD) + IAsp to IGlar OD + IAsp, by demonstrating that the upper limit of the 95% confidence interval of the rate ratio is below or equal to a non-inferiority margin of 1.10, and if confirmed, to a superiority limit of 1.00.

The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice, and 21 CFR 312.120.

06 Jan 2014

No

No

Poland: 43

United States: 458

501

43

0

0

0

0

0

0

448

53

0

Overall Study (overall period)

Randomised - controlled

Yes

Insulin glargine

Lantus®

Solution for injection

Subcutaneous use

Subjects received IGlar for a total of 32 weeks (16-week titration period and a 16-week maintenance period). IGlar was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and were to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IGlar were reduced by 20% at the start of both the treatment periods. Doses of IGlar were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration (fasting glycaemic target of 4.0-5.0 mmol/L).

Insulin degludec

Solution for injection

Subcutaneous use

Subjects received IDeg for a total of 32 weeks (16-week titration period and a 16-week maintenance period). IDeg was administered subcutaneously (s.c.; under the skin) in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken once daily (OD) at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IDeg were reduced by 20% at the start of both the treatment periods. Doses of IDeg were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast self measured plasma glucose (SMPG) values measured on 3 consecutive days immediately prior to titration (fasting glycaemic target of 4.0-5.0 mmol/L).

Insulin glargine

Lantus®

Solution for injection

Subcutaneous use

Subjects received IGlar for a total of 32 weeks (16-week titration period and a 16-week maintenance period). IGlar was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and were to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IGlar were reduced by 20% at the start of both the treatment periods. Doses of IGlar were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration (fasting glycaemic target of 4.0-5.0 mmol/L).

Insulin degludec

Solution for injection

Subcutaneous use

Subjects received IDeg for a total of 32 weeks (16-week titration period and a 16-week maintenance period). IDeg was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IDeg were reduced by 20% at the start of both the treatment periods. Doses of IDeg were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration (fasting glycaemic target of 4.0-5.0 mmol/L).

Insulin degludec/insulin glargine (IDeg/IGlar)

Insulin glargine/insulin degludec (IGlar/IDeg)

Insulin degludec/insulin glargine (IDeg/IGlar)

Insulin glargine/insulin degludec (IGlar/IDeg)

Insulin degludec (IDeg)

Subjects received IDeg in treatment period 1 (from treatment sequence IDeg/IGlar) and in treatment period 2 (from treatment sequence IGlar/IDeg). Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IDeg were reduced by 20% at the start of both the treatment periods. Doses of IDeg were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration.

Insulin glargine (IGlar)

Subjects received IGlar in treatment period 1 (from treatment sequence IGlar/IDeg) and in treatment period 2 (from treatment sequence IDeg/IGlar). Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IGlar were reduced by 20% at the start of both the treatment periods. Doses of IGlar were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration.

Insulin degludec (IDeg)

Subjects received IDeg in treatment period 1 (from treatment sequence IDeg/IGlar) and in treatment period 2 (from treatment sequence IGlar/IDeg). Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IDeg were reduced by 20% at the start of both the treatment periods. Doses of IDeg were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration.

Insulin glargine (IGlar)

Subjects received IGlar in treatment period 1 (from treatment sequence IGlar/IDeg) and in treatment period 2 (from treatment sequence IDeg/IGlar). Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar was administered s.c. in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and was to be taken OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IGlar were reduced by 20% at the start of both the treatment periods. Doses of IGlar were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration.

Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with symptoms consistent with hypoglycaemia. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. The trial followed a cross over design. Descriptive analysis was based on the safety analysis set (SAS: subjects receiving at least 1 dose of the investigational product, IDeg or its comparator, IGlar; number of subjects (N)=500). Number of subjects analysed=subjects with available data for the endpoint as per individual trial product. Statistical analysis was based on the subjects in the full analysis set (FAS: included all randomised subjects (N=501)), who were exposed in at least one maintenance period (i.e., N=437).

Primary

After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64).

Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 1: Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the maintenance period. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 840. Actual “number of subjects included in analysis” is 437.

Insulin degludec (IDeg) v Insulin glargine (IGlar)

840

Pre-specified

0.89

2-sided

Severe or BG confirmed symptomatic nocturnal hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with symptoms consistent with hypoglycaemia and with time of onset between 00:01 and 05.59 a.m., both inclusive. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. The trial followed a cross over design. Descriptive analysis was based on the SAS (N=500). Number of subjects analysed=subjects with available data for the endpoint as per individual trial product. Statistical analysis was based on the subjects in the FAS (N=501), who were exposed in at least one maintenance period (i.e., N=437).

Secondary

After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)

Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 2: Number of treatment-emergent severe or BG confirmed symptomatic nocturnal hypoglycaemic episodes during the maintenance period. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 840. Actual “number of subjects included in analysis” is 437.

Insulin degludec (IDeg) v Insulin glargine (IGlar)

840

Pre-specified

0.64

2-sided

Percentage of subjects who experienced one or more severe hypoglycaemic episodes during the maintenance period. Severe hypoglycaemia (according to the American Diabetes Association 2013 definition): A hypoglycaemic episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose values may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. The trial followed a cross over design. Descriptive analysis was based on the SAS (N=500). Number of subjects analysed=subjects with available data for the endpoint as per individual trial product. Statistical analysis was based on the subjects in the FAS (N=501) who were exposed in both the maintenance periods (i.e., N=403).

Secondary

After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)

Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 3: Proportion of subjects with one or more severe hypoglycaemic episodes during the maintenance period. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 840. Actual “number of subjects included in analysis” is 403.

Insulin degludec (IDeg) v Insulin glargine (IGlar)

840

Pre-specified

Treatment emergent adverse event was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. The trial followed a cross over design. Results are based on the SAS (N=500). Total "number of subjects analysed" for this endpoint: 500.

Secondary

During 32 weeks of treatment for each treatment period

Change from baseline in HbA1c (glycosylated haemoglobin) at week 32 (treatment period 1) and at week 64 (treatment period 2). Week 32 HbA1c absolute values were considered as baseline for calculating change from baseline in HbA1c at week 64. Week 32 HbA1c absolute values: mean (standard deviation) = 6.9% (0.9) and 6.8% (0.8) for IDeg/IGlar and IGlar/IDeg treatment groups, respectively. Both descriptive analysis and statistical analysis were based on the FAS (n=501). Here, 'n' specifies the number of subjects with available data at specified time-point.

Secondary

Week 32, Week 64

Change from baseline in HbA1c at week 32 (treatment period 1). Before testing the primary endpoint, the secondary supportive efficacy endpoint “Change from baseline in HbA1c after 32 weeks of treatment” was tested for non-inferiority as a prerequisite for testing the primary endpoint. Analysis was based on mixed model for repeated measurement (MMRM); treatment, sex, region, pre-trial insulin treatment regimen, visit and dosing time were fixed effects, and age and baseline HbA1c were covariates.

Insulin degludec/insulin glargine (IDeg/IGlar) v Insulin glargine/insulin degludec (IGlar/IDeg)

501

Pre-specified

0.03

2-sided

Change from baseline in HbA1c at week 64 (treatment period 2). Before the primary endpoint was tested, the secondary supportive efficacy endpoint “Change from baseline in HbA1c after 32 weeks of treatment” was tested for non-inferiority as prerequisite for testing the primary endpoint. Analysis was based on MMRM; treatment, sex, region, pre-trial insulin treatment regimen, visit and dosing time were fixed effects, and age and baseline HbA1c were covariates.

Insulin degludec/insulin glargine (IDeg/IGlar) v Insulin glargine/insulin degludec (IGlar/IDeg)

501

Pre-specified

0.11

2-sided

Fasting plasma glucose values at week 32 and week 64. Results are based on the FAS (N=501). Here, 'n' specifies the number of subjects with available data at specified time-point.

Secondary

Week 32, Week 64

From the first day of exposure to randomised treatment and no later than the last day of randomised treatment (64 weeks).

The trial followed a cross over design. Subjects in the SAS (N=500) contributed to the evaluation of adverse events. Treatment emergent adverse event was defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.

18.1

Insulin glargine (IGlar)

Insulin degludec (IDeg)