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A Trial Comparing the Safety and Efficacy of Insulin Degludec and Insulin Glargine, Both With Insulin Aspart as Mealtime Insulin in Subjects With Type 1 Diabetes (SWITCH 1)

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ClinicalTrials.gov Identifier: NCT02034513
Recruitment Status : Completed
First Posted : January 13, 2014
Results First Posted : May 15, 2017
Last Update Posted : January 2, 2019
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 1
Interventions Drug: insulin degludec
Drug: insulin glargine
Drug: insulin aspart
Enrollment 501
Recruitment Details The trial was conducted at 90 sites in 2 countries, as follows: US: 84 sites, Poland: 6 sites.
Pre-assignment Details  
Arm/Group Title Insulin Degludec/Insulin Glargine (IDeg/IGlar) Insulin Glargine/Insulin Degludec (IGlar/IDeg)
Hide Arm/Group Description Subjects received insulin degludec (IDeg) in treatment period 1 and insulin glargine (IGlar) in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg and IGlar were 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 were 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 and IGlar were reduced by 20% at the start of both the treatment periods. Doses of IDeg and IGlar 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) Subjects received IGlar in treatment period 1 and IDeg in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar and IDeg were 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 and IDeg were reduced by 20% at the start of both the treatment periods. Doses of IGlar and 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).
Period Title: Overall Study
Started 249 252
Exposed 249 251
Completed 200 195
Not Completed 49 57
Reason Not Completed
Adverse Event             11             10
Lack of Efficacy             0             1
Lost to Follow-up             6             7
Pregnancy             0             3
Protocol Violation             7             10
Withdrawal by Subject             25             25
Unclassified             0             1
Arm/Group Title Insulin Degludec/Insulin Glargine (IDeg/IGlar) Insulin Glargine/Insulin Degludec (IGlar/IDeg) Total
Hide Arm/Group Description Subjects received IDeg in treatment period 1 and IGlar in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg and IGlar were 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 IDeg and IGlar were reduced by 20% at the start of both the treatment periods. Doses of IDeg and 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). Subjects received IGlar in treatment period 1 and IDeg in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar and IDeg were 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 and IDeg were reduced by 20% at the start of both the treatment periods. Doses of IGlar and 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). Total of all reporting groups
Overall Number of Baseline Participants 249 252 501
Hide Baseline Analysis Population Description
Baseline results are based on the full analysis set (FAS), which included all randomised subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 249 participants 252 participants 501 participants
45.4  (13.7) 46.4  (14.6) 45.9  (14.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 249 participants 252 participants 501 participants
Female
123
  49.4%
109
  43.3%
232
  46.3%
Male
126
  50.6%
143
  56.7%
269
  53.7%
Glycosylated hemoglobin (HbA1c)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of HbA1c
Number Analyzed 248 participants 252 participants 500 participants
7.7  (1.0) 7.5  (1.0) 7.6  (1.0)
[1]
Measure Analysis Population Description: The number of subjects that contributed to the measurement of HbA1c
Fasting plasma glucose (FPG)   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 248 participants 252 participants 500 participants
165.1  (77.3) 174.4  (81.7) 169.8  (79.6)
[1]
Measure Analysis Population Description: The number of subjects that contributed to the measurement of FPG
1.Primary Outcome
Title Number of Treatment Emergent Severe or BG (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period
Hide Description 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. Maintenance period: 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64).
Time Frame A 16-week treatment period.
Hide Outcome Measure Data
Hide Analysis Population Description
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 analysed=subjects in the SAS, who were exposed in at least one maintenance period.
Arm/Group Title Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Hide Arm/Group Description:
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
Overall Number of Participants Analyzed 418 422
Measure Type: Number
Unit of Measure: Event
2772 3126
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Degludec (IDeg), Insulin Glargine (IGlar)
Comments Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in at least one maintenance period. 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was considered confirmed if the 95% confidence interval for the rate ratio (IDeg/IGlar) was ≤1.10 or equivalently if the p-value for the 1-sided test of H0: RR >1.10 against HA: RR ≤1.10 was less than 2.5%, where RR is the estimated rate ratio IDeg/IGlar.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Poisson
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.85 to 0.94
Estimation Comments If non-inferiority was confirmed the superiority of IDeg/IGlar was investigated outside of the test hierarchy. Superiority was considered confirmed if the upper bound of the 2-sided 95% confidence interval was <1.00.
2.Secondary Outcome
Title Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episodes During the Maintenance Period
Hide Description 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.
Time Frame After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)
Hide Outcome Measure Data
Hide Analysis Population Description
The trial followed a cross over design. Descriptive analysis was based on the SAS. Number of subjects analysed=subjects in the SAS, who were exposed in at least one maintenance period.
Arm/Group Title Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Hide Arm/Group Description:
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
Overall Number of Participants Analyzed 418 422
Measure Type: Number
Unit of Measure: Event
349 544
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Degludec (IDeg), Insulin Glargine (IGlar)
Comments Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in at least one maintenance period. 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was considered confirmed if the 95% confidence interval for the rate ratio (IDeg/IGlar) was ≤1.10 or equivalently if the p-value for the 1-sided test of H0: RR >1.10 against HA: RR ≤1.10 was less than 2.5%, where RR is the estimated rate ratio IDeg/IGlar.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Poisson
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.56 to 0.73
Estimation Comments If non-inferiority was confirmed the superiority of IDeg/IGlar was investigated outside of the test hierarchy. Superiority was considered confirmed if the upper bound of the 2-sided 95% confidence interval was <1.00.
3.Secondary Outcome
Title Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period
Hide Description 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.
Time Frame After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)
Hide Outcome Measure Data
Hide Analysis Population Description
The trial followed a cross over design. Descriptive analysis was based on the SAS. Number of subjects analysed=subjects in the SAS, who were exposed in at least one maintenance period.
Arm/Group Title Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Hide Arm/Group Description:
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
Overall Number of Participants Analyzed 418 422
Measure Type: Number
Unit of Measure: Percentage of subjects
10.3 17.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Degludec (IDeg), Insulin Glargine (IGlar)
Comments Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in both the maintenance periods. 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0016
Comments Superiority was confirmed if the p-value was less than 0.025.
Method McNemar
Comments [Not Specified]
4.Secondary Outcome
Title Incidence of Treatment Emergent Adverse Events
Hide Description 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.
Time Frame During 32 weeks of treatment for each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
The trial followed a cross over design. Results are based on the SAS.
Arm/Group Title Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Hide Arm/Group Description:
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
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 (fasting glycaemic target of 4.0-5.0 mmol/L).
Overall Number of Participants Analyzed 454 460
Measure Type: Number
Unit of Measure: Event
925 937
5.Secondary Outcome
Title Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Hide Description Change from baseline in HbA1c (glycosylated haemoglobin) at week 32 (treatment period 1) and at week 64 (treatment period 2). Week 32 HbA1c absolute value was considered as baseline for calculating change from baseline in HbA1c at week 64.
Time Frame Week 32, Week 64
Hide Outcome Measure Data
Hide Analysis Population Description
Both descriptive analysis and statistical analysis were based on the FAS. Here, 'n' specifies the number of subjects with available data at specified time-point.
Arm/Group Title Insulin Degludec/Insulin Glargine (IDeg/IGlar) Insulin Glargine/Insulin Degludec (IGlar/IDeg)
Hide Arm/Group Description:
Subjects received IDeg in treatment period 1 and IGlar in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg and IGlar were 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 IDeg and IGlar were reduced by 20% at the start of both the treatment periods. Doses of IDeg and 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).
Subjects received IGlar in treatment period 1 and IDeg in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar and IDeg were 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 and IDeg were reduced by 20% at the start of both the treatment periods. Doses of IGlar and 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).
Overall Number of Participants Analyzed 249 252
Mean (Standard Deviation)
Unit of Measure: Percentage of glycosylated haemoglobin
week 32 (n=209, 205) -0.73  (0.89) -0.66  (0.76)
week 64 (n=203, 199) 0.04  (0.51) 0.17  (0.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Degludec/Insulin Glargine (IDeg/IGlar), Insulin Glargine/Insulin Degludec (IGlar/IDeg)
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was considered confirmed if the upper bound of the two-sided 95% confidence interval was below or equal to 0.40%. Comparison groups: IDeg versus IGlar. Number of subjects included in analysis is 437 (n=220 for IDeg and n=217 for IGlar).
Method of Estimation Estimation Parameter Treatment contrast
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.10 to 0.15
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Insulin Degludec/Insulin Glargine (IDeg/IGlar), Insulin Glargine/Insulin Degludec (IGlar/IDeg)
Comments Change from baseline in HbA1c at week 64 (treatment period 2). The baseline values are week 32 values. 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
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was considered confirmed if the upper bound of the two-sided 95% confidence interval was below or equal to 0.40%. Comparison groups: IDeg versus IGlar. Number of subjects included in analysis is 410 (n=202 for IDeg and n=208 for IGlar).
Method of Estimation Estimation Parameter Treatment contrast
Estimated Value 0.11
Confidence Interval (2-Sided) 95%
-0.00 to 0.23
Estimation Comments [Not Specified]
6.Secondary Outcome
Title FPG (Fasting Plasma Glucose)
Hide Description Fasting plasma glucose values at week 32 and week 64.
Time Frame Week 32 and Week 64
Hide Outcome Measure Data
Hide Analysis Population Description
Results are based on the FAS. Here, 'n' specifies the number of subjects with available data at specified time-point.
Arm/Group Title Insulin Degludec/Insulin Glargine (IDeg/IGlar) Insulin Glargine/Insulin Degludec (IGlar/IDeg)
Hide Arm/Group Description:
Subjects received IDeg in treatment period 1 and IGlar in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg and IGlar were 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 IDeg and IGlar were reduced by 20% at the start of both the treatment periods. Doses of IDeg and 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).
Subjects received IGlar in treatment period 1 and IDeg in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar and IDeg were 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 and IDeg were reduced by 20% at the start of both the treatment periods. Doses of IGlar and 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).
Overall Number of Participants Analyzed 249 252
Mean (Standard Deviation)
Unit of Measure: mmol/L
week 32 (n=208, 204) 7.45  (3.57) 8.12  (3.56)
week 64 (n=203, 201) 8.62  (4.24) 7.54  (3.68)
Time Frame From the first day of exposure to randomised treatment and no later than the last day of randomised treatment (64 weeks).
Adverse Event Reporting Description Subjects in the SAS contributed to the evaluation of adverse events. The following displayed "number of subjects at risk"=454 and 460 for IDeg and IGlar, respectively (i.e, out of a total of 500 exposed subjects, 454 received IDeg and 460 received IGlar in a cross-over manner in 2 treatment periods.
 
Arm/Group Title Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Hide Arm/Group Description 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 (fasting glycaemic target of 4.0-5.0 mmol/L). 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 (fasting glycaemic target of 4.0-5.0 mmol/L).
All-Cause Mortality
Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   58/454 (12.78%)      70/460 (15.22%)    
Cardiac disorders     
Acute coronary syndrome  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Acute myocardial infarction  1  1/454 (0.22%)  1 1/460 (0.22%)  1
Supraventricular tachycardia  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Ventricular tachycardia  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Wolff-Parkinson-White syndrome  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Eye disorders     
Optic ischaemic neuropathy  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Gastrointestinal disorders     
Abdominal pain  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Ascites  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Colitis  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Constipation  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Gastrointestinal haemorrhage  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Ileus  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Impaired gastric emptying  1  1/454 (0.22%)  1 1/460 (0.22%)  1
Large intestine polyp  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Pancreatitis  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Vomiting  1  1/454 (0.22%)  1 2/460 (0.43%)  2
General disorders     
Non-cardiac chest pain  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Pyrexia  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Hepatobiliary disorders     
Biliary dyskinesia  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Cholelithiasis  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Infections and infestations     
Bacterial sepsis  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Cellulitis  1  2/454 (0.44%)  3 0/460 (0.00%)  0
Clostridium difficile colitis  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Fungal skin infection  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Influenza  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Osteomyelitis  1  1/454 (0.22%)  1 1/460 (0.22%)  1
Pneumonia  1  2/454 (0.44%)  2 3/460 (0.65%)  3
Pneumonia bacterial  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Sepsis  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Injury, poisoning and procedural complications     
Accidental overdose  1  2/454 (0.44%)  2 3/460 (0.65%)  3
Fall  1  2/454 (0.44%)  2 0/460 (0.00%)  0
Gun shot wound  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Overdose  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Pelvic fracture  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Respiratory fume inhalation disorder  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Road traffic accident  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Tibia fracture  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Diabetic ketoacidosis  1  2/454 (0.44%)  4 3/460 (0.65%)  3
Hypoglycaemia  1  17/454 (3.74%)  32 33/460 (7.17%)  47
Musculoskeletal and connective tissue disorders     
Intervertebral disc degeneration  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Intervertebral disc displacement  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Lumbar spinal stenosis  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Rhabdomyolysis  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer in situ  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Papillary thyroid cancer  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Uterine leiomyoma  1  2/454 (0.44%)  2 0/460 (0.00%)  0
Nervous system disorders     
Cerebrovascular accident  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Dizziness  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Headache  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Hypoglycaemic coma  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Hypoglycaemic seizure  1  3/454 (0.66%)  5 5/460 (1.09%)  5
Hypoglycaemic unconsciousness  1  18/454 (3.96%)  23 19/460 (4.13%)  24
Loss of consciousness  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Multiple sclerosis  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Optic neuritis  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Syncope  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Psychiatric disorders     
Mental status changes  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Schizophrenia  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Renal and urinary disorders     
Calculus ureteric  1  0/454 (0.00%)  0 1/460 (0.22%)  1
Respiratory, thoracic and mediastinal disorders     
Pneumothorax  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Surgical and medical procedures     
Pancreas transplant  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Vascular disorders     
Haematoma  1  1/454 (0.22%)  1 0/460 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Insulin Degludec (IDeg) Insulin Glargine (IGlar)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   97/454 (21.37%)      97/460 (21.09%)    
Infections and infestations     
Nasopharyngitis  1  68/454 (14.98%)  92 61/460 (13.26%)  73
Upper respiratory tract infection  1  29/454 (6.39%)  34 39/460 (8.48%)  41
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
EMail: clinicaltrials@novonordisk.com
Layout table for additonal information
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT02034513    
Other Study ID Numbers: NN1250-3995
U1111-1129-9668 ( Other Identifier: WHO )
2012-001930-32 ( EudraCT Number )
First Submitted: January 7, 2014
First Posted: January 13, 2014
Results First Submitted: January 11, 2017
Results First Posted: May 15, 2017
Last Update Posted: January 2, 2019