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)

• 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: Novo Nordisk A/S
• 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

Participant Flow

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)
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

Baseline Characteristics

Arm/Group Title		Insulin Degludec/Insulin Glargine (IDeg/IGlar)	Insulin Glargine/Insulin Degludec (IGlar/IDeg)	Total
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
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

Outcome Measures

1. Primary Outcome

Title	Number of Treatment Emergent Severe or BG (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period
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.

Outcome Measure Data

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)
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

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
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)

Outcome Measure Data

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)
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

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
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)

Outcome Measure Data

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)
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

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
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

Outcome Measure Data

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)
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)
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

Outcome Measure Data

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)
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)

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]

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)
Description	Fasting plasma glucose values at week 32 and week 64.
Time Frame	Week 32 and Week 64

Outcome Measure Data

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)
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)

Adverse Events

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)
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	--/--		--/--
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Public Access to Clinical Trials
• Organization: Novo Nordisk A/S
• EMail: clinicaltrials@novonordisk.com

Publications of Results:

Lane W, Bailey TS, Gerety G, Gumprecht J, Philis-Tsimikas A, Hansen CT, Nielsen TSS, Warren M; Group Information; SWITCH 1. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):33-44. doi: 10.1001/jama.2017.7115.

Evans M, Mehta R, Gundgaard J, Chubb B. Cost-Effectiveness of Insulin Degludec vs. Insulin Glargine U100 in Type 1 and Type 2 Diabetes Mellitus in a UK Setting. Diabetes Ther. 2018 Oct;9(5):1919-1930. doi: 10.1007/s13300-018-0478-1. Epub 2018 Aug 10.

DeVries JH, Bailey TS, Bhargava A, Gerety G, Gumprecht J, Heller S, Lane W, Wysham CH, Zinman B, Bak BA, Hachmann-Nielsen E, Philis-Tsimikas A. Day-to-day fasting self-monitored blood glucose variability is associated with risk of hypoglycaemia in insulin-treated patients with type 1 and type 2 diabetes: A post hoc analysis of the SWITCH Trials. Diabetes Obes Metab. 2019 Mar;21(3):622-630. doi: 10.1111/dom.13565. Epub 2018 Nov 26.

• 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