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Clinical Trial Results:
A 38 week trial comparing effect and safety of insulin degludec/insulin aspart vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification

Summary
EudraCT number	2015-004768-12
Trial protocol	CZ
Global end of trial date	24 Dec 2017

Results information
Results version number	v1(current)
This version publication date	23 Dec 2018
First version publication date	23 Dec 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NN5401-4266

ISRCTN number

US NCT number

NCT02906917

WHO universal trial number (UTN)

U1111-1175-7895

Sponsor organisation name

Novo Nordisk A/S

Sponsor organisation address

Novo Allé, Bagsvaerd, Denmark, 2880

Public contact

Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Scientific contact

Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Jun 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Aug 2017

Global end of trial reached?

Yes

Global end of trial date

24 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

To confirm the effect of insulin degludec/insulin aspart once daily versus insulin glargine once daily in combination with insulin aspart once daily in controlling glycaemia after 26 weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association (WMA) Assembly, October 2013), International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (10 June 1996) and 21 United States Code of Federal Regulations (CFR) 312.120.

Background therapy

The following products were regarded as non-investigational medicinal products (non-IMPs) in this trial: Oral antidiabetic drugs (OADs) and washout insulins. OADs: Subjects were allowed to take the following OADs throughout the treatment period (week 0-38): 1) Metformin, 2) α-glucosidase-inhibitors, 3) Dipeptidyl peptidase-IV (DPP-4) inhibitors, 4) sodium/glucose co-transporter 2 (SGLT-2) inhibitors, and 5) Oral combination products (of the allowed individual OADs above). Washout insulins: The ‘washout’ insulin products used in the follow-up period between the end-of-treatment visit (week 38) and the 7-day follow-up visit (week 39) are as follows: 1) Human isophane insulin (NPH) (Insulatard®, Protaphane®, Novolin® N), 2) Biphasic insulin aspart 30 (BIAsp 30) (NovoMix® 30, NovoLog® Mix 70/30), and 3) Insulin aspart (NovoRapid®/NovoLog®).

Evidence for comparator

Not applicable.

Actual start date of recruitment

20 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Algeria: 46

Country: Number of subjects enrolled

Czech Republic: 60

Country: Number of subjects enrolled

India: 51

Country: Number of subjects enrolled

Russian Federation: 110

Country: Number of subjects enrolled

Serbia: 46

Country: Number of subjects enrolled

Turkey: 66

Country: Number of subjects enrolled

United States: 153

Worldwide total number of subjects

532

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

383

From 65 to 84 years

149

85 years and over

Subject disposition

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Recruitment details

The trial was conducted at 71 sites in 7 countries, as follows: Algeria (4), Czech Republic (6), India (10), Russian Federation (11), Serbia (5), Turkey (7), and United States (28). Additionally, 1 site in the United States screened, but didn’t randomise any subject.

Screening details

Not applicable.

Period 1 title

Initiation period (Week 0-26)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable.

Are arms mutually exclusive

Yes

Insulin degludec/insulin aspart

Arm description

Subjects received Insulin degludec/insulin aspart (IDegAsp) once daily (OD) with or without OAD(s) for 26 weeks (week 0-26).

Arm type

Experimental

Investigational medicinal product name

Insulin degludec/insulin aspart

Investigational medicinal product code

Other name

Ryzodeg®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IDegAsp OD was administered with the largest meal each day. Subjects switching from pre-trial basal insulin OD or more to IDegAsp OD at trial entry were to transfer unit-to-unit.

Insulin glargine + insulin aspart

Arm description

Subjects received Insulin glargine (IGlar) OD and insulin aspart (IAsp) OD with or without OAD(s) for 26 weeks (week 0-26).

Arm type

Active comparator

Investigational medicinal product name

Insulin glargine

Investigational medicinal product code

Other name

Lantus®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IGlar OD was administered in accordance with local labelling. Subjects switching from pre-trial basal insulin OD to IGlar OD were to transfer unit-to-unit to IGlar, while subjects switching from basal insulin more than OD to IGlar OD were to reduce the initial total daily dose by 20% or according to local labelling.

Investigational medicinal product name

Insulin aspart

Investigational medicinal product code

Other name

NovoRapid®, NovoLog®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IAsp OD was administered with the largest meal. IAsp was to be initiated at 4 units.

Number of subjects in period 1	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Started	267	265
Exposed	265	263
Completed	261	254
Not completed	6	11
Consent withdrawn by subject	3	4
Adverse event, non-fatal	1	-
Unclassified	1	3
Lost to follow-up	1	4

Period 2 title

Intensification period (Week 26-38)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable.

Are arms mutually exclusive

Yes

Insulin degludec/insulin aspart

Arm description

Subjects received IDegAsp OD/twice a day (BID) with or without OAD(s) for 12 weeks (week 26-38).

Arm type

Experimental

Investigational medicinal product name

Insulin degludec/insulin aspart

Investigational medicinal product code

Other name

Ryzodeg®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IDegAsp OD/BID was administered with the largest meal(s) each day (in the case of BID dosing, one meal being dinner) based on individual needs.

Insulin glargine + insulin aspart

Arm description

Subjects received IGlar OD and IAsp 1−3 times daily with or without OAD(s) for 12 weeks (week 26-38).

Arm type

Active comparator

Investigational medicinal product name

Insulin glargine

Investigational medicinal product code

Other name

Lantus®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IGlar OD was administered in accordance with local labelling.

Investigational medicinal product name

Insulin aspart

Investigational medicinal product code

Other name

NovoRapid®, NovoLog®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IAsp 1−3 times daily was administered with main meals based on individual needs.

Number of subjects in period 2	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Started	261	254
Completed	252	247
Not completed	9	7
Adverse event, serious fatal	-	2
Consent withdrawn by subject	3	2
Unclassified	3	2
Lost to follow-up	3	1

Baseline characteristics

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Reporting group title

Insulin degludec/insulin aspart

Reporting group description

Subjects received Insulin degludec/insulin aspart (IDegAsp) once daily (OD) with or without OAD(s) for 26 weeks (week 0-26).

Reporting group title

Insulin glargine + insulin aspart

Reporting group description

Subjects received Insulin glargine (IGlar) OD and insulin aspart (IAsp) OD with or without OAD(s) for 26 weeks (week 0-26).

Reporting group values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart	Total
Number of subjects	267	265	532
Age Categorical
Units: Subjects
Adults (18-64 years)	203	180	383
From 65-84 years	64	85	149
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.2 ± 8.9	59.2 ± 9.1	-
Gender Categorical
Units: Subjects
Female	142	128	270
Male	125	137	262

End points

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Reporting group title

Insulin degludec/insulin aspart

Reporting group description

Subjects received Insulin degludec/insulin aspart (IDegAsp) once daily (OD) with or without OAD(s) for 26 weeks (week 0-26).

Reporting group title

Insulin glargine + insulin aspart

Reporting group description

Subjects received Insulin glargine (IGlar) OD and insulin aspart (IAsp) OD with or without OAD(s) for 26 weeks (week 0-26).

Reporting group title

Insulin degludec/insulin aspart

Reporting group description

Subjects received IDegAsp OD/twice a day (BID) with or without OAD(s) for 12 weeks (week 26-38).

Reporting group title

Insulin glargine + insulin aspart

Reporting group description

Subjects received IGlar OD and IAsp 1−3 times daily with or without OAD(s) for 12 weeks (week 26-38).

Subject analysis set title

Insulin degludec/insulin aspart

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received IDegAsp OD with or without OAD(s) for 26 weeks (week 0-26 (Initiation period; period-1)).

Subject analysis set title

Insulin glargine + insulin aspart

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received IGlar OD and IAsp OD with or without OAD(s) for 26 weeks (week 0-26 (Initiation period; period-1)).

Subject analysis set title

Insulin degludec/insulin aspart

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received treatment for 38 weeks as per the following sequence: 1) Initiation period (period-1, week 0−26): IDegAsp OD was administered with or without OAD(s). 2) Intensification period (period-2, week 26−38): IDegAsp OD/BID was administered with or without OAD(s).

Subject analysis set title

Insulin glargine + insulin aspart

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received treatment for 38 weeks as per the following sequence: 1) Initiation period (period-1, week 0−26): IGlar OD and IAsp OD was administered with or without OAD(s). 2) Intensification period (period-2, week 26−38): IGlar OD and IAsp 1−3 times daily was administered with or without OAD(s).

Subject analysis set title

Insulin degludec/insulin aspart

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Insulin glargine + insulin aspart

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

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End point title

Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

End point description

Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated 26 weeks after randomisation. Results are based on the full analysis set (FAS), which included all randomised subjects. ‘n’ represents the ‘number of subjects analysed’ at specified time point, which is the number of subjects contributed to the analysis at specified time point.

End point type

Primary

End point timeframe

From baseline after 26 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	267	265
Units: % of HbA1c
arithmetic mean (standard deviation)
Baseline (week 0): n=261, 264	8.2 ± 0.8	8.1 ± 0.7
Change from baseline (week 26): n=251, 248	-1.1 ± 0.9	-1.1 ± 0.8

Change in HbA1c (%) - Week 26

Statistical analysis description

The response and change from baseline in response are analysed on 1000 complete, imputed data sets after multiple imputation for each treatment arm separately. A penalty of 0.4% is added to the week 26 values for all premature treatment discontinued subjects and subject with missing HbA1c values at week 26 in the IDegAsp arm. Each of the imputed data sets are analysed through an analysis of covariance (ANCOVA).

Comparison groups

Insulin glargine + insulin aspart v Insulin degludec/insulin aspart

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

< 0.0001 ^[2]

Method

ANCOVA

Parameter type

Treatment contrast

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.21

Notes
[1] - Non-inferiority of IDegAsp OD versus IGlar OD + IAsp OD was considered confirmed if the 95% confidence interval for the mean treatment difference was entirely below 0.4%. Treatment, region, sex, previous insulin treatment and previous OAD treatment as categorical fixed effects and baseline response and age as covariate.
[2] - One-sided p-value for test of non-inferiority.

Secondary: Responder (Yes/No) for HbA1c <7% - Week 26

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End point title

Responder (Yes/No) for HbA1c <7% - Week 26

End point description

Participants achieving (yes/no) HbA1c <7% was evaluated 26 weeks after randomisation. Results are based on the FAS. ‘n’ represents the ‘number of subjects analysed’ at specified time point, which is the number of subjects contributed to the analysis at specified time point.

End point type

Secondary

End point timeframe

After 26 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	267	265
Units: Number of participants
Yes: n=241, 242	120	120
No: n=241, 242	121	122

No statistical analyses for this end point

Secondary: Change from baseline in HbA1c (%) - Week 38

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End point title

Change from baseline in HbA1c (%) - Week 38

End point description

Change from baseline (week 0) in HbA1c was evaluated 38 weeks after randomisation. Results are based on the FAS. ‘n’ represents the ‘number of subjects analysed’ at specified time point, which is the number of subjects contributed to the analysis at specified time point.

End point type

Secondary

End point timeframe

After 38 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	267	265
Units: % of HbA1c
arithmetic mean (standard deviation)
Baseline (week 0): n=261, 264	8.2 ± 0.8	8.1 ± 0.7
Change from baseline (week 38): n=247, 242	-1.2 ± 0.9	-1.2 ± 0.9

No statistical analyses for this end point

Secondary: Responder (Yes/No) for HbA1c <7% - Week 38

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End point title

Responder (Yes/No) for HbA1c <7% - Week 38

End point description

Participants achieving (yes/no) HbA1c <7% was evaluated 38 weeks after randomisation. Results are based on the FAS. ‘n’ represents the ‘number of subjects analysed’ at specified time point, which is the number of subjects contributed to the analysis at specified time point.

End point type

Secondary

End point timeframe

After 38 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	267	265
Units: Number of participants
Yes: n=234, 233	139	140
No: n=234, 233	95	93

No statistical analyses for this end point

Secondary: Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

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End point title

Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

End point description

Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were analysed during week 0-26. Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Treatment emergent: hypoglycaemic episodes were defined as treatment emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Results are based on the safety analysis set, which included all subjects receiving at least one dose of the investigational product (IDegAsp) or comparator (IGlar).

End point type

Secondary

End point timeframe

During 26 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	265	263
Units: Episodes	329	376

No statistical analyses for this end point

Secondary: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

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End point title

Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

End point description

Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were analysed during week 0-38. Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Treatment emergent: hypoglycaemic episodes were defined as treatment emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Results are based on the safety analysis set.

End point type

Secondary

End point timeframe

During 38 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	265	263
Units: Episodes	537	640

No statistical analyses for this end point

Secondary: Incidence of treatment-emergent adverse events (TEAEs)

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End point title

Incidence of treatment-emergent adverse events (TEAEs)

End point description

Number of TEAEs were analysed during week 0-38. Treatment emergent: An adverse event that had an onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. If an event had an onset date before the first day of exposure on randomised treatment and increased in severity during the treatment period, or if it had an onset date within 7 days after the last drug date, then this event was also to be considered as a TEAE. Results are based on the safety analysis set.

End point type

Secondary

End point timeframe

During 38 weeks

End point values	Insulin degludec/insulin aspart	Insulin glargine + insulin aspart
Number of subjects analysed	265	263
Units: Events	614	525

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Week 0 to week 38 (treatment period) + 7 days (follow-up period).

Adverse event reporting additional description

All presented adverse events are treatment emergent (i.e., TEAEs). Results are based on the safety analysis set. Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Insulin glargine + insulin aspart

Reporting group description

Reporting group title

Insulin degludec/insulin aspart

Reporting group description

Serious adverse events	Insulin glargine + insulin aspart	Insulin degludec/insulin aspart
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 263 (7.60%)	18 / 265 (6.79%)
number of deaths (all causes)	2	0
number of deaths resulting from adverse events	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	2 / 263 (0.76%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pituitary tumour benign
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Cholecystectomy
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hernia repair
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 263 (0.38%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 263 (0.38%)	2 / 265 (0.75%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 263 (0.38%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Nervous system disorders
Facial paralysis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VIth nerve paralysis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 263 (0.76%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric polyps
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hidradenitis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Tubulointerstitial nephritis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Adrenal mass
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epiglottitis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Furuncle
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	1 / 263 (0.38%)	0 / 265 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 263 (0.38%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 263 (0.00%)	1 / 265 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Insulin glargine + insulin aspart	Insulin degludec/insulin aspart
Total subjects affected by non serious adverse events
subjects affected / exposed	57 / 263 (21.67%)	74 / 265 (27.92%)
Nervous system disorders
Headache
subjects affected / exposed	16 / 263 (6.08%)	27 / 265 (10.19%)
occurrences all number	23	52
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	9 / 263 (3.42%)	16 / 265 (6.04%)
occurrences all number	9	17
Infections and infestations
Nasopharyngitis
subjects affected / exposed	22 / 263 (8.37%)	36 / 265 (13.58%)
occurrences all number	27	49
Upper respiratory tract infection
subjects affected / exposed	17 / 263 (6.46%)	15 / 265 (5.66%)
occurrences all number	17	17

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Were there any global substantial amendments to the protocol? Yes

08 Feb 2017

Following are the key changes done to the protocol amendment: 1) Extension of the recruitment period; planned last patient last visit (LPLV) changed from 16-Nov-2017 to 12-Dec-2017. 2) Clarification of adverse event (AE) collection during follow-up. 3) Clarification of data collection for antidiabetic concomitant medications and other concomitant medications. 4) Addition of supportive secondary endpoint: HbA1c responders without severe or BG confirmed symptomatic hypoglycaemia. 5) Implementation of a new standard for statistical data handling in line with new requirements from US Food and Drug Administration (FDA) (changes to the statistical analysis of hypoglycaemic rate during the maintenance period). 6) Correction of errors. 7) Provision of clarifications/specification of processes.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A 38 week trial comparing effect and safety of insulin degludec/insulin aspart vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

Primary: Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

Secondary: Responder (Yes/No) for HbA1c <7% - Week 26

Secondary: Responder (Yes/No) for HbA1c <7% - Week 26

Secondary: Change from baseline in HbA1c (%) - Week 38

Secondary: Change from baseline in HbA1c (%) - Week 38

Secondary: Responder (Yes/No) for HbA1c <7% - Week 38

Secondary: Responder (Yes/No) for HbA1c <7% - Week 38

Secondary: Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

Secondary: Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

Secondary: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

Secondary: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

Secondary: Incidence of treatment-emergent adverse events (TEAEs)

Secondary: Incidence of treatment-emergent adverse events (TEAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A 38 week trial comparing effect and safety of insulin degludec/insulin aspart vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

Primary: Change in glycosylated haemoglobin (HbA1c) (%) - Week 26

Secondary: Responder (Yes/No) for HbA1c <7% - Week 26

Secondary: Responder (Yes/No) for HbA1c <7% - Week 26

Secondary: Change from baseline in HbA1c (%) - Week 38

Secondary: Change from baseline in HbA1c (%) - Week 38

Secondary: Responder (Yes/No) for HbA1c <7% - Week 38

Secondary: Responder (Yes/No) for HbA1c <7% - Week 38

Secondary: Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

Secondary: Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes - 26 weeks

Secondary: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

Secondary: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes - 38 weeks

Secondary: Incidence of treatment-emergent adverse events (TEAEs)

Secondary: Incidence of treatment-emergent adverse events (TEAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 38 week trial comparing effect and safety of insulin degludec/insulin aspart vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification