Trial Outcomes & Findings for Comparison of NN5401 Plus Insulin Aspart With Insulin Detemir Plus Insulin Aspart in Type 1 Diabetes (NCT NCT00978627)

NCT ID: NCT00978627

Last Updated: 2017-03-20

Results Overview

Change from baseline in HbA1c after 26 weeks of treatment

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

548 participants

Primary outcome timeframe

Week 0, Week 26

Results posted on

2017-03-20

Participant Flow

The trial was conducted at 79 sites in 9 countries: Denmark (3 sites), Poland (6 sites), Romania (8 sites), France (3 sites), United Kingdom (8 sites), Russian Federation (11 sites), Israel (4 sites), Australia (7 sites), and United States (29 sites). Some sites did not enrol subjects in the extension period.

The total duration of treatment was up to 52 weeks (26 weeks \[main trial: NN5401-3594, NCT00978627\] + 26 weeks \[extension trial: NN5401-3645\]), separated by 1 week of wash-out period; during which subjects were treated with Neutral Protamine Hagedorn (NPH) insulin twice daily (BID) in combination with insulin aspart.

Participant milestones

Participant milestones
Measure	IDegAsp OD Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDet Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main: Week 0 to 26 (NN5401-3594) STARTED	366	182
Main: Week 0 to 26 (NN5401-3594) Exposed	362	180
Main: Week 0 to 26 (NN5401-3594) COMPLETED	320	156
Main: Week 0 to 26 (NN5401-3594) NOT COMPLETED	46	26
Extension: Week 27 to 52 (NN5401-3645) STARTED	254	122
Extension: Week 27 to 52 (NN5401-3645) COMPLETED	233	113
Extension: Week 27 to 52 (NN5401-3645) NOT COMPLETED	21	9

Reasons for withdrawal

Reasons for withdrawal
Measure	IDegAsp OD Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDet Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main: Week 0 to 26 (NN5401-3594) Adverse Event	4	3
Main: Week 0 to 26 (NN5401-3594) Lack of Efficacy	2	0
Main: Week 0 to 26 (NN5401-3594) Protocol Violation	8	6
Main: Week 0 to 26 (NN5401-3594) Withdrawal criteria	7	5
Main: Week 0 to 26 (NN5401-3594) Unclassified	25	12
Extension: Week 27 to 52 (NN5401-3645) Adverse Event	3	0
Extension: Week 27 to 52 (NN5401-3645) Protocol Violation	4	1
Extension: Week 27 to 52 (NN5401-3645) Withdrawal criteria	2	1
Extension: Week 27 to 52 (NN5401-3645) Unclassified	12	7

Baseline Characteristics

Comparison of NN5401 Plus Insulin Aspart With Insulin Detemir Plus Insulin Aspart in Type 1 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IDegAsp OD n=366 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDet n=182 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	Total n=548 Participants Total of all reporting groups
Age, Continuous	40.7 years STANDARD_DEVIATION 12.8 • n=5 Participants	42.6 years STANDARD_DEVIATION 13.8 • n=7 Participants	41.3 years STANDARD_DEVIATION 13.2 • n=5 Participants
Sex: Female, Male Female	176 Participants n=5 Participants	100 Participants n=7 Participants	276 Participants n=5 Participants
Sex: Female, Male Male	190 Participants n=5 Participants	82 Participants n=7 Participants	272 Participants n=5 Participants
Glycosylated haemoglobin (HbA1c)	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 • n=7 Participants	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants
Fasting plasma glucose (FPG)	10.3 mmol/L STANDARD_DEVIATION 4.7 • n=5 Participants	11.0 mmol/L STANDARD_DEVIATION 4.8 • n=7 Participants	10.5 mmol/L STANDARD_DEVIATION 4.8 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 26

Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF).

Change from baseline in HbA1c after 26 weeks of treatment

Outcome measures

Outcome measures
Measure	IDet n=182 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=366 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment	-0.68 percentage of glycosylated haemoglobin Standard Deviation 0.77	-0.73 percentage of glycosylated haemoglobin Standard Deviation 0.83

PRIMARY outcome

Timeframe: Week 0 to Week 53 + 7 days follow up

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol /L.

Outcome measures

Outcome measures
Measure	IDet n=180 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=362 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	3673 Episodes/100 years of patient exposure	3183 Episodes/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0 to Week 53 + 7 days follow up

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Outcome measures

Outcome measures
Measure	IDet n=180 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=362 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes	541 Episodes/100 years of patient exposure	309 Episodes/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0 to Week 53 + 7 days of follow up

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.

Outcome measures

Outcome measures
Measure	IDet n=180 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=362 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Adverse event (AE)	442 Events/100 years of patient exposure	408 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Serious AE	19 Events/100 years of patient exposure	24 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Severe AE	48 Events/100 years of patient exposure	33 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Moderate AE	83 Events/100 years of patient exposure	93 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Mild AE	311 Events/100 years of patient exposure	282 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Fatal AE	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 26 + 7 days follow up

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Outcome measures

Outcome measures
Measure	IDet n=180 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=362 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	4434 Episodes/100 years of patient exposure	3917 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 26

Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). For 22 subjects all 9-point SMPG values were missing.

Overall mean of 9-point SMPG at 26 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime, at 4 am and before breakfast.

Outcome measures

Outcome measures
Measure	IDet n=177 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=349 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26	8.4 mmol/L Standard Deviation 2.5	8.0 mmol/L Standard Deviation 2.2

SECONDARY outcome

Timeframe: Week 0, Week 53

Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF).

Change from baseline in HbA1c after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	IDet n=182 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=366 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment	-0.56 percentage of glycosylated haemoglobin Standard Deviation 0.80	-0.65 percentage of glycosylated haemoglobin Standard Deviation 0.81

SECONDARY outcome

Timeframe: Week 0 to Week 26 + 7 days follow up

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Outcome measures

Outcome measures
Measure	IDet n=180 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=362 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes	572 Episodes/100 years of patient exposure	371 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0, Week 53

Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). For 2 subjects, FPG values were missing.

Change from baseline in FPG after 52 weeks of treatment.

Outcome measures

Outcome measures
Measure	IDet n=181 Participants Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDegAsp OD n=365 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment	-2.40 mmol/L Standard Deviation 5.86	-1.83 mmol/L Standard Deviation 5.69

Adverse Events

IDegAsp OD

Serious events: 46 serious events

Other events: 166 other events

Deaths: 0 deaths

IDet

Serious events: 20 serious events

Other events: 90 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	IDegAsp OD n=362 participants at risk Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDet n=180 participants at risk Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Gastrointestinal disorders Diarrhoea	3.6% 13/362 • Number of events 14 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	6.7% 12/180 • Number of events 12 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Nausea	3.9% 14/362 • Number of events 24 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	5.0% 9/180 • Number of events 10 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
General disorders Injection site reaction	1.4% 5/362 • Number of events 8 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	5.0% 9/180 • Number of events 36 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Gastroenteritis	3.9% 14/362 • Number of events 15 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	5.0% 9/180 • Number of events 10 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Influenza	6.9% 25/362 • Number of events 25 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	5.0% 9/180 • Number of events 12 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Nasopharyngitis	24.6% 89/362 • Number of events 139 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	21.1% 38/180 • Number of events 62 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Upper respiratory tract infection	9.1% 33/362 • Number of events 48 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	11.1% 20/180 • Number of events 30 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemia	8.0% 29/362 • Number of events 40 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	13.3% 24/180 • Number of events 50 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Headache	9.7% 35/362 • Number of events 102 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	8.9% 16/180 • Number of events 22 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.
Publication restrictions are in place

Restriction type: OTHER

Measure	IDegAsp OD n=362 participants at risk Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.	IDet n=180 participants at risk Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Angina pectoris	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Pericardial effusion	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Tachyarrhythmia	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Eye disorders Eye haemorrhage	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Abdominal pain	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Food poisoning	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Gastric polyps	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Hiatus hernia	0.55% 2/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Immune system disorders Hypersensitivity	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Abscess limb	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Gastroenteritis	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Meningitis	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Pulmonary tuberculosis	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Wound infection	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Injury, poisoning and procedural complications Ankle fracture	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Injury, poisoning and procedural complications Intentional overdose	0.28% 1/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Injury, poisoning and procedural complications Wrong drug administered	0.55% 2/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.28% 1/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	1.7% 3/180 • Number of events 3 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemia	4.1% 15/362 • Number of events 25 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	5.0% 9/180 • Number of events 9 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemic seizure	0.55% 2/362 • Number of events 3 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemic unconsciousness	1.9% 7/362 • Number of events 7 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	2.2% 4/180 • Number of events 4 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Arthralgia	0.55% 2/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Hypoglycaemic coma	0.28% 1/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Migraine	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Psychiatric disorders Depression	0.55% 2/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Psychiatric disorders Suicidal ideation	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Psychiatric disorders Suicide attempt	0.28% 1/362 • Number of events 2 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/362 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.56% 1/180 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Social circumstances Victim of crime	0.28% 1/362 • Number of events 1 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/180 • Week 0 to Week 53 + 7 days of follow up. The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.