Trial Outcomes & Findings for A Trial Comparing Efficacy and Safety of Insulin Degludec/Insulin Aspart and BIAsp 30 in Insulin naïve Subjects With Type 2 Diabetes (NCT NCT01513590)

NCT ID: NCT01513590

Last Updated: 2019-03-26

Results Overview

Change from baseline in HbA1c after 26 weeks of treatment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

394 participants

Primary outcome timeframe

Week 0, week 26

Results posted on

2019-03-26

Participant Flow

The trial was conducted at 47 sites in 10 countries: Algeria (4), Bulgaria (7), Croatia (5), Czech Republic (4), Germany (5), Poland (5), Romania (5), Slovakia (3), Turkey (2), and Ukraine (7).

Subjects continued their metformin monotherapy or metformin in any combination with one of the following OADs: insulin secretagogue (sulphonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitor, α-glucosidase inhibitors for at least 12 weeks prior to randomisation.

Participant milestones

Participant milestones
Measure	IDegAsp BID Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Overall Study STARTED	197	197
Overall Study Exposed	196	195
Overall Study COMPLETED	187	184
Overall Study NOT COMPLETED	10	13

Reasons for withdrawal

Reasons for withdrawal
Measure	IDegAsp BID Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Overall Study Adverse Event	2	3
Overall Study Withdrawal Criteria	3	0
Overall Study Unclassified	5	10

Baseline Characteristics

A Trial Comparing Efficacy and Safety of Insulin Degludec/Insulin Aspart and BIAsp 30 in Insulin naïve Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IDegAsp BID n=197 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=197 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.	Total n=394 Participants Total of all reporting groups
Age, Continuous	59.0 years STANDARD_DEVIATION 9.5 • n=5 Participants	58.8 years STANDARD_DEVIATION 8.4 • n=7 Participants	58.9 years STANDARD_DEVIATION 8.9 • n=5 Participants
Sex: Female, Male Female	95 Participants n=5 Participants	96 Participants n=7 Participants	191 Participants n=5 Participants
Sex: Female, Male Male	102 Participants n=5 Participants	101 Participants n=7 Participants	203 Participants n=5 Participants
Glycosylated Haemoglobin (HbA1c)	8.5 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	8.3 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.7 • n=7 Participants	8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants
Fasting plasma glucose (FPG)	10.5 mmol/L STANDARD_DEVIATION 2.4 • n=5 Participants	10.0 mmol/L STANDARD_DEVIATION 2.3 • n=7 Participants	10.2 mmol/L STANDARD_DEVIATION 2.3 • n=5 Participants
Body Weight	88.0 kg STANDARD_DEVIATION 15.0 • n=5 Participants	88.5 kg STANDARD_DEVIATION 14.9 • n=7 Participants	88.2 kg STANDARD_DEVIATION 14.9 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, week 26

Population: The full analysis set (FAS) included all randomised subjects. 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	IDegAsp BID n=197 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=197 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Change From Baseline in HbA1c (Glycosylated Haemoglobin)	-1.85 Percent (%) glycosylated haemoglobin Standard Deviation 0.97	-1.73 Percent (%) glycosylated haemoglobin Standard Deviation 0.93

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The full analysis set (FAS) included all randomised subjects. Missing data were imputed using LOCF. At baseline 195 subjects each in IDegAsp BID and BIAsp 30 BID treatment group were analysed.

Change from baseline in fasting plasma glucose (FPG) after 26 weeks of treatment.

Outcome measures

Outcome measures
Measure	IDegAsp BID n=195 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Change From Baseline in Fasting Plasma Glucose (FPG)	-4.44 mmol/L Standard Deviation 2.97	-3.03 mmol/L Standard Deviation 2.90

SECONDARY outcome

Timeframe: Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product

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

The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes, which is presented here. 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. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 am.

Outcome measures

Outcome measures
Measure	IDegAsp BID n=196 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or Minor Hypoglycaemic Episodes	60 episodes	260 episodes

SECONDARY outcome

Timeframe: Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product

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	IDegAsp BID n=196 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes	553 episodes	1221 episodes

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator. Missing data were imputed using last observation carried forward (LOCF).

Change from baseline in body weight after 26 weeks of treatment.

Outcome measures

Outcome measures
Measure	IDegAsp BID n=196 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Change From Baseline in Body Weight	2.8 kg Standard Deviation 4.1	2.0 kg Standard Deviation 4.3

SECONDARY outcome

Timeframe: Week 26

Population: The full analysis set (FAS) included all randomised subjects. Missing data were imputed using LOCF. Data for 15 subjects were excluded, as only subjects exposed for at least 12 weeks were included in this measurement.

Responder for HbA1c (\<7.0%) without severe and minor treatment emergent hypoglycaemic episodes during the last 12 weeks of treatment. Severe + minor hypoglycaemic episodes = confirmed hypoglycaemic episodes. Severe hypoglycaemic episodes: requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: able to treat her/himself and plasma glucose below 3.1 mmol/L.

Outcome measures

Outcome measures
Measure	IDegAsp BID n=192 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Responder for HbA1c (Below 7.0%) Without Severe and Minor Treatment Emergent Hypoglycaemic Episodes During the Last 12 Weeks of Treatment Including Only Subjects Exposed for at Least 12 Weeks	77 participants	59 participants

SECONDARY outcome

Timeframe: Onset on or after the first day of exposure to investigational product and no later than 7 days after exposure to investigational product

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

A Treatment Emergent Adverse Event (TEAE) was defined as an event that had 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. Severity was assessed by investigator.

Outcome measures

Outcome measures
Measure	IDegAsp BID n=196 Participants Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Number of Treatment Emergent AEs (Adverse Events) Events	197 events	137 events
Number of Treatment Emergent AEs (Adverse Events) Serious	20 events	12 events
Number of Treatment Emergent AEs (Adverse Events) Severe	13 events	8 events
Number of Treatment Emergent AEs (Adverse Events) Moderate	45 events	27 events
Number of Treatment Emergent AEs (Adverse Events) Mild	139 events	102 events
Number of Treatment Emergent AEs (Adverse Events) Fatal	2 events	2 events

Adverse Events

IDegAsp BID

Serious events: 13 serious events

Other events: 15 other events

Deaths: 0 deaths

BIAsp 30 BID

Serious events: 10 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	IDegAsp BID n=196 participants at risk Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Infections and infestations Nasopharyngitis	7.7% 15/196 • Number of events 17 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	3.6% 7/195 • Number of events 10 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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 BID n=196 participants at risk Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal.	BIAsp 30 BID n=195 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal.
Cardiac disorders Acute coronary syndrome	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Acute myocardial infarction	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Angina unstable	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Cardiac failure	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Coronary artery insufficiency	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Myocardial ischaemia	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	1.0% 2/195 • Number of events 2 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Ear and labyrinth disorders Deafness neurosensory	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Eye disorders Optic ischaemic neuropathy	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Colonic stenosis	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Diarrhoea	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Flatulence	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Inguinal hernia, obstructive	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
General disorders Non-cardiac chest pain	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Hepatobiliary disorders Cholelithiasis	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Meningitis pneumococcal	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Peritonsillar abscess	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Pneumonia	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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 Foot fracture	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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	1.0% 2/196 • Number of events 2 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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 Arthritis	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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) Colon cancer stage I	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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) Pancreatic carcinoma metastatic	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Hypoglycaemic unconsciousness	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). 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 Pulmonary oedema	0.51% 1/196 • Number of events 2 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Skin and subcutaneous tissue disorders Skin lesion	0.51% 1/196 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/195 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Hypertension	0.00% 0/196 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.	0.51% 1/195 • Number of events 1 • From the first trial-related activity after the subject had signed the informed consent (Week -1) and until post-treatment follow-up period (Week 27). The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.