Trial Outcomes & Findings for Comparison of NN1250 With Insulin Glargine Plus Insulin Aspart With/Without Metformin and With/Without Pioglitazone in Type 2 Diabetes (NCT NCT00972283)

NCT ID: NCT00972283

Last Updated: 2017-04-06

Results Overview

Change from baseline in HbA1c after 52 weeks of treatment

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1006 participants

Primary outcome timeframe

Week 0, Week 52

Results posted on

2017-04-06

Participant Flow

The trial was conducted at 123 sites in 12 countries: Bulgaria (8 sites), Germany (8), Hong Kong (1), Ireland (4), Italy (11), Romania (5), Russia (6), Slovakia (4), South Africa (5), Spain (9), Turkey (3) and the United States (U.S.) (59). Some sites did not enroll subjects in the extension period. One site from United States was closed.

All subjects who completed the 52-week main trial (NN1250-3582, NCT00972283) and were found to be eligible for the extension trial were offered to participate in the 26-week extension trial (NN1250-3667). The total duration of treatment was up to 78 weeks (52 weeks + 26 weeks).

Participant milestones

Participant milestones
Measure	IDeg OD Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Main: Week 0 to 52 (NN1250-3582) STARTED	755	251
Main: Week 0 to 52 (NN1250-3582) Full Analysis Set	744	248
Main: Week 0 to 52 (NN1250-3582) Exposed	753	251
Main: Week 0 to 52 (NN1250-3582) COMPLETED	618	211
Main: Week 0 to 52 (NN1250-3582) NOT COMPLETED	137	40
Extension: Week 53 to 78 (NN1250-3667) STARTED	566	191
Extension: Week 53 to 78 (NN1250-3667) COMPLETED	539	183
Extension: Week 53 to 78 (NN1250-3667) NOT COMPLETED	27	8

Reasons for withdrawal

Reasons for withdrawal
Measure	IDeg OD Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Main: Week 0 to 52 (NN1250-3582) Adverse Event	31	9
Main: Week 0 to 52 (NN1250-3582) Lack of Efficacy	3	0
Main: Week 0 to 52 (NN1250-3582) Protocol Violation	23	12
Main: Week 0 to 52 (NN1250-3582) Withdrawal criteria	8	2
Main: Week 0 to 52 (NN1250-3582) Unclassified	72	17
Extension: Week 53 to 78 (NN1250-3667) Adverse Event	4	0
Extension: Week 53 to 78 (NN1250-3667) Lack of Efficacy	1	1
Extension: Week 53 to 78 (NN1250-3667) Protocol Violation	5	0
Extension: Week 53 to 78 (NN1250-3667) Withdrawal criteria	6	2
Extension: Week 53 to 78 (NN1250-3667) Unclassified	11	5

Baseline Characteristics

Comparison of NN1250 With Insulin Glargine Plus Insulin Aspart With/Without Metformin and With/Without Pioglitazone in Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IDeg OD n=744 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=248 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	Total n=992 Participants Total of all reporting groups
Age, Continuous	59.2 years STANDARD_DEVIATION 9.1 • n=5 Participants	58.1 years STANDARD_DEVIATION 10.0 • n=7 Participants	58.9 years STANDARD_DEVIATION 9.3 • n=5 Participants
Sex: Female, Male Female	339 Participants n=5 Participants	115 Participants n=7 Participants	454 Participants n=5 Participants
Sex: Female, Male Male	405 Participants n=5 Participants	133 Participants n=7 Participants	538 Participants n=5 Participants
Glycosylated Haemoglobin (HbA1c)	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 • n=7 Participants	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 52

Population: Full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF)

Change from baseline in HbA1c after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	IDeg OD n=744 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=248 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 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 52 Weeks of Treatment	-1.17 percentage of glycosylated haemoglobin Standard Deviation 1.03	-1.29 percentage of glycosylated haemoglobin Standard Deviation 0.98

PRIMARY outcome

Timeframe: Week 0 to Week 78 + 7 days follow up

Population: Safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.

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 are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.

Outcome measures

Outcome measures
Measure	IDeg OD n=753 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	1039 Episodes/100 years of patient exposure	1271 Episodes/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0 to Week 78 + 7 days follow up

Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.

Outcome measures

Outcome measures
Measure	IDeg OD n=753 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 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	134 Episodes/100 years of patient exposure	176 Episodes/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0 to Week 78 + 7 days follow up

Population: The SAS 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. Mild AEs: no or transient symptoms, no interference with subject's daily activities. Moderate AEs: marked symptoms, moderate interference with subject's daily activities. Severe AEs: considerable interference with subject's daily activities, unacceptable. Serious adverse event (SAE): 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	IDeg OD n=753 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Rate of Treatment Emergent Adverse Events (AEs) Fatal AE	1 Events/100 years of patient exposure	1 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Adverse events (AEs)	411 Events/100 years of patient exposure	403 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Serious AE	20 Events/100 years of patient exposure	20 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Severe AE	24 Events/100 years of patient exposure	20 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Moderate AE	113 Events/100 years of patient exposure	118 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Mild AE	274 Events/100 years of patient exposure	266 Events/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0, Week 78

Population: The FAS included all randomised subjects in the main trial including subjects carried through to the extension trial and missing data was imputed using LOCF

Change from baseline in HbA1c after 78 weeks of treatment

Outcome measures

Outcome measures
Measure	IDeg OD n=744 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=248 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 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 78 Weeks of Treatment	-0.95 percentage of glycosylated haemoglobin Standard Deviation 1.13	-1.15 percentage of glycosylated haemoglobin Standard Deviation 0.99

SECONDARY outcome

Timeframe: Week 52

Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 36 subjects all 9-point SMPG values were missing.

Mean of 9-point SMPG at 52 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	IDeg OD n=715 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=241 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 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 52	7.3 mmol/L Standard Deviation 1.8	6.9 mmol/L Standard Deviation 1.5

SECONDARY outcome

Timeframe: Week 78

Population: The FAS included all randomised subjects in the main trial including subjects carried through to the extension trial and missing data was imputed using LOCF. For 36 subjects all 9-point SMPG values were missing.

Mean of the SMPG at 78 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, before breakfast.

Outcome measures

Outcome measures
Measure	IDeg OD n=716 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=240 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 78	7.2 mmol/L Standard Deviation 1.9	6.8 mmol/L Standard Deviation 1.4

SECONDARY outcome

Timeframe: Week 0 to Week 52 + 7 days follow up

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

Outcome measures

Outcome measures
Measure	IDeg OD n=753 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	1109 Episodes/100 years of patient exposure	1363 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 52 + 7 days follow up

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

Outcome measures

Outcome measures
Measure	IDeg OD n=753 Participants Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 Participants Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 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	139 Episodes/100 years of patient exposure	184 Episodes/100 years of patient exposure

Adverse Events

IDeg OD

Serious events: 139 serious events

Other events: 447 other events

Deaths: 0 deaths

IGlar OD

Serious events: 53 serious events

Other events: 146 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

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	IDeg OD n=753 participants at risk Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.	IGlar OD n=251 participants at risk Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period.
Gastrointestinal disorders Diarrhoea	7.8% 59/753 • Number of events 73 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	10.4% 26/251 • Number of events 31 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
General disorders Oedema peripheral	7.3% 55/753 • Number of events 69 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	6.8% 17/251 • Number of events 20 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Infections and infestations Influenza	7.7% 58/753 • Number of events 68 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	8.0% 20/251 • Number of events 23 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Infections and infestations Nasopharyngitis	16.5% 124/753 • Number of events 212 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	14.7% 37/251 • Number of events 61 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Infections and infestations Upper respiratory tract infection	16.3% 123/753 • Number of events 212 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	16.7% 42/251 • Number of events 70 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Injury, poisoning and procedural complications Wrong drug administered	7.7% 58/753 • Number of events 66 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	3.6% 9/251 • Number of events 9 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Musculoskeletal and connective tissue disorders Arthralgia	5.7% 43/753 • Number of events 55 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	10.4% 26/251 • Number of events 36 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Musculoskeletal and connective tissue disorders Back pain	7.4% 56/753 • Number of events 66 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	8.4% 21/251 • Number of events 25 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Musculoskeletal and connective tissue disorders Pain in extremity	6.2% 47/753 • Number of events 55 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	7.6% 19/251 • Number of events 19 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Nervous system disorders Headache	9.4% 71/753 • Number of events 153 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	8.0% 20/251 • Number of events 32 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Cough	8.1% 61/753 • Number of events 71 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	8.4% 21/251 • Number of events 29 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Vascular disorders Hypertension	6.6% 50/753 • Number of events 59 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	5.6% 14/251 • Number of events 15 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Gastrointestinal disorders Vomiting	3.7% 28/753 • Number of events 39 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	5.6% 14/251 • Number of events 20 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Gastrointestinal disorders Nausea	5.2% 39/753 • Number of events 45 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	6.0% 15/251 • Number of events 18 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Bronchitis	6.5% 49/753 • Number of events 64 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	5.2% 13/251 • Number of events 19 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.
Infections and infestations Sinusitis	6.0% 45/753 • Number of events 64 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.	7.2% 18/251 • Number of events 21 • Adverse events were collected in a time frame of 78 weeks + 7 days follow up. The SAS included all subjects who received at least one dose of investigational product or its comparator.