Trial Outcomes & Findings for Comparison of NN1250 Plus Insulin Aspart With Insulin Glargine Plus Insulin Aspart in Type 1 Diabetes (NCT NCT00982228)

NCT ID: NCT00982228

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

629 participants

Primary outcome timeframe

Week 0, Week 52

Results posted on

2017-04-06

Participant Flow

The trial was conducted at 79 sites in 6 countries: France (6), Germany (5), Russia (7), South Africa (3), United Kingdom (U.K.) (6) and United States (U.S.) (52).

All subjects who completed the 52-week main trial (NN1250-3583, NCT00982228) and were found to be eligible for the extension trial were offered to participate in the 52-week extension trial (NN1250-3644).

Participant milestones

Participant milestones
Measure	IDeg OD Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main: Week 0 to 52 (NN1250-3583) STARTED	472	157
Main: Week 0 to 52 (NN1250-3583) Full Analysis Set	472	157
Main: Week 0 to 52 (NN1250-3583) Exposed	472	154
Main: Week 0 to 52 (NN1250-3583) COMPLETED	404	137
Main: Week 0 to 52 (NN1250-3583) NOT COMPLETED	68	20
Extension: Week 53 to 104 (NN1250-3644) STARTED	351	118
Extension: Week 53 to 104 (NN1250-3644) COMPLETED	330	113
Extension: Week 53 to 104 (NN1250-3644) NOT COMPLETED	21	5

Reasons for withdrawal

Reasons for withdrawal
Measure	IDeg OD Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main: Week 0 to 52 (NN1250-3583) Adverse Event	12	2
Main: Week 0 to 52 (NN1250-3583) Lack of Efficacy	2	0
Main: Week 0 to 52 (NN1250-3583) Protocol Violation	11	2
Main: Week 0 to 52 (NN1250-3583) Withdrawal criteria	15	3
Main: Week 0 to 52 (NN1250-3583) Unclassified	28	13
Extension: Week 53 to 104 (NN1250-3644) Adverse Event	3	2
Extension: Week 53 to 104 (NN1250-3644) Lack of Efficacy	1	0
Extension: Week 53 to 104 (NN1250-3644) Protocol Violation	1	2
Extension: Week 53 to 104 (NN1250-3644) Withdrawal criteria	5	0
Extension: Week 53 to 104 (NN1250-3644) Unclassified	11	1

Baseline Characteristics

Comparison of NN1250 Plus Insulin Aspart With Insulin Glargine Plus Insulin Aspart in Type 1 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IDeg OD n=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=157 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.	Total n=629 Participants Total of all reporting groups
Age, Continuous	42.8 years STANDARD_DEVIATION 13.7 • n=5 Participants	43.7 years STANDARD_DEVIATION 13.3 • n=7 Participants	43.0 years STANDARD_DEVIATION 13.6 • n=5 Participants
Sex: Female, Male Female	194 Participants n=5 Participants	67 Participants n=7 Participants	261 Participants n=5 Participants
Sex: Female, Male Male	278 Participants n=5 Participants	90 Participants n=7 Participants	368 Participants n=5 Participants
Glycosylated haemoglobin (HbA1c)	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 • n=5 Participants	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.0 • n=7 Participants	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.0 • n=5 Participants
Fasting plasma glucose (FPG)	9.1 mmol/L STANDARD_DEVIATION 4.0 • n=5 Participants	9.7 mmol/L STANDARD_DEVIATION 4.4 • n=7 Participants	9.3 mmol/L STANDARD_DEVIATION 4.1 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 52

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

Change from baseline in HbA1c after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	IDeg OD n=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=157 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment	-0.40 percentage of glycosylated haemoglobin Standard Deviation 0.73	-0.39 percentage of glycosylated haemoglobin Standard Deviation 0.84

PRIMARY outcome

Timeframe: Week 0 to Week 104 + 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.

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	IDeg OD n=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Adverse events (AE)	383 Events/100 years of patient exposure	374 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Serious AE	14 Events/100 years of patient exposure	17 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Severe AE	22 Events/100 years of patient exposure	26 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Moderate AE	105 Events/100 years of patient exposure	106 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Mild AE	256 Events/100 years of patient exposure	242 Events/100 years of patient exposure
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) Fatal AE	1 Events/100 years of patient exposure	1 Events/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0 to Week 104 + 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.

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=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	3750 Episodes/100 years of patient exposure	3743 Episodes/100 years of patient exposure

PRIMARY outcome

Timeframe: Week 0, Week 106

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.

The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing and after a 1-week wash-out period.

Outcome measures

Outcome measures
Measure	IDeg OD n=335 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=111 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Primary Endpoint): Cross-reacting Antibodies to Human Insulin	11.3 %B/T Standard Deviation 15.6	11.0 %B/T Standard Deviation 16.0

SECONDARY outcome

Timeframe: Week 0 to Week 104 + 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=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes	390 Episodes/100 years of patient exposure	532 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0, Week 104

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 104 weeks of treatment

Outcome measures

Outcome measures
Measure	IDeg OD n=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=157 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment	-0.27 percentage of glycosylated haemoglobin Standard Deviation 0.75	-0.24 percentage of glycosylated haemoglobin Standard Deviation 0.86

SECONDARY outcome

Timeframe: Treatment week 104

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 12 subjects all 9-point SMPG values were missing.

Mean of 9-point self-measured plasma glucose profile (SMPG) after 104 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=463 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 of Treatment	8.0 mmol/L Standard Deviation 2.2	8.1 mmol/L Standard Deviation 2.2

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=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes	4254 Episodes/100 years of patient exposure	4018 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=472 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes	441 Episodes/100 years of patient exposure	586 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 52

Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 7 subjects all 9-point SMPG values were missing.

Mean of 9-point self-measured plasma glucose profile (SMPG) after 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=467 Participants Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=155 Participants Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52	8.1 mmol/L Standard Deviation 2.3	8.3 mmol/L Standard Deviation 2.4

Adverse Events

IDeg OD

Serious events: 71 serious events

Other events: 353 other events

Deaths: 0 deaths

IGlar OD

Serious events: 29 serious events

Other events: 118 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=472 participants at risk Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period.	IGlar OD n=154 participants at risk Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period.
Gastrointestinal disorders Diarrhoea	8.3% 39/472 • Number of events 44 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.8% 9/154 • Number of events 12 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Nausea	8.5% 40/472 • Number of events 57 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	9.1% 14/154 • Number of events 18 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Vomiting	5.3% 25/472 • Number of events 26 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.1% 11/154 • Number of events 15 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Bronchitis	8.1% 38/472 • Number of events 46 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.1% 11/154 • Number of events 17 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Gastroenteritis	9.3% 44/472 • Number of events 49 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.8% 9/154 • Number of events 10 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Influenza	9.3% 44/472 • Number of events 53 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	11.0% 17/154 • Number of events 19 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Nasopharyngitis	33.9% 160/472 • Number of events 284 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	33.1% 51/154 • Number of events 105 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Sinusitis	12.3% 58/472 • Number of events 93 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	14.9% 23/154 • Number of events 31 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Upper respiratory tract infection	25.8% 122/472 • Number of events 208 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	20.1% 31/154 • Number of events 48 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Urinary tract infection	7.4% 35/472 • Number of events 40 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.8% 12/154 • Number of events 16 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Injury, poisoning and procedural complications Wrong drug administered	6.6% 31/472 • Number of events 35 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	3.9% 6/154 • Number of events 6 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemia	9.3% 44/472 • Number of events 70 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	8.4% 13/154 • Number of events 18 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Headache	17.8% 84/472 • Number of events 162 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	14.3% 22/154 • Number of events 39 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Cough	7.0% 33/472 • Number of events 37 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	11.0% 17/154 • Number of events 19 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	7.2% 34/472 • Number of events 46 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	9.1% 14/154 • Number of events 19 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Immune system disorders Seasonal allergy	2.1% 10/472 • Number of events 11 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	6.5% 10/154 • Number of events 10 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Gastrointestinal viral	5.3% 25/472 • Number of events 27 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	3.9% 6/154 • Number of events 9 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Back Pain	7.0% 33/472 • Number of events 46 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.8% 9/154 • Number of events 15 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Nasal congestion	3.6% 17/472 • Number of events 18 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.1% 11/154 • Number of events 13 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Sinus congestion	4.7% 22/472 • Number of events 25 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.8% 9/154 • Number of events 12 • The adverse events were collected in a time frame of 104 weeks + 1 week after last dose in main trial + 1 more week after last dose in extension trial. The SAS included all subjects who received at least one dose of the investigational product or its comparator.