Trial Outcomes & Findings for Benralizumab Efficacy in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History (NCT NCT02138916)

Last Updated: 2019-06-13

Results Overview

A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1656 participants

Primary outcome timeframe

From first IP to week 56

Results posted on

2019-06-13

Participant Flow

1656 patients randomized to Benralizumab 30 mg, Benralizumab 100 mg, or Placebo. All randomized patients were treated. 554 (33.5%) were randomized to Benralizumab 30 mg, 552 (33.3%) were randomized to Benralizumab 100 mg, and 550 (33.2%) were randomized to Placebo.

Participant milestones

Participant milestones
Measure	Benralizumab 30 mg Every 8 weeks administered subcutaneously	Benralizumab 100 mg Every 8 weeks administered subcutaneously	Placebo Every 8 weeks administered subcutaneously
Overall Study STARTED	554	552	550
Overall Study COMPLETED	497	492	491
Overall Study NOT COMPLETED	57	60	59

Reasons for withdrawal

Reasons for withdrawal
Measure	Benralizumab 30 mg Every 8 weeks administered subcutaneously	Benralizumab 100 mg Every 8 weeks administered subcutaneously	Placebo Every 8 weeks administered subcutaneously
Overall Study eg., meds change, lack of efficacy, etc.	6	9	7
Overall Study Death	14	11	12
Overall Study Withdrawal by Subject	27	31	32
Overall Study Study specific withdrawal criteria	0	0	1
Overall Study incorrect enrolment	1	1	0
Overall Study Severe non-compliance	1	2	1
Overall Study Lost to Follow-up	4	2	3
Overall Study Adverse Event	4	4	3

Baseline Characteristics

Full analysis set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Benralizumab 30 mg n=554 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=552 Participants Every 8 weeks administered subcutaneously	Placebo n=550 Participants Every 8 weeks administered subcutaneously	Total n=1656 Participants Total of all reporting groups
Age, Continuous	65.9 Year STANDARD_DEVIATION 7.77 • n=5 Participants • Full analysis set	65.3 Year STANDARD_DEVIATION 8.05 • n=7 Participants • Full analysis set	65.2 Year STANDARD_DEVIATION 8.22 • n=5 Participants • Full analysis set	65.5 Year STANDARD_DEVIATION 8.01 • n=4 Participants • Full analysis set
Sex: Female, Male Female	172 Participants n=5 Participants • Full analysis set	180 Participants n=7 Participants • Full analysis set	175 Participants n=5 Participants • Full analysis set	527 Participants n=4 Participants • Full analysis set
Sex: Female, Male Male	382 Participants n=5 Participants • Full analysis set	372 Participants n=7 Participants • Full analysis set	375 Participants n=5 Participants • Full analysis set	1129 Participants n=4 Participants • Full analysis set
Race/Ethnicity, Customized White	496 Participants n=5 Participants • Full analysis set	493 Participants n=7 Participants • Full analysis set	488 Participants n=5 Participants • Full analysis set	1477 Participants n=4 Participants • Full analysis set
Race/Ethnicity, Customized Black or African American	4 Participants n=5 Participants • Full analysis set	11 Participants n=7 Participants • Full analysis set	10 Participants n=5 Participants • Full analysis set	25 Participants n=4 Participants • Full analysis set
Race/Ethnicity, Customized Asian	48 Participants n=5 Participants • Full analysis set	46 Participants n=7 Participants • Full analysis set	46 Participants n=5 Participants • Full analysis set	140 Participants n=4 Participants • Full analysis set
Race/Ethnicity, Customized Other	6 Participants n=5 Participants • Full analysis set	2 Participants n=7 Participants • Full analysis set	6 Participants n=5 Participants • Full analysis set	14 Participants n=4 Participants • Full analysis set

PRIMARY outcome

Timeframe: From first IP to week 56

Population: Full analysis set with baseline EOS\>=220/uL

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=379 Participants Every 8 weeks administered subcutaneously	Placebo n=359 Participants Every 8 weeks administered subcutaneously
Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL	1.19 Exacerbations per year Interval 1.04 to 1.36	1.03 Exacerbations per year Interval 0.9 to 1.19	1.24 Exacerbations per year Interval 1.08 to 1.42

SECONDARY outcome

Timeframe: From first IP to week 56

Population: Full analysis set with baseline EOS\<220/uL

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=172 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=173 Participants Every 8 weeks administered subcutaneously	Placebo n=191 Participants Every 8 weeks administered subcutaneously
Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL	1.4 Exacerbations per year Interval 1.19 to 1.64	1.32 Exacerbations per year Interval 1.12 to 1.56	1.30 Exacerbations per year Interval 1.11 to 1.52

SECONDARY outcome

Timeframe: First IP up to end of treatment Week 56

Population: Full analysis set, baseline EOS\>=220/uL

Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=329 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=326 Participants Every 8 weeks administered subcutaneously	Placebo n=317 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL	0.014 Liter Standard Deviation 0.282	0.031 Liter Standard Deviation 0.294	0.010 Liter Standard Deviation 0.275

SECONDARY outcome

Timeframe: First IP up to Week 56

Population: Full analysis set, baseline EOS\>=220/uL

SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=338 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=331 Participants Every 8 weeks administered subcutaneously	Placebo n=317 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL	-5.025 Percentage Standard Deviation 14.677	-6.723 Percentage Standard Deviation 15.723	-3.913 Percentage Standard Deviation 15.039

SECONDARY outcome

Timeframe: First IP up to Week 56

Population: Full analysis set, baseline EOS\>=220/uL

CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=338 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=335 Participants Every 8 weeks administered subcutaneously	Placebo n=319 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL	-1.50 Score on a scale Standard Deviation 6.89	-2.43 Score on a scale Standard Deviation 6.34	-1.22 Score on a scale Standard Deviation 6.53

SECONDARY outcome

Timeframe: First IP up to Week 56

Population: Full analysis set, baseline EOS\>=220/uL

The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=324 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=328 Participants Every 8 weeks administered subcutaneously	Placebo n=295 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL	-1.085 Score on a scale Standard Deviation 5.273	-1.354 Score on a scale Standard Deviation 5.599	-0.504 Score on a scale Standard Deviation 5.674

SECONDARY outcome

Timeframe: First IP up to Week 56

Population: Full analysis set, baseline EOS\>=220/uL

The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=321 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=322 Participants Every 8 weeks administered subcutaneously	Placebo n=291 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL	-0.05 Puffs/day Standard Deviation 3.21	-0.27 Puffs/day Standard Deviation 2.71	0.29 Puffs/day Standard Deviation 3.03

SECONDARY outcome

Timeframe: First IP up to Week 56

Population: Full analysis set, baseline EOS\>=220/uL

Change from baseline to week 56 in proportion of nights awakenings due to respiratory symptoms.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=325 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=323 Participants Every 8 weeks administered subcutaneously	Placebo n=297 Participants Every 8 weeks administered subcutaneously
Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL	-0.088 Proportion of nights Standard Deviation 0.310	-0085 Proportion of nights Standard Deviation 0.283	-0.049 Proportion of nights Standard Deviation 0.307

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, EOS\>=220/uL

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=378 Participants Every 8 weeks administered subcutaneously	Placebo n=358 Participants Every 8 weeks administered subcutaneously
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 9	1 Participants	2 Participants	1 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 10	0 Participants	1 Participants	0 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 3	25 Participants	14 Participants	15 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 4	17 Participants	13 Participants	14 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 0	180 Participants	184 Participants	179 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 1	101 Participants	103 Participants	99 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 2	42 Participants	49 Participants	34 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 5	5 Participants	6 Participants	5 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 6	4 Participants	4 Participants	2 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 7	6 Participants	1 Participants	5 Participants
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL 8	1 Participants	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=202 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=194 Participants Every 8 weeks administered subcutaneously	Placebo n=179 Participants Every 8 weeks administered subcutaneously
Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL	51.5 Score on a scale Standard Deviation 11.30	50.8 Score on a scale Standard Deviation 10.70	52.0 Score on a scale Standard Deviation 11.20

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery. That is, duration of the exacerbation is the time elapse between onset and recovery of the event.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=202 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=194 Participants Every 8 weeks administered subcutaneously	Placebo n=179 Participants Every 8 weeks administered subcutaneously
Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL	82.2 Days Standard Deviation 95.80	88.3 Days Standard Deviation 105.30	101.7 Days Standard Deviation 113.70

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Annual EXACT-PRO exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=378 Participants Every 8 weeks administered subcutaneously	Placebo n=358 Participants Every 8 weeks administered subcutaneously
Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL	1.14 Exacerbations per year Interval 0.98 to 1.31	1.02 Exacerbations per year Interval 0.88 to 1.19	1.04 Exacerbations per year Interval 0.9 to 1.21

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=379 Participants Every 8 weeks administered subcutaneously	Placebo n=359 Participants Every 8 weeks administered subcutaneously
Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL	204 Participants	203 Participants	198 Participants

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=379 Participants Every 8 weeks administered subcutaneously	Placebo n=359 Participants Every 8 weeks administered subcutaneously
Time to First COPD Exacerbation	333 Days Interval 273.0 to 400.0	329 Days Interval 262.0 to 396.0	337 Days Interval 261.0 to 390.0

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

Annual COPD exacerbations rate that result in ER or hospitalization is calculated by number of exacerbations resulting ER or hospitalization divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=379 Participants Every 8 weeks administered subcutaneously	Placebo n=359 Participants Every 8 weeks administered subcutaneously
Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL	0.27 Exacerbations per year Interval 0.2 to 0.35	0.15 Exacerbations per year Interval 0.11 to 0.2	0.25 Exacerbations per year Interval 0.19 to 0.33

SECONDARY outcome

Timeframe: Immediately following first IP up to week 56

Population: Full analysis set, baseline EOS\>=220/uL

Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=382 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=379 Participants Every 8 weeks administered subcutaneously	Placebo n=359 Participants Every 8 weeks administered subcutaneously
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Hospitalisations	60 Participants	38 Participants	50 Participants
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Emergency Department Visits	36 Participants	35 Participants	43 Participants
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Unscheduled Outpatient Visits	219 Participants	236 Participants	202 Participants
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Home Visits	18 Participants	22 Participants	18 Participants
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Telephone calls	110 Participants	111 Participants	104 Participants
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL Ambulance transports	16 Participants	12 Participants	20 Participants

SECONDARY outcome

Timeframe: From first dose date to last dose date, 48 weeks per protocol.

Population: Safety analysis set

Duration of study treatment is calculated from first dose date to last dose date + 1 day.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=554 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=552 Participants Every 8 weeks administered subcutaneously	Placebo n=550 Participants Every 8 weeks administered subcutaneously
Duration of Study Treatment Administration	302.4 Days Standard Deviation 85.73	304.0 Days Standard Deviation 82.40	302.5 Days Standard Deviation 88.47

SECONDARY outcome

Timeframe: Pre-first dose and pre-dose at end of treatment (week 56)

Population: PK analysis set

PK serum samples were collected pre-dose at each visit.

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=553 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=550 Participants Every 8 weeks administered subcutaneously	Placebo Every 8 weeks administered subcutaneously
Serum Concentration of Benralizumab Baseline	NA ng/mL Geometric Coefficient of Variation NA \<LLOQ (Lower limit of quantification)	NA ng/mL Geometric Coefficient of Variation NA \<LLOQ (Lower limit of quantification)	—
Serum Concentration of Benralizumab Week 56	219.45 ng/mL Geometric Coefficient of Variation 233.21	699.89 ng/mL Geometric Coefficient of Variation 243.20	—

SECONDARY outcome

Timeframe: Pre-treatment until end of follow-up, week 60 per protocol.

Population: safety analysis set. For each parameter, the number of subjects at risk is to be analyzed.

Antidrug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented

Outcome measures

Outcome measures
Measure	Benralizumab 30 mg n=554 Participants Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=552 Participants Every 8 weeks administered subcutaneously	Placebo n=550 Participants Every 8 weeks administered subcutaneously
Immunogenicity of Benralizumab ADA prevalence	53 Participants	64 Participants	39 Participants
Immunogenicity of Benralizumab ADA incidence	44 Participants	47 Participants	24 Participants
Immunogenicity of Benralizumab Both base/post-baseline positive	5 Participants	7 Participants	17 Participants
Immunogenicity of Benralizumab Only post baseline positive	43 Participants	46 Participants	20 Participants
Immunogenicity of Benralizumab Only baseline positive	5 Participants	11 Participants	2 Participants
Immunogenicity of Benralizumab ADA persistently positive	28 Participants	34 Participants	14 Participants
Immunogenicity of Benralizumab ADA transiently positive	15 Participants	12 Participants	6 Participants
Immunogenicity of Benralizumab nAb prevalence	43 Participants	43 Participants	25 Participants
Immunogenicity of Benralizumab nAb incidence	41 Participants	37 Participants	18 Participants

Adverse Events

Benralizumab 30 mg

Serious events: 151 serious events

Other events: 293 other events

Deaths: 15 deaths

Benralizumab 100 mg

Serious events: 177 serious events

Other events: 318 other events

Deaths: 11 deaths

Placebo

Serious events: 176 serious events

Other events: 282 other events

Deaths: 13 deaths

Serious adverse events

Other adverse events

Additional Information

Ulbaldo Martin

AstraZeneca

Phone: 1.301.398.0163

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee ≥ 60 days prior to submission of material for publication/presentation, Institution and PI shall jointly provide AZ with material for review. No publication/presentation may include any of AZ's Confidential Information without AZ's written approval. AZ can request Inst. and PI to withhold material from submission for publication/presentation for an additional 90 days to allow AZ to establish and preserve its proprietary rights in the material being submitted for publication or presentation.
Publication restrictions are in place

Restriction type: OTHER

Measure	Benralizumab 30 mg n=554 participants at risk Every 8 weeks administered subcutaneously	Benralizumab 100 mg n=552 participants at risk Every 8 weeks administered subcutaneously	Placebo n=550 participants at risk Every 8 weeks administered subcutaneously
Gastrointestinal disorders Constipation	3.1% 17/554 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.4% 19/552 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.7% 15/550 • Number of events 17 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Gastrointestinal disorders Diarrhoea	3.1% 17/554 • Number of events 18 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.7% 15/552 • Number of events 18 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	1.1% 6/550 • Number of events 7 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Gastrointestinal disorders Nausea	2.3% 13/554 • Number of events 17 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.3% 18/552 • Number of events 22 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.4% 13/550 • Number of events 15 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
General disorders Oedema peripheral	2.0% 11/554 • Number of events 13 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	4.7% 26/552 • Number of events 28 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.0% 11/550 • Number of events 11 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Bronchitis	10.6% 59/554 • Number of events 74 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	15.2% 84/552 • Number of events 113 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	14.5% 80/550 • Number of events 121 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Lower respiratory tract infection	9.0% 50/554 • Number of events 76 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	5.8% 32/552 • Number of events 47 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	5.3% 29/550 • Number of events 39 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Oral candidiasis	3.1% 17/554 • Number of events 21 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.4% 13/552 • Number of events 18 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.7% 15/550 • Number of events 16 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Respiratory tract infection	1.8% 10/554 • Number of events 10 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.0% 11/552 • Number of events 14 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.3% 18/550 • Number of events 26 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Respiratory tract infection viral	2.7% 15/554 • Number of events 21 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.2% 12/552 • Number of events 18 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.5% 19/550 • Number of events 23 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Sinusitis	2.3% 13/554 • Number of events 16 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.1% 17/552 • Number of events 22 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.6% 20/550 • Number of events 22 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Upper respiratory tract infection	12.5% 69/554 • Number of events 87 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	13.4% 74/552 • Number of events 104 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	11.8% 65/550 • Number of events 97 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Urinary tract infection	4.2% 23/554 • Number of events 27 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	4.0% 22/552 • Number of events 30 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.7% 15/550 • Number of events 22 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Infections and infestations Viral upper respiratory tract infection	15.0% 83/554 • Number of events 126 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	17.2% 95/552 • Number of events 134 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	12.0% 66/550 • Number of events 98 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Musculoskeletal and connective tissue disorders Back pain	3.8% 21/554 • Number of events 23 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	4.5% 25/552 • Number of events 30 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.5% 19/550 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Nervous system disorders Headache	3.8% 21/554 • Number of events 29 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	4.7% 26/552 • Number of events 30 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.6% 20/550 • Number of events 21 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Respiratory, thoracic and mediastinal disorders Cough	2.9% 16/554 • Number of events 18 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.5% 14/552 • Number of events 20 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.8% 21/550 • Number of events 30 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.3% 24/554 • Number of events 30 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.1% 17/552 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	4.2% 23/550 • Number of events 37 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.5% 14/554 • Number of events 15 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.3% 18/552 • Number of events 21 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	2.4% 13/550 • Number of events 17 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Vascular disorders Hypertension	3.4% 19/554 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.4% 19/552 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).	3.3% 18/550 • Number of events 19 • From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).