Trial Outcomes & Findings for Study to Compare Safety and Efficacy of HX575 Epoetin Alfa and US-licensed Epoetin Alfa (NCT NCT01693029)

Last Updated: 2017-07-02

Results Overview

Response to epoetin alfa in anemic patients with chronic renal failure is manifested by increased hematocrit, hemoglobin, reduced transfusion requirements and increase in quality of life. Hemoglobin (laboratory haematology parameter) is the primary endpoint of the study .

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

435 participants

Primary outcome timeframe

Week -4 to Day1 and Week 21-28

Results posted on

2017-07-02

Participant Flow

Participant milestones

Participant milestones
Measure	HX575 Epoetin Alfa HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Overall Study STARTED	217	218
Overall Study COMPLETED	173	161
Overall Study NOT COMPLETED	44	57

Reasons for withdrawal

Reasons for withdrawal
Measure	HX575 Epoetin Alfa HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Overall Study Withdrawal by Subject	15	22
Overall Study Kidney transplantation	7	7
Overall Study Bindinging anti-EPO antibodies	6	2
Overall Study Protocol Violation	6	7
Overall Study Change in dialysis modality	2	1
Overall Study Physician Decision	0	2
Overall Study Lost to Follow-up	0	1
Overall Study Adverse Event	1	6
Overall Study Death	5	8
Overall Study Non-compliance	2	1

Baseline Characteristics

Study to Compare Safety and Efficacy of HX575 Epoetin Alfa and US-licensed Epoetin Alfa

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HX575 Epoetin Alfa n=217 Participants HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=218 Participants US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.	Total n=435 Participants Total of all reporting groups
Age, Continuous	59.8 years STANDARD_DEVIATION 13.76 • n=5 Participants	57.6 years STANDARD_DEVIATION 13.40 • n=7 Participants	58.7 years STANDARD_DEVIATION 13.61 • n=5 Participants
Sex: Female, Male Female	82 Participants n=5 Participants	103 Participants n=7 Participants	185 Participants n=5 Participants
Sex: Female, Male Male	135 Participants n=5 Participants	115 Participants n=7 Participants	250 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	95 Participants n=5 Participants	93 Participants n=7 Participants	188 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	122 Participants n=5 Participants	125 Participants n=7 Participants	247 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	11 Participants n=5 Participants	5 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	13 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Black or African American	57 Participants n=5 Participants	72 Participants n=7 Participants	129 Participants n=5 Participants
Race (NIH/OMB) White	139 Participants n=5 Participants	128 Participants n=7 Participants	267 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	217 participants n=5 Participants	218 participants n=7 Participants	435 participants n=5 Participants
Height	167.2 cm STANDARD_DEVIATION 10.17 • n=5 Participants	166.0 cm STANDARD_DEVIATION 10.33 • n=7 Participants	166.6 cm STANDARD_DEVIATION 10.26 • n=5 Participants
Weight	82.8 kg STANDARD_DEVIATION 20.75 • n=5 Participants	86.5 kg STANDARD_DEVIATION 24.32 • n=7 Participants	84.6 kg STANDARD_DEVIATION 22.66 • n=5 Participants
BMI	29.55 kg/m^2 STANDARD_DEVIATION 6.872 • n=5 Participants	31.41 kg/m^2 STANDARD_DEVIATION 8.783 • n=7 Participants	30.48 kg/m^2 STANDARD_DEVIATION 7.933 • n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Diabetes mellitus	115 Participants n=5 Participants	122 Participants n=7 Participants	237 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Hypertension	65 Participants n=5 Participants	52 Participants n=7 Participants	117 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Chronic glomerulonephritis	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Kidney abnormalities	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Polycystic kidney disease	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Urinary tract obstruction	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Vasculitis	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Amyloidosis	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Unknown	3 Participants n=5 Participants	9 Participants n=7 Participants	12 Participants n=5 Participants
Primary cause of Chronic Kidney Disease (CKD) Other	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Type of last Erythropoiesis Stimulating Agent (ESA) therapy prior Epogen	217 Participants n=5 Participants	215 Participants n=7 Participants	432 Participants n=5 Participants
Type of last Erythropoiesis Stimulating Agent (ESA) therapy prior Procrit	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Time since start of ESA therapy	30.59 months n=5 Participants	36.24 months n=7 Participants	32.95 months n=5 Participants
Time since start of dialysis	36.11 months n=5 Participants	41.08 months n=7 Participants	38.60 months n=5 Participants
Method of dialysis at Baseline Hemodialysis	192 Participants n=5 Participants	192 Participants n=7 Participants	384 Participants n=5 Participants
Method of dialysis at Baseline Peritoneal dialysis	25 Participants n=5 Participants	26 Participants n=7 Participants	51 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week -4 to Day1 and Week 21-28

Population: The intent-to-treat (ITT) population consists of all randomized patients who were exposed to treatment with study drug for at least four weeks and have at least one Hb value available at week 4 or later. Following the intent-to-treat principle, patients are analyzed according to the treatment they were assigned to at randomization.

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa n=210 Participants HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=212 Participants US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Mean Absolute Change in Hemoglobin Levels Between the Screening/Baseline Period (Week -4 to Day 1) and the Evaluation Period (Week 21-28)	-0.0960 g/dL Standard Error 0.0575	-0.0035 g/dL Standard Error 0.0573

PRIMARY outcome

Timeframe: Week -4 to Day1 and Week 21-28

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa n=210 Participants HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=212 Participants US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Change in Mean Hb Level Between Baseline (Week -4 to Day1) and Evaluation Period (Week 21-28) Baseline period	10.53 g/dL Standard Deviation 0.635	10.50 g/dL Standard Deviation 0.615
Change in Mean Hb Level Between Baseline (Week -4 to Day1) and Evaluation Period (Week 21-28) Evaluation period	10.42 g/dL Standard Deviation 0.826	10.51 g/dL Standard Deviation 0.873
Change in Mean Hb Level Between Baseline (Week -4 to Day1) and Evaluation Period (Week 21-28) Change from baseline period to evaluation period	-0.11 g/dL Standard Deviation 1.011	0.01 g/dL Standard Deviation 0.953

SECONDARY outcome

Timeframe: Week 21-28

Mean weekly study drug dose during evaluation period (Week 21-28)

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa n=210 Participants HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=212 Participants US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Mean Weekly Dose During Evaluation Period (Week 21-28)	5876.5 international units Standard Deviation 5785.50	5804.0 international units Standard Deviation 6343.70

SECONDARY outcome

Timeframe: 52 weeks

Population: All patients treated with study drug with a post-baseline antibody assessment

Number of patients with positive antidrug antibody (ADA) finding at any time during their treatment period. Count includes 2 patients (1 in each arm) that already had a positive ADA Baseline finding. ADA testing performed by by Radio-Immuno-Precipitation assay. No patient developed neutralizing antibodies.

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa n=214 Participants HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=216 Participants US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Incidence of Antibody Formation Against Epoetin	7 Participants	2 Participants

Adverse Events

HX575 Epoetin Alfa

Serious events: 91 serious events

Other events: 112 other events

Deaths: 5 deaths

US-licensed Epoetin Alfa

Serious events: 90 serious events

Other events: 123 other events

Deaths: 11 deaths

Serious adverse events

Other adverse events

Additional Information

Biopharmaceutical Clinical Development, Strategic Planning

Sandoz

Phone: 004980244760

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor shall have the right to the first publication or presentation of the results of the study which is intended to be a joint, multi-center publication of the study results. Following the first publication, institutions and/or Principal Investigators may publish or present data or results from the study per the terms of the clinical trial agreement.
Publication restrictions are in place

Restriction type: OTHER

Measure	HX575 Epoetin Alfa n=217 participants at risk HX575, recombinant human epoetin alfa HX575 epoetin alfa: Solution for subcutaneous injection. The drug is administered subcutaneously at least once per week over 52 weeks. The dose will be individually titrated to maintain hemoglobin levels between 10 to 11 g/dL.	US-licensed Epoetin Alfa n=218 participants at risk US-licensed recombinant human epoetin alfa US-licensed epoetin alfa: Solution for subcutaneous injection.
Infections and infestations Upper respiratory tract infection	5.5% 12/217 • Number of events 14 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	10.1% 22/218 • Number of events 24 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Infections and infestations Urinary tract infection	5.5% 12/217 • Number of events 15 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	4.6% 10/218 • Number of events 13 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Injury, poisoning and procedural complications Fall	6.0% 13/217 • Number of events 20 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	8.3% 18/218 • Number of events 31 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	6.9% 15/217 • Number of events 17 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	5.0% 11/218 • Number of events 16 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Gastrointestinal disorders Diarrhoea	9.7% 21/217 • Number of events 26 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	8.7% 19/218 • Number of events 24 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Gastrointestinal disorders Nausea	7.8% 17/217 • Number of events 20 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	9.2% 20/218 • Number of events 23 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Gastrointestinal disorders Vomiting	4.6% 10/217 • Number of events 18 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.9% 15/218 • Number of events 18 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Gastrointestinal disorders Constipation	4.6% 10/217 • Number of events 10 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.0% 13/218 • Number of events 13 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
General disorders Pyrexia	5.5% 12/217 • Number of events 16 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	4.1% 9/218 • Number of events 10 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Musculoskeletal and connective tissue disorders Pain in extremity	5.5% 12/217 • Number of events 16 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	7.3% 16/218 • Number of events 18 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Musculoskeletal and connective tissue disorders Arthralgia	4.6% 10/217 • Number of events 10 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.0% 13/218 • Number of events 15 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Musculoskeletal and connective tissue disorders Muscle spasms	3.7% 8/217 • Number of events 8 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.4% 14/218 • Number of events 16 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Metabolism and nutrition disorders Hyperkalaemia	5.5% 12/217 • Number of events 13 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.4% 14/218 • Number of events 14 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Metabolism and nutrition disorders Hypophosphataemia	4.6% 10/217 • Number of events 11 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	5.0% 11/218 • Number of events 12 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Vascular disorders Hypertension	11.1% 24/217 • Number of events 40 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	12.4% 27/218 • Number of events 34 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Vascular disorders Hypotension	4.1% 9/217 • Number of events 10 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	5.5% 12/218 • Number of events 12 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.1% 9/217 • Number of events 11 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.9% 15/218 • Number of events 18 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Respiratory, thoracic and mediastinal disorders Cough	0.92% 2/217 • Number of events 2 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	5.5% 12/218 • Number of events 12 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Nervous system disorders Headache	6.9% 15/217 • Number of events 17 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	6.9% 15/218 • Number of events 18 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.
Nervous system disorders Dizziness	4.1% 9/217 • Number of events 11 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.	5.5% 12/218 • Number of events 14 • Adverse events were collected from the date of informed consent until the end of the treatment period, for approximately 1 year. Adverse events recorded before first study drug were considered pre-treatment adverse events, adverse events recorded more than 30 days after last study drug treatment were considered post-treatment emergent adverse event. Only treatment-emergent adverse events are shown in adverse events counts.