Trial Outcomes & Findings for Long Term Safety of Clopidogrel in Neonates/Infants With Systemic to Pulmonary Artery Shunt Palliation (NCT NCT00833703)

Last Updated: 2011-08-22

Results Overview

All bleeding events experienced during the study period were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from inclusion in the extension study up to 28 days after treatment discontinuation, and participants who experienced bleeding events during that period were counted.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

49 participants

Primary outcome timeframe

Up to a maximum of 6 months

Results posted on

2011-08-22

Participant Flow

49 participants were enrolled between January 2009 and January 2010 in 25 sites in 15 countries (7 countries involved in CLARINET study were not selected as the delay in obtaining IRB/IEC and Health Authorities approvals would prevent recruitment and/or no patient would be recruited as the second surgery is always performed before 1 year of age).

Participant milestones

Participant milestones
Measure	Placebo 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Overall Study STARTED	23	26
Overall Study Treated	23	26
Overall Study Completed Treatment	22	24
Overall Study COMPLETED	23	25
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Overall Study Parent(s)/guardian(s)'s request	0	1

Baseline Characteristics

Long Term Safety of Clopidogrel in Neonates/Infants With Systemic to Pulmonary Artery Shunt Palliation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=23 Participants 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 Participants 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily	Total n=49 Participants Total of all reporting groups
Age Continuous at randomization in CLARINET study	45.2 days STANDARD_DEVIATION 26.1 • n=99 Participants	33.1 days STANDARD_DEVIATION 20.5 • n=107 Participants	38.8 days STANDARD_DEVIATION 23.8 • n=206 Participants
Age Continuous at inclusion	368.1 days STANDARD_DEVIATION 4.2 • n=99 Participants	368.0 days STANDARD_DEVIATION 2.7 • n=107 Participants	368.0 days STANDARD_DEVIATION 3.5 • n=206 Participants
Sex: Female, Male Female	10 Participants n=99 Participants	14 Participants n=107 Participants	24 Participants n=206 Participants
Sex: Female, Male Male	13 Participants n=99 Participants	12 Participants n=107 Participants	25 Participants n=206 Participants
Region of Enrollment United States	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Region of Enrollment Portugal	3 participants n=99 Participants	1 participants n=107 Participants	4 participants n=206 Participants
Region of Enrollment Taiwan	4 participants n=99 Participants	5 participants n=107 Participants	9 participants n=206 Participants
Region of Enrollment Spain	0 participants n=99 Participants	2 participants n=107 Participants	2 participants n=206 Participants
Region of Enrollment Russian Federation	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
Region of Enrollment United Kingdom	1 participants n=99 Participants	2 participants n=107 Participants	3 participants n=206 Participants
Region of Enrollment Italy	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Region of Enrollment India	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Region of Enrollment France	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Region of Enrollment Hungary	2 participants n=99 Participants	1 participants n=107 Participants	3 participants n=206 Participants
Region of Enrollment Mexico	6 participants n=99 Participants	4 participants n=107 Participants	10 participants n=206 Participants
Region of Enrollment Brazil	4 participants n=99 Participants	2 participants n=107 Participants	6 participants n=206 Participants
Region of Enrollment Malaysia	1 participants n=99 Participants	1 participants n=107 Participants	2 participants n=206 Participants
Region of Enrollment Poland	1 participants n=99 Participants	1 participants n=107 Participants	2 participants n=206 Participants
Region of Enrollment Germany	0 participants n=99 Participants	3 participants n=107 Participants	3 participants n=206 Participants
Weight at inclusion	7.9 kilograms (kg) STANDARD_DEVIATION 1.1 • n=99 Participants	8.1 kilograms (kg) STANDARD_DEVIATION 1.2 • n=107 Participants	8.0 kilograms (kg) STANDARD_DEVIATION 1.2 • n=206 Participants
Height at inclusion	71.8 centimeters (cm) STANDARD_DEVIATION 2.8 • n=99 Participants	70.0 centimeters (cm) STANDARD_DEVIATION 10.4 • n=107 Participants	70.8 centimeters (cm) STANDARD_DEVIATION 7.8 • n=206 Participants
Type of initial shunt palliation Modified Blalock Taussig Shunt with Norwood	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Type of initial shunt palliation Modified Blalock Taussig Shunt without Norwood	18 participants n=99 Participants	20 participants n=107 Participants	38 participants n=206 Participants
Type of initial shunt palliation Sano procedure with Norwood	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
Type of initial shunt palliation Sano procedure without Norwood	1 participants n=99 Participants	1 participants n=107 Participants	2 participants n=206 Participants
Type of initial shunt palliation Central shunt	1 participants n=99 Participants	3 participants n=107 Participants	4 participants n=206 Participants
Type of initial shunt palliation Stent of ductus arteriosus	3 participants n=99 Participants	1 participants n=107 Participants	4 participants n=206 Participants
Shunt on cardiopulmonary bypass Yes	2 participants n=99 Participants	5 participants n=107 Participants	7 participants n=206 Participants
Shunt on cardiopulmonary bypass No	21 participants n=99 Participants	21 participants n=107 Participants	42 participants n=206 Participants
Age at shunt palliation	25.7 days STANDARD_DEVIATION 28.7 • n=99 Participants	13.7 days STANDARD_DEVIATION 12.7 • n=107 Participants	19.4 days STANDARD_DEVIATION 22.3 • n=206 Participants

PRIMARY outcome

Timeframe: Up to a maximum of 6 months

Population: The analysis was performed on the Intent-to-treat (ITT) population that consisted of all included participants. Participants were analyzed in the treatment arm allocated at randomization into the CLARINET study.

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 Participants 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Number of Participants With Bleeding Events Any bleeding event	0 participants	2 participants
Number of Participants With Bleeding Events - Serious	0 participants	0 participants
Number of Participants With Bleeding Events - Serious with an outcome of death	0 participants	0 participants
Number of Participants With Bleeding Events - Leading to permanent treatment discontinuation	0 participants	0 participants

PRIMARY outcome

Timeframe: Up to a maximum of 6 months

Population: The analysis was performed on the same population as previously (i.e. ITT population).

For all reported bleeding events, the type and the etiology of the bleeding event were collected. Participants who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology.

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 Participants 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Number of Participants According to Bleeding Type/Etiology Spontaneous	0 participants	1 participants
Number of Participants According to Bleeding Type/Etiology Puncture (vascular access site)	0 participants	1 participants

SECONDARY outcome

Timeframe: Up to a maximum of 6 months

Outcome events, shunt thrombosis requiring intervention or death, experienced during the study period were recorded. Participants were counted excluding the events that occured after the participant's protocol study end (occurrence of shunt thrombosis, next surgical procedure for correction of the congenital heart disease, death, or 18 months of age, whichever came first).

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 Participants 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths shunt thrombosis requiring intervention	0 participants	0 participants
Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths death	1 participants	0 participants

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

Clopidogrel 0.2 mg/kg/Day

Serious events: 6 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=23 participants at risk 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 participants at risk 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Infections and infestations Bronchiolitis	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Croup infectious	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Gastroenteritis	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Urinary tract infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Viral infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Cardiac disorders Low cardiac output syndrome	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Cardiac disorders Nodal arrhythmia	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
General disorders Pyrexia	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Respiratory, thoracic and mediastinal disorders Diaphragmatic paralysis	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	0.00% 0/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Respiratory, thoracic and mediastinal disorders Pulmonary artery stenosis	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	0.00% 0/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Nervous system disorders Ischaemic stroke	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	0.00% 0/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).

Other adverse events

Additional Information

Trial Transparency Team

sanofi-aventis

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months after trial completion, the Investigator can publish the results. Prior to publication, the sponsor shall review the manuscript and can request changes, provided they do not jeopardize the accuracy and/or the scientific value of the publication. The approval is given in writing by the sponsor, not exceeding 90 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=23 participants at risk 0.2 mL/kg/day matching placebo solution once daily	Clopidogrel 0.2 mg/kg/Day n=26 participants at risk 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily
Infections and infestations Any infections and infestations	26.1% 6/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	53.8% 14/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Upper respiratory tract infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	23.1% 6/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Gastroenteritis	8.7% 2/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Ear infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Lower respiratory tract infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Viral infection	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Pharyngitis	13.0% 3/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Infections and infestations Nasopharyngitis	8.7% 2/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	3.8% 1/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Gastrointestinal disorders Any gastrointestinal disorders	8.7% 2/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	23.1% 6/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Gastrointestinal disorders Diarrhoea	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	11.5% 3/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
General disorders Any general disorders and administration site conditions	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	23.1% 6/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
General disorders Pyrexia	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	15.4% 4/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Respiratory, thoracic and mediastinal disorders Any respiratory, thoracic and mediastinal disorders	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	15.4% 4/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	11.5% 3/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Injury, poisoning and procedural complications Any injury, poisoning and procedural complications	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	11.5% 3/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Skin and subcutaneous tissue disorders Any skin and subcutaneous tissue disorders	4.3% 1/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).
Cardiac disorders Any cardiac disorders	0.00% 0/23 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).	7.7% 2/26 • Up to a maximum of 6 months. All Adverse Events (AE) experienced during the study period were collected regardless of seriousness or relationship to the drug . The analysis was performed on the intent-to-treat population and included all AE that developed/worsened during the 'on-treatment period' (i.e. from inclusion in the extension study up to 28 days after treatment discontinuation).