Trial Outcomes & Findings for Survey of Inhibitors in Plasma-Product Exposed Toddlers (NCT NCT01064284)

Last Updated: 2017-08-25

Results Overview

Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

303 participants

Primary outcome timeframe

During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Results posted on

2017-08-25

Participant Flow

303 boys were assessed for eligibility, 39 were excluded, therefore, of those 303, only 264 patients underwent randomization. Of these 264, only 251 were analyzed.

Participant milestones

Participant milestones
Measure	pd vWF/FVIII Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
Overall Study STARTED	125	126
Overall Study COMPLETED	107	109
Overall Study NOT COMPLETED	18	17

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

There were no cells or DNA available for 17 patients.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	pd vWF/FVIII n=125 Participants Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=126 Participants Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	Total n=251 Participants Total of all reporting groups
Age, Continuous	19.1 months STANDARD_DEVIATION 14.3 • n=125 Participants	21.3 months STANDARD_DEVIATION 16.3 • n=126 Participants	20.2 months STANDARD_DEVIATION 21.68 • n=251 Participants
Sex: Female, Male Female	0 Participants n=125 Participants	0 Participants n=126 Participants	0 Participants n=251 Participants
Sex: Female, Male Male	125 Participants n=125 Participants	126 Participants n=126 Participants	251 Participants n=251 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=125 Participants	0 Participants n=126 Participants	0 Participants n=251 Participants
Race (NIH/OMB) Asian	41 Participants n=125 Participants	43 Participants n=126 Participants	84 Participants n=251 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=125 Participants	0 Participants n=126 Participants	0 Participants n=251 Participants
Race (NIH/OMB) Black or African American	5 Participants n=125 Participants	2 Participants n=126 Participants	7 Participants n=251 Participants
Race (NIH/OMB) White	39 Participants n=125 Participants	45 Participants n=126 Participants	84 Participants n=251 Participants
Race (NIH/OMB) More than one race	0 Participants n=125 Participants	0 Participants n=126 Participants	0 Participants n=251 Participants
Race (NIH/OMB) Unknown or Not Reported	40 Participants n=125 Participants	36 Participants n=126 Participants	76 Participants n=251 Participants
Region of Enrollment Argentina	2 participants n=125 Participants	0 participants n=126 Participants	2 participants n=251 Participants
Region of Enrollment Austria	2 participants n=125 Participants	2 participants n=126 Participants	4 participants n=251 Participants
Region of Enrollment Brazil	2 participants n=125 Participants	2 participants n=126 Participants	4 participants n=251 Participants
Region of Enrollment Chile	1 participants n=125 Participants	3 participants n=126 Participants	4 participants n=251 Participants
Region of Enrollment Egypt	38 participants n=125 Participants	37 participants n=126 Participants	75 participants n=251 Participants
Region of Enrollment India	40 participants n=125 Participants	43 participants n=126 Participants	83 participants n=251 Participants
Region of Enrollment Iran	14 participants n=125 Participants	18 participants n=126 Participants	32 participants n=251 Participants
Region of Enrollment Italy	5 participants n=125 Participants	4 participants n=126 Participants	9 participants n=251 Participants
Region of Enrollment Mexico	4 participants n=125 Participants	2 participants n=126 Participants	6 participants n=251 Participants
Region of Enrollment Saudi Arabia	1 participants n=125 Participants	0 participants n=126 Participants	1 participants n=251 Participants
Region of Enrollment South Africa	2 participants n=125 Participants	2 participants n=126 Participants	4 participants n=251 Participants
Region of Enrollment Spain	3 participants n=125 Participants	3 participants n=126 Participants	6 participants n=251 Participants
Region of Enrollment Turkey	2 participants n=125 Participants	1 participants n=126 Participants	3 participants n=251 Participants
Region of Enrollment United States	9 participants n=125 Participants	9 participants n=126 Participants	18 participants n=251 Participants
Mutation Status Non-null mutation	16 participants n=117 Participants • There were no cells or DNA available for 17 patients.	21 participants n=117 Participants • There were no cells or DNA available for 17 patients.	37 participants n=234 Participants • There were no cells or DNA available for 17 patients.
Mutation Status Null mutation	101 participants n=117 Participants • There were no cells or DNA available for 17 patients.	96 participants n=117 Participants • There were no cells or DNA available for 17 patients.	197 participants n=234 Participants • There were no cells or DNA available for 17 patients.
Treatment Regimen On-demand	61 participants n=125 Participants	56 participants n=126 Participants	117 participants n=251 Participants
Treatment Regimen Standard prophylaxis	21 participants n=125 Participants	19 participants n=126 Participants	40 participants n=251 Participants
Treatment Regimen Modified prophylaxis	43 participants n=125 Participants	51 participants n=126 Participants	94 participants n=251 Participants

PRIMARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients

Outcome measures

Outcome measures
Measure	pd vWF/FVIII n=125 Participants Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=126 Participants Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs	29 participants Interval 18.4 to 35.2	47 participants Interval 34.7 to 54.3

SECONDARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Population: Data were not collected and the Outcome will never be analyzed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: In the 6 months after inhibitor development

Population: Data at 6-month follow-up were missing for two patients assigned to plasma- derived factor VIII and three patients assigned to recombinant factor VIII.

Number of participants for each group who developed transient inhibitors (this means, those inhibitors which disappeared spontaneously within 6 months without immunotolerance treatment).

Outcome measures

Outcome measures
Measure	pd vWF/FVIII n=123 Participants Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=123 Participants Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
To Evaluate the Frequency of Transient Inhibitors	7 participants	12 participants

SECONDARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Number of EDs: Number of Exposure Days (EDs) after which the inhibitors develop

Outcome measures

Outcome measures
Measure	pd vWF/FVIII n=125 Participants Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=126 Participants Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs)	8 Exposure days Interval 3.0 to 33.0	8 Exposure days Interval 2.0 to 38.0

SECONDARY outcome

Timeframe: During 6 months of observation, from the inhibitor occurrence

Inhibitor Titre at Onset

Outcome measures

Outcome measures
Measure	pd vWF/FVIII n=125 Participants Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=126 Participants Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset)	12 Bethesda Units Interval 0.8 to 1100.0	16.3 Bethesda Units Interval 0.7 to 1850.0

SECONDARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Population: Data were not collected and the Outcome will never be analyzed

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Population: Data were not collected and the Outcome will never be analyzed

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Population: Data were not collected and the Outcome will never be analyzed

Outcome measures

Outcome data not reported

Adverse Events

pd vWF/FVIII

Serious events: 20 serious events

Other events: 95 other events

Deaths: 0 deaths

rFVIII

Serious events: 13 serious events

Other events: 86 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	pd vWF/FVIII n=133 participants at risk Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=131 participants at risk Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
Blood and lymphatic system disorders Anaemia	3.0% 4/133 • Number of events 4 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	6.1% 8/131 • Number of events 8 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Bronchitis	5.3% 7/133 • Number of events 8 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	3.8% 5/131 • Number of events 6 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Respiratory, thoracic and mediastinal disorders Cough	7.5% 10/133 • Number of events 12 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	6.9% 9/131 • Number of events 34 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Diarrhoea	4.5% 6/133 • Number of events 8 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	5.3% 7/131 • Number of events 9 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Nasopharyngitis	12.0% 16/133 • Number of events 19 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	7.6% 10/131 • Number of events 42 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Pharyngitis	2.3% 3/133 • Number of events 9 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	6.1% 8/131 • Number of events 10 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
General disorders Pyrexia	16.5% 22/133 • Number of events 37 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	12.2% 16/131 • Number of events 37 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Upper respiratory tract infection	8.3% 11/133 • Number of events 17 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	6.9% 9/131 • Number of events 12 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Viral infection	6.0% 8/133 • Number of events 13 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	4.6% 6/131 • Number of events 9 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Vomiting	6.0% 8/133 • Number of events 11 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	6.1% 8/131 • Number of events 9 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.

Additional Information

Prof. Flora Peyvandi

Centro Emofilia e Trombosi "Angelo Bianchi Bonomi", Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico di Milano

Phone: 0039 0255035414

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	pd vWF/FVIII n=133 participants at risk Plasma-derived vWF/FVIII PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding	rFVIII n=131 participants at risk Recombinant FVIII Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
Gastrointestinal disorders Abdominal wall haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Abdominal pain	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Blood and lymphatic system disorders Anaemia	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Ascites	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Cerebral haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Surgical and medical procedures Circumcision	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Epidural Haemorrage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Fall	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Gastroenteritis	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Musculoskeletal and connective tissue disorders Haemarthrosis	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Haematemesis	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Vascular disorders Haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Haemorrhage intracranial	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	2.3% 3/131 • Number of events 3 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Blood and lymphatic system disorders Haemorrhagic anaemia	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Head Injury	1.5% 2/133 • Number of events 2 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Hemiparesis	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Hemiplegia	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Hepatobiliary disorders Hepatomegaly	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Hypersomnia	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Influenza	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Joint injury	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Respiratory, thoracic and mediastinal disorders Lower Respiratory Tract Infection	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Blood and lymphatic system disorders Lymphadenopathy	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Musculoskeletal and connective tissue disorders Muscle haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Gastrointestinal disorders Nausea	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Blood and lymphatic system disorders Pancytopenia	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Vascular disorders Poor venous access	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
General disorders Pyrexia	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Road traffic accident	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Seizure	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Skin and subcutaneous tissue disorders Skin haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Speech disorder developmental	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Nervous system disorders Status epilepticus	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Skin and subcutaneous tissue disorders Subcutaneous haematoma	1.5% 2/133 • Number of events 3 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Subdural haematoma	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Injury, poisoning and procedural complications Subdural haemorrhage	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Surgical and medical procedures Talipes correction	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Musculoskeletal and connective tissue disorders Torticollis	0.00% 0/133 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.76% 1/131 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
Infections and infestations Urinary tract infection	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.
General disorders Vessel puncture site haemorrhage	0.75% 1/133 • Number of events 1 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.	0.00% 0/131 • 5 years Systematic Assessment has been applied through the use of a specific routinary questions focusing on averse events and a patient's diary.