Trial Outcomes & Findings for A Multiple-Dose Study To Evaluate The Pharmacokinetics And Safety Of Voriconazole In Immunocompromised Adolescents (NCT NCT00556998)

Last Updated: 2016-05-05

Results Overview

AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

26 participants

Primary outcome timeframe

Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion

Results posted on

2016-05-05

Participant Flow

Participant milestones

Participant milestones
Measure	All Treatments Voriconazole intravenous (IV) loading dose (6 mg/kg) was administered in the morning and evening on Day 1, and the IV maintenance dose (4 mg/kg) was administered in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen (300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg) was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
Voriconazole Intravenous (IV) STARTED	26
Voriconazole Intravenous (IV) Treated	26
Voriconazole Intravenous (IV) COMPLETED	21
Voriconazole Intravenous (IV) NOT COMPLETED	5
Voriconazole Oral STARTED	22
Voriconazole Oral COMPLETED	20
Voriconazole Oral NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	All Treatments Voriconazole intravenous (IV) loading dose (6 mg/kg) was administered in the morning and evening on Day 1, and the IV maintenance dose (4 mg/kg) was administered in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen (300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg) was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
Voriconazole Intravenous (IV) Adverse Event	1
Voriconazole Intravenous (IV) Other	4
Voriconazole Oral Adverse Event	1
Voriconazole Oral Intolerant of oral treatment	1

Baseline Characteristics

A Multiple-Dose Study To Evaluate The Pharmacokinetics And Safety Of Voriconazole In Immunocompromised Adolescents

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Treatments n=26 Participants Voriconazole intravenous (IV) loading dose (6 mg/kg) was administered in the morning and evening on Day 1, and the IV maintenance dose (4 mg/kg) was administered in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen (300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg) was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
Age, Customized 12	4 Years n=5 Participants
Age, Customized 13	10 Years n=5 Participants
Age, Customized >13 to <17	12 Years n=5 Participants
Sex/Gender, Customized Female	9 Participants n=5 Participants
Sex/Gender, Customized Male	17 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: Intent to treat (ITT) population of participants who had completed pharmacokinetic (PK) blood sampling for at least one day. N = number of participants with analyzable data.

AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=23 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration	22.39 μg*h/mL Standard Deviation 21.47

PRIMARY outcome

Timeframe: Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=23 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration	3.89 μg/mL Standard Deviation 2.59

PRIMARY outcome

Timeframe: Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=23 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Time to Reach Cmax (Tmax) Following IV Administration	1.30 hours Interval 1.17 to 3.95

PRIMARY outcome

Timeframe: Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
AUC12,ss Following Oral Administration	16.74 μg*h/mL Standard Deviation 13.50

PRIMARY outcome

Timeframe: Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Cmax,ss Following Oral Administration	2.35 μg/mL Standard Deviation 1.41

PRIMARY outcome

Timeframe: Day 7 (up to Day 30) Predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Tmax Following Oral Administration	2.00 hours Interval 0.67 to 8.1

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

AUC12 = Area under the plasma concentration-time profile from time zero (predose) to twelve hours. AUC12 was obtained by the Linear/Log trapezoidal method.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=22 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
AUC12 Following IV Loading Dose	9.14 μg*h/mL Standard Deviation 4.90

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=22 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Tmax Following an IV Loading Dose	1.97 hours Interval 1.9 to 2.08

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=22 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Cmax Following an IV Loading Dose	2.25 μg/mL Standard Deviation 0.86

SECONDARY outcome

Timeframe: Day 7 (up to Day 20) for IV; Day 7 (up to Day 30) for oral at predose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data; n = number of participants who contributed to data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=21 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Minimum Observed Plasma Trough Concentration (Cmin) IV Day 7 (up to Day 20) (n=21)	1.05 μg/mL Standard Deviation 1.85
Minimum Observed Plasma Trough Concentration (Cmin) Oral Day 7 (up to Day 30) (n=19)	0.72 μg/mL Standard Deviation 0.81

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion and on Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=25 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 1	21.18 μg*h/mL Standard Deviation 6.80
AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 7 (up to Day 20)	36.21 μg*h/mL Standard Deviation 9.20

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion and on Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=25 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 1	2.50 μg/mL Standard Deviation 0.84
Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 7 (up to Day 20)	3.48 μg/mL Standard Deviation 0.73

SECONDARY outcome

Timeframe: Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion and on Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=25 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 1	4.00 μg*h/mL Interval 1.97 to 8.03
Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration Day 7 (up to Day 20)	4.03 μg*h/mL Interval 0.0 to 12.1

SECONDARY outcome

Timeframe: On Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration	44.07 μg*h/mL Standard Deviation 13.86

SECONDARY outcome

Timeframe: Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration	4.44 μg/mL Standard Deviation 1.43

SECONDARY outcome

Timeframe: Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose

Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.

Outcome measures

Outcome measures
Measure	Voriconazole IV n=19 Participants Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).
Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration	5.97 hours Interval 1.0 to 8.1

OTHER_PRE_SPECIFIED outcome

Voriconazole IV

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

Voriconazole Oral

Serious events: 4 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Voriconazole IV n=26 participants at risk Voriconazole IV loading dose (6 mg/kg) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg) in the morning and evening on Days 2 to 7 (up to Day 20 if clinically indicated).	Voriconazole Oral n=22 participants at risk Oral maintenance dosing regimen (300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg) was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
Blood and lymphatic system disorders Neutropenia	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericardial effusion	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Caecitis	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Mucosal inflammation	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Immune system disorders Acute graft versus host disease in intestine	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Immune system disorders Acute graft versus host disease in liver	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Alpha haemolytic streptococcal infection	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Bacteraemia	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Herpes simplex	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Sepsis	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Blood bilirubin increased	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Depression	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Cystitis haemorrhagic	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Renal failure acute	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Respiratory distress	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Capillary leak syndrome	3.8% 1/26 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.5% 1/22 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.