Trial Outcomes & Findings for Voriconazole For Chronic Bronchopulmonary Aspergillosis (NCT NCT00159822)

Last Updated: 2010-01-20

Results Overview

Successful global outcome: composite assessment of radiological and mycological responses; defined as complete or partial radiological response and mycological eradication (absence of aspergillus); no success=criteria not met. Assessment was determined by the Data Review Committee (DRC). Complete response: resolution of radiographic and or bronchoscopic abnormalities attributable to aspergillosis present at baseline; partial response: reduction in diameter ≥ 50 percent on chest tomodensitometry (TDM) or regressed lesion on endoscopy witnessed by 2 different operators without any new lesion.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

48 participants

Primary outcome timeframe

at 6 months of treatment

Results posted on

2010-01-20

Participant Flow

18 active centers in France; planned recruitment of 48 minimally immunocompromised or non-immunocompromised subjects with chronic bronchopulmonary aspergillosis.

56 subjects were screened; 48 subjects included; 8 subjects did not meet criteria and were not included.

Participant milestones

Participant milestones
Measure	Voriconazole Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Voriconazole Treatment Period STARTED	48
Voriconazole Treatment Period COMPLETED	26
Voriconazole Treatment Period NOT COMPLETED	22
Post-treatment Follow-up Period STARTED	26
Post-treatment Follow-up Period COMPLETED	23
Post-treatment Follow-up Period NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Voriconazole Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Voriconazole Treatment Period Lack of Efficacy	3
Voriconazole Treatment Period Adverse Event	9
Voriconazole Treatment Period Death	4
Voriconazole Treatment Period Protocol Violation	2
Voriconazole Treatment Period Lost to Follow-up	2
Voriconazole Treatment Period Withdrawal by Subject	2
Post-treatment Follow-up Period Death	1
Post-treatment Follow-up Period Withdrawal by Subject	1
Post-treatment Follow-up Period Reason unspecified	1

Baseline Characteristics

Voriconazole For Chronic Bronchopulmonary Aspergillosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Voriconazole n=48 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Age Continuous	57.27 years STANDARD_DEVIATION 13.85 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants
Sex: Female, Male Male	29 Participants n=5 Participants

PRIMARY outcome

Timeframe: at 6 months of treatment

Population: Modified Intent to Treat (mITT): all subjects in ITT population (took at least 1 dose of voriconazole and had at least 1 post-inclusion efficacy assessment) who had diagnosis of chronic bronchopulmonary aspergillosis confirmed by the Data Review Committee (DRC); 5 subjects excluded from mITT population due to unproven diagnosis.

Outcome measures

Outcome measures
Measure	Voriconazole n=41 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis Success	13 participants
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis No success	28 participants

SECONDARY outcome

Timeframe: Month 3 and End of Treatment (Month 9 or Month 12)

Population: mITT; End of treatment (EOT) or at last visit available \[LVA\] (EOT or LVA includes data from 6, 9 or 12 months in case of extension of the treatment period beyond 6 months). Month 6 analysis is reported in the primary outcome measure.

Successful global outcome: composite assessment of radiological and mycological responses; defined as complete (resolution of radiographic and or bronchoscopic abnormalities attributable to aspergillosis present at baseline) or partial (reduction in diameter ≥ 50 percent on chest TDM or regressed lesion on endoscopy witnessed by 2 different operators without any new lesion) radiological response and mycological eradication after 3 months of treatment and after 9 or 12 months (in case of extension of treatment period beyond 6 months); no success=criteria not met. Assessment determined by DRC.

Outcome measures

Outcome measures
Measure	Voriconazole n=41 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis Month 3 success=yes	12 participants
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis Month 3 success=no	24 participants
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis Month 3 success=missing values	5 participants
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis EOT [LVA] success=yes	18 participants
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis EOT [LVA] success=no	23 participants

SECONDARY outcome

Timeframe: at 6 months of treatment

Population: mITT

Successful global outcome: composite assessment of radiological and mycological responses; defined as complete or partial radiological response and mycological eradication (absence of aspergillus); no success=criteria not met. Assessment was determined by the Data Review Committee (DRC). Complete response: resolution of all radiographic and or bronchoscopic abnormalities attributable to the aspergillosis present at baseline; partial response: reduction in diameter ≥ 50% on chest tomodensitometry (TDM) or regressed lesion on endoscopy witnessed by 2 different operators without any new lesion.

Outcome measures

Outcome measures
Measure	Voriconazole n=19 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis Success	10 participants
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis No success	9 participants

SECONDARY outcome

Timeframe: at 6 months of treatment

Population: mITT

Successful global outcome: composite assessment of radiological and mycological responses; defined as complete or partial radiological response and mycological eradication (absence of aspergillus); no success=criteria not met. Assessment was determined by the Data Review Committee (DRC). Complete response: resolution of all radiographic and or bronchoscopic abnormalities attributable to the aspergillosis present at baseline; partial response: reduction in diameter ≥ 50% on chest tomodensitometry (TDM) or regressed lesion on endoscopy witnessed by 2 different operators without any new lesion.

Outcome measures

Outcome measures
Measure	Voriconazole n=22 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma Success	3 paticipants
Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma No success	19 paticipants

SECONDARY outcome

Timeframe: Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and End of study ([EOS] EOT + 6 months)

Population: mITT; 6, 9 or 12 months (in case of extension of the treatment period beyond 6 months) as EOT or last visit available; (n) = number of subjects with analyzable data at observation. Subject may be represented in \>1 category.

Subject assessment of improvement of respiratory clinical signs and symptoms as indicated by the subject placing a mark on a 10 cm VAS scored 0 (better state of health) to 100 (poor state of health) for cough, dyspnea, sputum, hemoptysis, chest tightness, and nocturnal awakening. Change from baseline: mean of (value of scores on scale at treatment visit minus baseline value).

Outcome measures

Outcome measures
Measure	Voriconazole n=41 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Cough Month 3 (n=30)	-15.80 scores on scale 95% Confidence Interval 33.40 • Interval -28.27 to -3.33
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Cough Month 6 (n=27)	-19.63 scores on scale 95% Confidence Interval 35.48 • Interval -33.67 to -5.59
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Cough Month 9 (n=20)	-17.45 scores on scale 95% Confidence Interval 43.01 • Interval -37.58 to 2.68
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Cough Month 12 (n=16)	-30.13 scores on scale 95% Confidence Interval 37.01 • Interval -49.85 to -10.4
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Cough EOS (n=20)	-13.65 scores on scale 95% Confidence Interval 41.31 • Interval -32.98 to 5.68
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Dyspnea Month 3 (n=30)	-2.67 scores on scale 95% Confidence Interval 24.22 • Interval -11.71 to 6.38
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Dyspnea Month 6 (n=27)	-4.22 scores on scale 95% Confidence Interval 25.16 • Interval -14.17 to 5.73
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Dyspnea Month 9 (n=20)	-1.40 scores on scale 95% Confidence Interval 24.66 • Interval -12.94 to 10.14
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Dyspnea Month 12 (n=16)	-8.69 scores on scale 95% Confidence Interval 25.15 • Interval -22.09 to 4.71
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Dyspnea EOS (n=20)	1.75 scores on scale 95% Confidence Interval 31.30 • Interval -12.9 to 16.4
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Sputum Month 3 (n=30)	-8.03 scores on scale 95% Confidence Interval 27.44 • Interval -18.28 to 2.21
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Sputum Month 6 (n=28)	-14.86 scores on scale 95% Confidence Interval 37.11 • Interval -29.25 to -0.47
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Sputum Month 9 (n=21)	-12.62 scores on scale 95% Confidence Interval 37.35 • Interval -29.62 to 4.38
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Sputum Month 12 (n=17)	-26.47 scores on scale 95% Confidence Interval 26.59 • Interval -40.14 to -12.8
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Sputum EOS (n=21)	-13.67 scores on scale 95% Confidence Interval 36.20 • Interval -30.15 to 2.81
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Hemoptysis Month 3 (n=30)	-2.13 scores on scale 95% Confidence Interval 28.05 • Interval -12.61 to 8.34
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Hemoptysis Month 6 (n=28)	5.11 scores on scale 95% Confidence Interval 27.41 • Interval -5.52 to 15.73
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Hemoptysis Month 9 (n=21)	-4.52 scores on scale 95% Confidence Interval 30.32 • Interval -18.33 to 9.28
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Hemoptysis Month 12 (n=16)	-8.31 scores on scale 95% Confidence Interval 31.44 • Interval -25.07 to 8.44
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Hemoptysis EOS (n=21)	1.14 scores on scale 95% Confidence Interval 20.72 • Interval -7.73 to 10.02
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Chest tightness Month 3 (n=30)	0.03 scores on scale 95% Confidence Interval 37.85 • Interval -14.1 to 14.17
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Chest tightness Month 6 (n=28)	0.86 scores on scale 95% Confidence Interval 29.83 • Interval -10.71 to 12.42
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Chest tightness Month 9 (n=21)	-1.52 scores on scale 95% Confidence Interval 33.03 • Interval -16.56 to 13.51
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Chest tightness Month 12 (n=17)	-9.29 scores on scale 95% Confidence Interval 31.27 • Interval -25.37 to 6.78
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Chest tightness EOS (n=20)	-4.00 scores on scale 95% Confidence Interval 22.31 • Interval -14.44 to 6.44
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Nocturnal awakening Month 3 (n=30)	0.57 scores on scale 95% Confidence Interval 29.33 • Interval -10.39 to 11.52
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Nocturnal awakening Month 6 (n=28)	-2.86 scores on scale 95% Confidence Interval 36.84 • Interval -17.14 to 11.43
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Nocturnal awakening Month 9 (n=21)	-2.40 scores on scale 95% Confidence Interval 31.13 • Interval -16.57 to 11.76
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Nocturnal awakening Month 12 (n=16)	4.00 scores on scale 95% Confidence Interval 31.45 • Interval -12.76 to 20.76
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Nocturnal awakening EOS (n=21)	5.29 scores on scale 95% Confidence Interval 41.96 • Interval -13.81 to 24.38
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Mean VAS Month 3 (n=30)	-4.67 scores on scale 95% Confidence Interval 18.29 • Interval -11.5 to 2.16
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Mean VAS Month 6 (n=27)	-5.99 scores on scale 95% Confidence Interval 20.82 • Interval -14.22 to 2.25
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Mean VAS Month 9 (n=20)	-7.16 scores on scale 95% Confidence Interval 24.31 • Interval -18.54 to 4.21
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Mean VAS Month 12 (n=15)	-15.87 scores on scale 95% Confidence Interval 20.67 • Interval -27.32 to -4.42
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) Mean VAS EOS (n=19)	-6.58 scores on scale 95% Confidence Interval 20.43 • Interval -16.43 to 3.27

SECONDARY outcome

Timeframe: During the 6 months following EOT (EOT + 3 months, EOT + 6 months)

Population: mITT; due to the small number of radiological reappearance (4 subjects), no formal analysis of this endpoint was performed.

Relapse: any proven reappearance of pulmonary aspergillosis during the follow-up period, following a successful global outcome at EOT, and defined as a deterioration of clinical signs and symptoms, confirmed radiologically (chest \[TDM\] and or endoscopy) and mycologically (histology and or culture and or serology).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: During the 6 months following EOT (EOT + 3 months, EOT + 6 months)

Population: mITT; due to the small number of radiological reappearance (4 subjects), no formal analysis of this endpoint was performed.

Time (months) to relapse: any proven reappearance of pulmonary aspergillosis during the follow-up period, following a successful global outcome at EOT, and defined as a deterioration of clinical signs and symptoms, confirmed radiologically (chest \[TDM\] and or endoscopy) and mycologically (histology and or culture and or serology).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline through EOS (EOT + 6 months)

Population: Safety population (SAF): all subjects who took at least 1 dose of voriconazole.

Number of subjects with an outcome of death (adverse event with a fatal outcome) through end of study.

Outcome measures

Outcome measures
Measure	Voriconazole n=48 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Global Survival: Number of Subjects With an Outcome of Death	5 participants Interval 0.725 to 0.976

SECONDARY outcome

Timeframe: Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and EOS (EOT + 6 months)

Population: mITT; 6, 9 or 12 months (in case of extension of the treatment period beyond 6 months) as EOT or last visit available; (n) = number of subjects with analyzable data at observation.

Subject administered questionnaire to measure improvement in QOL; 50 questions exploring 3 different areas: symptoms, impact on activity profile (activity), and impact on daily life (impacts). Each item in an area is weighted based on empirical data; scores range from lowest possible weight 0 to highest possible weight 100. Scores for each section and total score calculated using score calculation algorithms with higher scores indicating poor health. Change from baseline: mean of (value of scores on scale at treatment visit minus baseline value).

Outcome measures

Outcome measures
Measure	Voriconazole n=41 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Symptoms Month 3 (n=35)	-5.50 scores on scale 95% Confidence Interval 22.53 • Interval -13.24 to 2.24
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Symptoms Month 6 (n=29)	-3.32 scores on scale 95% Confidence Interval 7.37 • Interval -14.01 to 7.37
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Symptoms Month 9 (n=19)	0.96 scores on scale 95% Confidence Interval 29.78 • Interval -13.39 to 15.32
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Symptoms Month 12 (n=17)	-2.72 scores on scale 95% Confidence Interval 23.80 • Interval -14.95 to 9.52
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Symptoms EOS (n=23)	-6.84 scores on scale 95% Confidence Interval 23.53 • Interval -17.01 to 3.34
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Activity Month 3 (n=31)	-4.15 scores on scale 95% Confidence Interval 17.72 • Interval -10.65 to 2.35
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Activity Month 6 (n=28)	-9.43 scores on scale 95% Confidence Interval 17.30 • Interval -16.13 to -2.72
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Activity Month 9 (n=18)	-0.03 scores on scale 95% Confidence Interval 18.04 • Interval -9.0 to 8.94
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Activity Month 12 (n=18)	-5.88 scores on scale Interval -10.98 to -0.78
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Activity EOS (n=23)	-8.06 scores on scale Interval -14.58 to -1.54
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Impacts Month 3 (n=33)	-6.72 scores on scale Interval -12.42 to -1.03
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Impacts Month 6 (n=28)	-8.41 scores on scale Interval -15.22 to -1.61
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Impacts Month 9 (n=20)	-3.78 scores on scale Interval -14.72 to 7.16
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Impacts Month 12 (n=18)	-7.97 scores on scale Interval -16.49 to 0.55
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Impacts EOS (n=21)	-7.93 scores on scale Interval -13.46 to -2.4
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Total Month 3 (n=35)	-5.70 scores on scale Interval -10.6 to -0.81
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Total Month 6 (n=30)	-8.39 scores on scale Interval -14.02 to -2.76
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Total Month 9 (n=20)	-1.87 scores on scale Interval -11.26 to 7.51
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Total Month 12 (n=18)	-6.63 scores on scale Interval -12.97 to -0.28
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire Total EOS (n=24)	-8.19 scores on scale Interval -12.41 to -3.96

SECONDARY outcome

Timeframe: Month 3, and Month 6, Month 9, or Month 12 [EOT]

Population: mITT; End of treatment (EOT) or at last visit available \[LVA\](EOT or LVA includes data from 6, 9 or 12 months in case of extension of the treatment period beyond 6 months).

Radiological response: based on chest TDM except for tracheo-bronchialaspergillosis which was assessed by bronchoscopy. Complete response: resolution of all radiographic and or bronchoscopic abnormalities attributable to aspergillosis present at baseline; partial response: reduction in diameter ≥ 50% on chest TDM or regressed lesion on endoscopy witnessed by 2 different operators without any new lesion.

Outcome measures

Outcome measures
Measure	Voriconazole n=37 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Complete or Partial Radiological Response Month 3 Complete response	4 participants
Number of Subjects With Complete or Partial Radiological Response Month 3 Partial response	9 participants
Number of Subjects With Complete or Partial Radiological Response EOT [LVA] Complete response	6 participants
Number of Subjects With Complete or Partial Radiological Response EOT [LVA] Partial response	14 participants

SECONDARY outcome

Timeframe: Month 3, and Month 6, Month 9, or Month 12 [EOT]

Population: mITT; 6, 9 or 12 months (in case of extension of the treatment period beyond 6 months) as EOT or last visit available.

Mycological response: eradication: absence of aspergillus species (spp) in bronchopulmonary samples: sputum, bronchial aspirate or bronchoalveolar lavage (BAL) (negative direct examination \[exam\] and negative culture), and negative histological exam when available; persistence (no eradication): presence of aspergillus spp in any relevant bronchopulmonary samples. Not done (presumed eradication): case reviewed by DRC for any mycological exams not performed to assess if case should constitute presumed eradication (no sputum due to clinical improvement).

Outcome measures

Outcome measures
Measure	Voriconazole n=35 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Mycological Response of Eradication Month 3 Eradication	29 participants
Number of Subjects With Mycological Response of Eradication Month 3 Persistence	3 participants
Number of Subjects With Mycological Response of Eradication Month 3 Not done (presume eradication)	3 participants
Number of Subjects With Mycological Response of Eradication Month 6 Eradication	26 participants
Number of Subjects With Mycological Response of Eradication Month 6 Not done (presume eradication)	6 participants
Number of Subjects With Mycological Response of Eradication Month 9 Eradication	14 participants
Number of Subjects With Mycological Response of Eradication Month 9 Not done (presume eradication)	7 participants
Number of Subjects With Mycological Response of Eradication Month 12 Eradication	15 participants
Number of Subjects With Mycological Response of Eradication Month 12 Not done (presume eradication)	2 participants

SECONDARY outcome

Timeframe: Month 3, and Month 6, Month 9, or Month 12 [EOT]

Population: mITT (with serology at inclusion); 6, 9 or 12 months (in case of extension of the treatment period beyond 6 months) as EOT or last visit available. Data summarized as Worsening (failure), No change (stabilization), or Improvement (complete or partial response) due to large number of missing results values.

Serological response: normalization (complete response) defined as return to normal values (≤ 1 arc); partial response defined as significant decrease but not complete (decrease of 2 or more arcs compared to baseline). Complete or partial response summarized as Improvement; based on arc values at visit compared to arc values at baseline (inclusion).

Outcome measures

Outcome measures
Measure	Voriconazole n=40 Participants Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Number of Subjects With Complete or Partial Serological Response Month 3 Improvement	10 participants
Number of Subjects With Complete or Partial Serological Response Month 6 Improvement	14 participants
Number of Subjects With Complete or Partial Serological Response Month 9 Improvement	9 participants
Number of Subjects With Complete or Partial Serological Response Month 12 Improvement	8 participants

Adverse Events

Voriconazole

Serious events: 21 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Voriconazole n=48 participants at risk Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Gastrointestinal disorders Abdominal pain	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Abdominal pain upper	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Constipation	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Vomiting	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
General disorders General physical health deterioration	4.2% 2/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Hepatobiliary disorders Cholecystitis	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Bronchitis	4.2% 2/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Bronchitis haemophilus	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Bronchitis viral	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Pneumonia	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Pseudomonas bronchitis	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Sepsis	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Septic shock	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Urinary tract infection	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations Electrocardiogram QT prolonged	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations Gamma-glutamyltransferase increased	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations General physical condition abnormal	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations Weight decreased	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Metabolism and nutrition disorders Hyponatraemia	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Musculoskeletal and connective tissue disorders Arthralgia	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Haemoptysis	10.4% 5/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Lung disorder	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Pneumothorax	4.2% 2/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Pulmonary pneumatocele	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Surgical and medical procedures Arterial stent insertion	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Surgical and medical procedures Surgery	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Vascular disorders Peripheral ischaemia	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	2.1% 1/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.

Other adverse events

Other adverse events
Measure	Voriconazole n=48 participants at risk Voriconazole (VFend®) initially administered intravenously (IV) or orally (PO) based on investigator's clinical decision. PO loading dose every 12 hours on Day 1 for body weight ≥ 40 kilograms (kg): 400 milligrams (mg) followed by maintenance dose of 200 mg every 12 hours; or for body weight \< 40 kg, loading dose every 12 hours on Day 1: 200 mg followed by maintenance dose of 100 mg every 12 hours. If initially IV, loading dose every 12 hours on Day 1: 6 mg/kg followed by maintenance dose of 4 mg/kg every 12 hours for 3 to 10 days; then, switched to PO maintenance dose based on body weight.
Eye disorders Vision blurred	12.5% 6/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Eye disorders Visual impairment	18.8% 9/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Constipation	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Nausea	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Gastrointestinal disorders Vomiting	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
General disorders Chills	8.3% 4/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Hepatobiliary disorders Cholestasis	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Infections and infestations Bronchitis	18.8% 9/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations Gamma-glutamyltransferase increased	8.3% 4/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Investigations Weight decreased	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Nervous system disorders Headache	6.2% 3/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Psychiatric disorders Insomnia	12.5% 6/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Respiratory, thoracic and mediastinal disorders Haemoptysis	14.6% 7/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Skin and subcutaneous tissue disorders Photosensitivity reaction	12.5% 6/48 Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.

Additional Information

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