Voriconazole For Chronic Bronchopulmonary Aspergillosis

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00159822
• Collaborator: (none)
• Enrollment: 48
• Locations: 18
• Arm: 1
• Duration (Months): 41
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the efficacy of voriconazole (VFend(R)) as first line treatment for proven chronic bronchopulmonary aspergillosis, in minimally immunocompromised or non-immunocompromised patients after 6 months of treatment i.e. chronic necrotizing pulmonary

Condition or Disease	Intervention/Treatment	Phase
Aspergillosis	Drug: Voriconazole	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Voriconazole For Primary Therapy Of Proven, Chronic Bronchopulmonary Aspergillosis, In Minimally Immunocompromised Or, Non-Immunocompromised Hosts
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: Voriconazole; Voriconazole oral : loading dose on day 1 : 400mg/12 hours; maintenance dose 200 mg /12 hours for 6 to 12 months depending on clinical response. Alternatively, patients may start on Voriconazole, IV, for 7 days loading dose, 6mg/Kg/12 hours on day one and maintenance dose 4 mg/Kg/12 hours

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis [at 6 months of treatment]

   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.

Secondary Outcome Measures

1. Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis [Month 3 and End of Treatment (Month 9 or Month 12)]

   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.

2. Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis [at 6 months of treatment]

   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.

3. Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma [at 6 months of treatment]

   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.

4. Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS) [Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and End of study ([EOS] EOT + 6 months)]

   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).

5. Number of Subjects With Relapse [During the 6 months following EOT (EOT + 3 months, EOT + 6 months)]

   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).

6. Time to Relapse After EOT [During the 6 months following EOT (EOT + 3 months, EOT + 6 months)]

   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).

7. Global Survival: Number of Subjects With an Outcome of Death [Baseline through EOS (EOT + 6 months)]

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

8. Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire [Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and EOS (EOT + 6 months)]

   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).

9. Number of Subjects With Complete or Partial Radiological Response [Month 3, and Month 6, Month 9, or Month 12 [EOT]]

   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.

10. Number of Subjects With Mycological Response of Eradication [Month 3, and Month 6, Month 9, or Month 12 [EOT]]

    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).

11. Number of Subjects With Complete or Partial Serological Response [Month 3, and Month 6, Month 9, or Month 12 [EOT]]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with a chronic bronchopulmonary aspergillosis assessed by a compatible chest imagery (CT scan) and/or an endoscopic lesion sourced by photo, would it be:

• Complex aspergilloma non primarily operable,

• Chronic necrotizing pulmonary aspergillosis,

• Tracheo-bronchial aspergillosis, obstructive or necrotizing/pseudo-membranous.

Exclusion Criteria:

• Patient with risk factor(s) of cardiac arrhythmia, symptomatic arrhythmia, treated by medication known to prolong QT interval, or prolongation of QTc interval > 450 msec in men and > 470 msec in women.

• Simple aspergilloma with primary indication of surgical treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Nantes	Cedex	France	44093
2	Pfizer Investigational Site	Angers Cedex		France	49033
3	Pfizer Investigational Site	Bobigny		France	93000
4	Pfizer Investigational Site	Brest Cedex		France	29609
5	Pfizer Investigational Site	Bris Sous Forges		France	94640
6	Pfizer Investigational Site	Caen Cedex		France	14033
7	Pfizer Investigational Site	Dinan Cedex		France	22101
8	Pfizer Investigational Site	Grenoble Cedex 09		France	38043
9	Pfizer Investigational Site	Lille Cedex		France	59037
10	Pfizer Investigational Site	Lyon Cedex		France	69394
11	Pfizer Investigational Site	Montpellier Cedex 5		France	34295
12	Pfizer Investigational Site	Paris Cedex 18		France	75877
13	Pfizer Investigational Site	Paris Cedex 20		France	75970
14	Pfizer Investigational Site	Paris		France	75010
15	Pfizer Investigational Site	Poitiers Cedex		France	86021
16	Pfizer Investigational Site	Reims Cedex		France	51092
17	Pfizer Investigational Site	Rouen Cedex		France	76031
18	Pfizer Investigational Site	Suresnes		France	92150

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00159822
• Other Study ID Numbers: A1501061
• First Posted: Sep 12, 2005
• Last Update Posted: Jan 20, 2010
• Last Verified: Jan 1, 2010

• Additional relevant MeSH terms: Aspergillosis; Pulmonary Aspergillosis; Voriconazole

Study Results

Participant Flow

Recruitment Details	18 active centers in France; planned recruitment of 48 minimally immunocompromised or non-immunocompromised subjects with chronic bronchopulmonary aspergillosis.
Pre-assignment Detail	56 subjects were screened; 48 subjects included; 8 subjects did not meet criteria and were not included.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Period Title: Voriconazole Treatment Period
STARTED	48
COMPLETED	26
NOT COMPLETED	22
Period Title: Voriconazole Treatment Period
STARTED	26
COMPLETED	23
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Overall Participants	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.27 (13.85)
Sex: Female, Male (Count of Participants)
Female	19 39.6%
Male	29 60.4%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis
Description	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.
Time Frame	at 6 months of treatment

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	41
Success	13 27.1%
No success	28 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	For sample size calculation, null hypothesis (p<p0) is defined as response rate <15% (ie, weak drug efficacy). Alternative hypothesis (p>pA) defined as response rate >30%. To reduce the chance of incorrectly rejecting the null hypothesis to 5% (α=5%) and incorrectly rejecting the alternate hypothesis to 20% (β=20%) it was calculated that a sample size of 48 subjects was required. Null hypothesis was rejected (assessing efficacy of study drug) if the number of eligible success was ≥ than n=12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of subjects with success
	Estimated Value	31.7
	Confidence Interval	() 95%; 18.08 to 48.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Number of subjects with successful global outcomes were summarized and 95% two-sided confidence intervals based on the exact Clopper-Pearson method for the binomial distribution provided.

2. Secondary Outcome

Title	Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis
Description	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.
Time Frame	Month 3 and End of Treatment (Month 9 or Month 12)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	41
Month 3 success=yes	12 25%
Month 3 success=no	24 50%
Month 3 success=missing values	5 10.4%
EOT [LVA] success=yes	18 37.5%
EOT [LVA] success=no	23 47.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Month 3 success=yes
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of subjects with success
	Estimated Value	33.3
	Confidence Interval	() 95%; 18.6 to 51.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Number of subjects with successful global outcomes were summarized and 95% two-sided confidence intervals based on the exact Clopper-Pearson method for the binomial distribution provided.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	EOT success=yes
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of subjects with success
	Estimated Value	43.9
	Confidence Interval	() 95%; 28.5 to 60.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Number of subjects with successful global outcomes were summarized and 95% two-sided confidence intervals based on the exact Clopper-Pearson method for the binomial distribution provided.

3. Secondary Outcome

Title	Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis
Description	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.
Time Frame	at 6 months of treatment

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	19
Success	10 20.8%
No success	9 18.8%

4. Secondary Outcome

Title	Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma
Description	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.
Time Frame	at 6 months of treatment

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	22
Success	3
No success	19

5. Secondary Outcome

Title	Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS)
Description	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).
Time Frame	Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and End of study ([EOS] EOT + 6 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	41
Cough Month 3 (n=30)	-15.80 (33.40)
Cough Month 6 (n=27)	-19.63 (35.48)
Cough Month 9 (n=20)	-17.45 (43.01)
Cough Month 12 (n=16)	-30.13 (37.01)
Cough EOS (n=20)	-13.65 (41.31)
Dyspnea Month 3 (n=30)	-2.67 (24.22)
Dyspnea Month 6 (n=27)	-4.22 (25.16)
Dyspnea Month 9 (n=20)	-1.40 (24.66)
Dyspnea Month 12 (n=16)	-8.69 (25.15)
Dyspnea EOS (n=20)	1.75 (31.30)
Sputum Month 3 (n=30)	-8.03 (27.44)
Sputum Month 6 (n=28)	-14.86 (37.11)
Sputum Month 9 (n=21)	-12.62 (37.35)
Sputum Month 12 (n=17)	-26.47 (26.59)
Sputum EOS (n=21)	-13.67 (36.20)
Hemoptysis Month 3 (n=30)	-2.13 (28.05)
Hemoptysis Month 6 (n=28)	5.11 (27.41)
Hemoptysis Month 9 (n=21)	-4.52 (30.32)
Hemoptysis Month 12 (n=16)	-8.31 (31.44)
Hemoptysis EOS (n=21)	1.14 (20.72)
Chest tightness Month 3 (n=30)	0.03 (37.85)
Chest tightness Month 6 (n=28)	0.86 (29.83)
Chest tightness Month 9 (n=21)	-1.52 (33.03)
Chest tightness Month 12 (n=17)	-9.29 (31.27)
Chest tightness EOS (n=20)	-4.00 (22.31)
Nocturnal awakening Month 3 (n=30)	0.57 (29.33)
Nocturnal awakening Month 6 (n=28)	-2.86 (36.84)
Nocturnal awakening Month 9 (n=21)	-2.40 (31.13)
Nocturnal awakening Month 12 (n=16)	4.00 (31.45)
Nocturnal awakening EOS (n=21)	5.29 (41.96)
Mean VAS Month 3 (n=30)	-4.67 (18.29)
Mean VAS Month 6 (n=27)	-5.99 (20.82)
Mean VAS Month 9 (n=20)	-7.16 (24.31)
Mean VAS Month 12 (n=15)	-15.87 (20.67)
Mean VAS EOS (n=19)	-6.58 (20.43)

6. Secondary Outcome

Title	Number of Subjects With Relapse
Description	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).
Time Frame	During the 6 months following EOT (EOT + 3 months, EOT + 6 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	0

7. Secondary Outcome

Title	Time to Relapse After EOT
Description	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).
Time Frame	During the 6 months following EOT (EOT + 3 months, EOT + 6 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	0

8. Secondary Outcome

Title	Global Survival: Number of Subjects With an Outcome of Death
Description	Number of subjects with an outcome of death (adverse event with a fatal outcome) through end of study.
Time Frame	Baseline through EOS (EOT + 6 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	48
Number [participants]	5 10.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier estimate overall survival
	Estimated Value	0.850
	Confidence Interval	() 95%; 0.725 to 0.976
	Parameter Dispersion	Type: Value:
	Estimation Comments	Global survival rate calculated using Kaplan-Meier estimate of overall survival.

9. Secondary Outcome

Title	Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire
Description	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).
Time Frame	Baseline, Month 3, and Month 6, Month 9, or Month 12 [EOT], and EOS (EOT + 6 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	41
Symptoms Month 3 (n=35)	-5.50 (22.53)
Symptoms Month 6 (n=29)	-3.32 (7.37)
Symptoms Month 9 (n=19)	0.96 (29.78)
Symptoms Month 12 (n=17)	-2.72 (23.80)
Symptoms EOS (n=23)	-6.84 (23.53)
Activity Month 3 (n=31)	-4.15 (17.72)
Activity Month 6 (n=28)	-9.43 (17.30)
Activity Month 9 (n=18)	-0.03 (18.04)
Activity Month 12 (n=18)	-5.88
Activity EOS (n=23)	-8.06
Impacts Month 3 (n=33)	-6.72
Impacts Month 6 (n=28)	-8.41
Impacts Month 9 (n=20)	-3.78
Impacts Month 12 (n=18)	-7.97
Impacts EOS (n=21)	-7.93
Total Month 3 (n=35)	-5.70
Total Month 6 (n=30)	-8.39
Total Month 9 (n=20)	-1.87
Total Month 12 (n=18)	-6.63
Total EOS (n=24)	-8.19

10. Secondary Outcome

Title	Number of Subjects With Complete or Partial Radiological Response
Description	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.
Time Frame	Month 3, and Month 6, Month 9, or Month 12 [EOT]

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	37
Month 3 Complete response	4 8.3%
Month 3 Partial response	9 18.8%
EOT [LVA] Complete response	6 12.5%
EOT [LVA] Partial response	14 29.2%

11. Secondary Outcome

Title	Number of Subjects With Mycological Response of Eradication
Description	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).
Time Frame	Month 3, and Month 6, Month 9, or Month 12 [EOT]

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	35
Month 3 Eradication	29 60.4%
Month 3 Persistence	3 6.3%
Month 3 Not done (presume eradication)	3 6.3%
Month 6 Eradication	26 54.2%
Month 6 Not done (presume eradication)	6 12.5%
Month 9 Eradication	14 29.2%
Month 9 Not done (presume eradication)	7 14.6%
Month 12 Eradication	15 31.3%
Month 12 Not done (presume eradication)	2 4.2%

12. Secondary Outcome

Title	Number of Subjects With Complete or Partial Serological Response
Description	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).
Time Frame	Month 3, and Month 6, Month 9, or Month 12 [EOT]

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Voriconazole
Arm/Group Description	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.
Measure Participants	40
Month 3 Improvement	10 20.8%
Month 6 Improvement	14 29.2%
Month 9 Improvement	9 18.8%
Month 12 Improvement	8 16.7%

Adverse Events

Adverse Event Reporting Description	Safety population (SAF): consisted of all subjects who took at least one dose of voriconazole.
Arm/Group Title	Voriconazole
Arm/Group Description	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.
All Cause Mortality
	Voriconazole
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Voriconazole
	Affected / at Risk (%)	# Events
Total	21/48 (43.8%)
Gastrointestinal disorders
Abdominal pain	1/48 (2.1%)
Abdominal pain upper	1/48 (2.1%)
Constipation	1/48 (2.1%)
Vomiting	1/48 (2.1%)
General disorders
General physical health deterioration	2/48 (4.2%)
Hepatobiliary disorders
Cholecystitis	1/48 (2.1%)
Infections and infestations
Bronchitis	2/48 (4.2%)
Bronchitis haemophilus	1/48 (2.1%)
Bronchitis viral	1/48 (2.1%)
Pneumonia	1/48 (2.1%)
Pseudomonas bronchitis	1/48 (2.1%)
Sepsis	1/48 (2.1%)
Septic shock	1/48 (2.1%)
Urinary tract infection	1/48 (2.1%)
Investigations
Electrocardiogram QT prolonged	1/48 (2.1%)
Gamma-glutamyltransferase increased	1/48 (2.1%)
General physical condition abnormal	1/48 (2.1%)
Weight decreased	1/48 (2.1%)
Metabolism and nutrition disorders
Hyponatraemia	1/48 (2.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/48 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/48 (2.1%)
Haemoptysis	5/48 (10.4%)
Lung disorder	1/48 (2.1%)
Pneumothorax	2/48 (4.2%)
Pulmonary pneumatocele	1/48 (2.1%)
Surgical and medical procedures
Arterial stent insertion	1/48 (2.1%)
Surgery	1/48 (2.1%)
Vascular disorders
Peripheral ischaemia	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Voriconazole
	Affected / at Risk (%)	# Events
Total	33/48 (68.8%)
Eye disorders
Vision blurred	6/48 (12.5%)
Visual impairment	9/48 (18.8%)
Gastrointestinal disorders
Constipation	3/48 (6.3%)
Nausea	3/48 (6.3%)
Vomiting	3/48 (6.3%)
General disorders
Chills	4/48 (8.3%)
Hepatobiliary disorders
Cholestasis	3/48 (6.3%)
Infections and infestations
Bronchitis	9/48 (18.8%)
Investigations
Gamma-glutamyltransferase increased	4/48 (8.3%)
Weight decreased	3/48 (6.3%)
Nervous system disorders
Headache	3/48 (6.3%)
Psychiatric disorders
Insomnia	6/48 (12.5%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	7/48 (14.6%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	6/48 (12.5%)

Limitations/Caveats

Study treatment duration is at least 6 months for subjects with best achievable response after 3 months of treatment, of 9 months for subjects with best achievable response after 6 months of treatment and of 12 months in other cases.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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