Aspergillosis
Conditions
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
Interventions
DRUGVoriconazole
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
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| 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). |
| 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). |
| 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. |
| 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). |
| 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. |
| 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). |
| 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). |
| 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. |
Countries
France
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 details
56 subjects were screened; 48 subjects included; 8 subjects did not meet criteria and were not included.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Post-treatment Follow-up Period | Death | 1 |
| Post-treatment Follow-up Period | Reason unspecified | 1 |
| Post-treatment Follow-up Period | Withdrawal by Subject | 1 |
| Voriconazole Treatment Period | Adverse Event | 9 |
| Voriconazole Treatment Period | Death | 4 |
| Voriconazole Treatment Period | Lack of Efficacy | 3 |
| Voriconazole Treatment Period | Lost to Follow-up | 2 |
| Voriconazole Treatment Period | Protocol Violation | 2 |
| Voriconazole Treatment Period | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Voriconazole |
|---|---|
| Age Continuous | 57.27 years STANDARD_DEVIATION 13.85 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 48 |
| serious Total, serious adverse events | 21 / 48 |
Outcome results
Primary
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis
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
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis | Success | 13 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Chronic Bronchopulmonary Aspergillosis | No success | 28 participants |
Comparison: 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=12.95% CI: [18.08, 48.09]
Secondary
Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | 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 23.8 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 17.3 |
| Voriconazole | 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 |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Activity Month 12 (n=18) | -5.88 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Activity EOS (n=23) | -8.06 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Impacts Month 3 (n=33) | -6.72 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Impacts Month 9 (n=20) | -3.78 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Impacts Month 12 (n=18) | -7.97 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Impacts EOS (n=21) | -7.93 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Total Month 3 (n=35) | -5.70 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Total Month 9 (n=20) | -1.87 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Total Month 12 (n=18) | -6.63 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Total EOS (n=24) | -8.19 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Impacts Month 6 (n=28) | -8.41 scores on scale | — |
| Voriconazole | Change From Baseline in Quality of Life (QOL): St. George's Hospital Respiratory Questionnaire | Total Month 6 (n=30) | -8.39 scores on scale | — |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
Secondary
Change From Baseline in Respiratory Clinical Signs and Symptoms on Visual Analog Scales (VAS)
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | 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 |
| Voriconazole | 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 36.2 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 33.4 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 31.3 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
| Voriconazole | 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 |
Secondary
Global Survival: Number of Subjects With an Outcome of Death
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)
Population: Safety population (SAF): all subjects who took at least 1 dose of voriconazole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole | Global Survival: Number of Subjects With an Outcome of Death | 5 participants |
95% CI: [0.725, 0.976]
Secondary
Number of Subjects With Complete or Partial Radiological Response
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]
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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Complete or Partial Radiological Response | Month 3 Partial response | 9 participants |
| Voriconazole | Number of Subjects With Complete or Partial Radiological Response | Month 3 Complete response | 4 participants |
| Voriconazole | Number of Subjects With Complete or Partial Radiological Response | EOT [LVA] Complete response | 6 participants |
| Voriconazole | Number of Subjects With Complete or Partial Radiological Response | EOT [LVA] Partial response | 14 participants |
Secondary
Number of Subjects With Complete or Partial Serological Response
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]
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Complete or Partial Serological Response | Month 3 Improvement | 10 participants |
| Voriconazole | Number of Subjects With Complete or Partial Serological Response | Month 6 Improvement | 14 participants |
| Voriconazole | Number of Subjects With Complete or Partial Serological Response | Month 9 Improvement | 9 participants |
| Voriconazole | Number of Subjects With Complete or Partial Serological Response | Month 12 Improvement | 8 participants |
Secondary
Number of Subjects With Mycological Response of Eradication
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]
Population: mITT; 6, 9 or 12 months (in case of extension of the treatment period beyond 6 months) as EOT or last visit available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 3 Eradication | 29 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 3 Not done (presume eradication) | 3 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 6 Eradication | 26 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 6 Not done (presume eradication) | 6 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 9 Eradication | 14 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 9 Not done (presume eradication) | 7 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 12 Eradication | 15 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 12 Not done (presume eradication) | 2 participants |
| Voriconazole | Number of Subjects With Mycological Response of Eradication | Month 3 Persistence | 3 participants |
Secondary
Number of Subjects With Relapse
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)
Population: mITT; due to the small number of radiological reappearance (4 subjects), no formal analysis of this endpoint was performed.
Secondary
Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis
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
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis | Success | 10 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Chronic Necrotizing Pulmonary Aspergillosis (CNPA) and Tracheo-bronchial Aspergillosis | No success | 9 participants |
Secondary
Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma
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
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma | Success | 3 paticipants |
| Voriconazole | Number of Subjects With Successful Global Outcome at 6 Months: Complex Aspergilloma | No success | 19 paticipants |
Secondary
Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis
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)
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis | Month 3 success=yes | 12 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis | Month 3 success=no | 24 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis | Month 3 success=missing values | 5 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis | EOT [LVA] success=yes | 18 participants |
| Voriconazole | Number of Subjects With Successful Global Outcome at Month 3 and End of Treatment: Chronic Bronchopulmonary Aspergillosis | EOT [LVA] success=no | 23 participants |
Comparison: Month 3 success=yes95% CI: [18.6, 51]
Comparison: EOT success=yes95% CI: [28.5, 60.3]
Secondary
Time to Relapse After EOT
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)
Population: mITT; due to the small number of radiological reappearance (4 subjects), no formal analysis of this endpoint was performed.