Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis
Study Details
Study Description
Brief Summary
The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
Detailed Description
Acute invasive fungal infections caused by aspergillus, zygomycetes and other filamentous fungi remain life threatening diseases. Early treatment with highly effective anti-fungals reduces mortality. This study investigates the efficacy and safety of isavuconazole in the treatment of invasive fungal diseases, caused by Aspergillus or other filamentous fungi.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Isavuconazole Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. |
Drug: Isavuconazole
Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
Other Names:
|
Active Comparator: Voriconazole Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Drug: Voriconazole
Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- All-cause Mortality Through Day 42 [Through Day 42]
All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation.
Secondary Outcome Measures
- Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.
- All-cause Mortality Through Day 84 [Through Day 84]
All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation.
- Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).
- Percentage of Participants With a Clinical Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.
- Percentage of Participants With a Mycological Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable". End of treatment is the last day of study drug administration.
- Percentage of Participants With a Radiological Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.
- Percentage of Participants With a Clinical Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.
- Percentage of Participants With a Mycological Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable". End of treatment is the last day of study drug administration.
- Percentage of Participants With a Radiological Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]
Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.
- Number of Participants With Adverse Events, Reported by System Organ Class [From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients must have proven, probable or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi
-
Female patients must be non-lactating and at no risk for pregnancy
Exclusion Criteria:
-
Patients with invasive fungal infections other than Aspergillus species or other filamentous fungi
-
Evidence of hepatic dysfunction at Baseline or moderate to severe renal dysfunction
-
Patients with chronic aspergillosis, or aspergilloma or allergic bronchopulmonary aspergillosis
-
Patients who have received more than 4 days of systemic antifungal therapy other than fluconazole within the 7 days prior to the first administration of study medication
-
Patients previously enrolled in a Phase III study with isavuconazole
-
Patients with a body weight </= 40 kg
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Alabama | Birmingham | Alabama | United States | 35294-0006 |
2 | University of California at San Francisco | San Francisco | California | United States | 94143 |
3 | University of Chicago, Division of Infectious Diseases | Chicago | Illinois | United States | 60637 |
4 | Indiana BMT | Springfield | Illinois | United States | 62703 |
5 | Springfield Clinic LLP | Springfield | Illinois | United States | 62703 |
6 | Infectious Disease of Indiana | Indianapolis | Indiana | United States | 46280 |
7 | Brigham & Womens Hospital | Boston | Massachusetts | United States | 02115 |
8 | Worcester | Massachusetts | United States | 01655 | |
9 | Upstate Infectious Diseases Association LLP | Albany | New York | United States | 12208 |
10 | Regional Infection Diseases Infusion Center Inc. | Lima | Ohio | United States | 45801 |
11 | University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
12 | Buenos Aires | Argentina | C1039AAO | ||
13 | Buenos Aires | Argentina | C1157ADP | ||
14 | Buenos Aires | Argentina | |||
15 | Capital Federal | Argentina | C1180AAV | ||
16 | Capital Federal | Argentina | C1405DCS | ||
17 | Hospital Italiano de Buenos Aires | Ciudad Autonoma | Argentina | 1181 | |
18 | Instituto Medico Especializado Alexander Fleming | Ciudad Autonoma | Argentina | 1426 | |
19 | Perth | Australia | 6000 | ||
20 | Mater Medical Centre | South Brisbane | Australia | 4101 | |
21 | Woolloongabba | Australia | 4102 | ||
22 | AZ ST Jan | Brugge | Belgium | 8000 | |
23 | Institut Jules Bordet | Brussels | Belgium | 1000 | |
24 | ULB Hospital Erasme | Bruxelles | Belgium | 1070 | |
25 | Universitair Ziekenhuis Gent | Gent | Belgium | 9000 | |
26 | Universitaire Ziekenhuizen Leuven | Leuven | Belgium | 3000 | |
27 | Felicio Rocho | Belo Horizonte | Brazil | 30110-908 | |
28 | Santa Casa de Misericordia de Belo Horizonte | Belo Horizonte | Brazil | 30150-221 | |
29 | Hospital das Clinicas da UFPR | Curitiba | Brazil | 80060-150 | |
30 | Hospital de Clinicas da FMUSP - Ribeirao Preto | Ribeirão Preto | Brazil | 14048-900 | |
31 | Hospital Universitario Clementino Fraga Filho | Rio de Janeiro | Brazil | 21941-913 | |
32 | The Ottawa Hospital - General Campus | Ottawa | Ontario | Canada | K1H 8L6 |
33 | Hamilton Health Sciences - Henderson Site | Hamilton | Canada | L8V 1C3 | |
34 | Santiago | Chile | |||
35 | Hospital Dr. Hernan Henriquez Aravena | Temuco | Chile | 4780000 | |
36 | Valdivia | Chile | 5090000 | ||
37 | 3rd Hospital, Peking University | Beijing | China | 100083 | |
38 | The 1st Hospital, Jilin University | Changchun | China | 130021 | |
39 | The Third Xiangya Hospital of Central South University | Changsha | China | 410013 | |
40 | West China Hospital of Sichuan University | Chengdu | China | 610041 | |
41 | The Affiliated Union Hospital of Fujian Medical University | Fuzhou | China | 350001 | |
42 | The First Affiliated Hospital, Med. School, Zhejiang Uni. | Hangzhou | China | 310003 | |
43 | The First Affiliated Hospital of Nanjing Medical University | Nanjing | China | 310009 | |
44 | The 1st Affiliated Hospital of Guangxi Medical University | Nanning | China | 530021 | |
45 | Huashan Hospital, Insitute of Antibiotics | Shanghai | China | 200040 | |
46 | No.6 Renmin Hosp. of Shanghai City | Shanghai | China | 200233 | |
47 | Chang Hai Hospital | Shanghai | China | 200433 | |
48 | Wuhan Union Hospital | Wuhan | China | 430022 | |
49 | Alexandria University Hospital | Alexandria | Egypt | 21131 | |
50 | National Cancer Institute | Cairo | Egypt | 11796 | |
51 | Nasser Institute | Cairo | Egypt | 12655 | |
52 | Dijon | France | 21079 | ||
53 | Hotel Dieu | Nantes Cedex 01 | France | 44093 | |
54 | CHU de Nantes - Hôpital Hôtel Dieu | Nantes Cedex | France | 44035 | |
55 | Hôpital Hautepierre | Strasbourg | France | 67098 | |
56 | Hôpital de brabois adultes | Vandoeuvre les Nancy | France | 54511 | |
57 | Universitaetsklinikum Aachen | Aachen | Germany | 52074 | |
58 | Charité Universitaetsmedizin Berlin- Campus Charité Mitte | Berlin | Germany | 12200 | |
59 | Universitaet Koeln | Köln | Germany | 50937 | |
60 | Universitaetsklinik Leipzig | Leipzig | Germany | 04289 | |
61 | Luebeck | Germany | 23538 | ||
62 | Klinikum Schwabing | Muenchen | Germany | 81737 | |
63 | Medizinische klinik und Polyklinik II | Würzburg | Germany | 97080 | |
64 | Budapest | Hungary | 1094 | ||
65 | Petz Aladar Megyei Oktato Korhaz | Györ | Hungary | 9024 | |
66 | Szegedi Tudomanyegyetem | Szeged | Hungary | 6720 | |
67 | Apollo Hospitals | Hyderabad | Andh Prad | India | 500033 |
68 | Sterling Hospital | Ahmedabad | Gujarat | India | 380052 |
69 | Kasturba Medical College and Hospital | Mangalore | Karna | India | 575001 |
70 | Shirdi Sai Baba Cancer Hospital K. M. C. Hospital | Manipal | Karna | India | 576104 |
71 | Tata Memorial Hopital, Department of Anesthesia | Mumbai | Mahara | India | 400012 |
72 | Deenanath Mangeshkar Hospital & Research Centre | Pune | Mahara | India | 411004 |
73 | Sahyadri Hospital | Pune | Mahara | India | 411004 |
74 | Noida | Uttar Prad | India | 201301 | |
75 | Rambam Health Care Campus | Haifa | Israel | 31096 | |
76 | Hadassah Universtiy Hospital - Ein Kerem | Jerusalem | Israel | 91200 | |
77 | Rabin MC | Petah Tikva | Israel | 49100 | |
78 | Chaim Sheba Medical Center | Ramat-Gan | Israel | 52621 | |
79 | Sourasky MC Ichilov Hospital Tel Aviv | Tel Aviv | Israel | 64239 | |
80 | Unità Funzionale di Ematologia; Azienda Ospedaliera Universitaria Careggi | Firenze | Italy | 50134 | |
81 | Azienda Ospedaliera Ospedale Niguarda Ca' Granda | Milano | Italy | 20162 | |
82 | Gachon University Gil Hospital | Incheon | Korea, Republic of | 405-760 | |
83 | Seoul | Korea, Republic of | 120-752 | ||
84 | Samsung Medical Center | Seoul | Korea, Republic of | 135-710 | |
85 | The Catholic University of Korea, St. Mary's Hospital | Seoul | Korea, Republic of | 137-701 | |
86 | Asan Medical Center | Seoul | Korea, Republic of | 138-736 | |
87 | Kuala Lumpur | Malaysia | 59100 | ||
88 | Kuala Lumpur | Malaysia | 68000 | ||
89 | Mexico | Mexico | 06726 | ||
90 | Hospital Universitario Dr Jose Eleuterio Gonzalez | Monterrey | Mexico | 64040 | |
91 | Nijmegen | Netherlands | 6525 | ||
92 | Palmerston North | New Zealand | 4442 | ||
93 | Samodzielny Publiczny Centralny Szpital Kliniczny | Warszawa | Poland | 02-097 | |
94 | State Institution "Hematology Research Center" RAMS | Moscow | Russian Federation | 125167 | |
95 | Republican Hospital named after V.A. Baranov | Petrozavodsk | Russian Federation | 185019 | |
96 | Leningrad Regional Hospital | St. Petersburg | Russian Federation | 194291 | |
97 | St-Petersburg MA Postgraduate Education | St. Petersburg | Russian Federation | 194291 | |
98 | St. Petersburg | Russian Federation | 197089 | ||
99 | Salamanca | Spain | 37007 | ||
100 | Zurich | Switzerland | 8091 | ||
101 | Songklanagarind Hospital | Hat Yai | Thailand | 90110 | |
102 | Khon Kaen | Thailand | 40002 | ||
103 | Maharat Nakhon Ratchasima Hospital | Muang | Thailand | 30000 | |
104 | Srinagarind Hospital | Muang | Thailand | 40002 | |
105 | Maharaj Nakorn Chiang Mai Hospital | Muang | Thailand | 50200 | |
106 | Songkla | Thailand | 90110 | ||
107 | Istanbul | Turkey | 34662 |
Sponsors and Collaborators
- Astellas Pharma Inc
- Basilea Pharmaceutica International Ltd
Investigators
- Study Director: Medical Director, Astellas Pharma Global Development
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 9766-CL-0104
- WSA-CS-004
- 2006-003868-59
Study Results
Participant Flow
Recruitment Details | Consenting adult patients with proven, probable or possible invasive fungal disease (IFD) caused by Aspergillus species or other filamentous fungi, meeting the inclusion/exclusion criteria, were enrolled in the study. |
---|---|
Pre-assignment Detail | Participants were stratified by geographic location (North America; Western Europe plus Australia and New Zealand; and Other Regions), whether or not they underwent an allogeneic bone marrow transplant (BMT) and whether or not they had uncontrolled malignancy. |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Period Title: Overall Study | ||
STARTED | 263 | 264 |
Received Treatment | 258 | 258 |
COMPLETED | 118 | 120 |
NOT COMPLETED | 145 | 144 |
Baseline Characteristics
Arm/Group Title | Isavuconazole | Voriconazole | Total |
---|---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. | Total of all reporting groups |
Overall Participants | 258 | 258 | 516 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
51.1
(16.15)
|
51.2
(15.85)
|
51.1
(15.98)
|
Sex: Female, Male (Count of Participants) | |||
Female |
113
43.8%
|
95
36.8%
|
208
40.3%
|
Male |
145
56.2%
|
163
63.2%
|
308
59.7%
|
Race/Ethnicity, Customized (participants) [Number] | |||
White |
211
81.8%
|
191
74%
|
402
77.9%
|
Black or African American |
1
0.4%
|
1
0.4%
|
2
0.4%
|
Asian |
45
17.4%
|
64
24.8%
|
109
21.1%
|
Other |
1
0.4%
|
1
0.4%
|
2
0.4%
|
Missing |
0
0%
|
1
0.4%
|
1
0.2%
|
Race/Ethnicity, Customized (participants) [Number] | |||
Hispanic or Latino |
22
8.5%
|
9
3.5%
|
31
6%
|
Not Hispanic or Latino |
236
91.5%
|
248
96.1%
|
484
93.8%
|
Missing |
0
0%
|
1
0.4%
|
1
0.2%
|
Hematologic Malignancy Status (participants) [Number] | |||
Yes |
211
81.8%
|
222
86%
|
433
83.9%
|
No |
47
18.2%
|
36
14%
|
83
16.1%
|
Prior Allogeneic Bone Marrow Transplant (BMT) (participants) [Number] | |||
Yes |
54
20.9%
|
51
19.8%
|
105
20.3%
|
No |
204
79.1%
|
207
80.2%
|
411
79.7%
|
Uncontrolled Malignancy Status (participants) [Number] | |||
Yes |
173
67.1%
|
187
72.5%
|
360
69.8%
|
No |
85
32.9%
|
71
27.5%
|
156
30.2%
|
Neutropenic Status (participants) [Number] | |||
Yes |
163
63.2%
|
175
67.8%
|
338
65.5%
|
No |
95
36.8%
|
83
32.2%
|
178
34.5%
|
Outcome Measures
Title | All-cause Mortality Through Day 42 |
---|---|
Description | All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation. |
Time Frame | Through Day 42 |
Outcome Measure Data
Analysis Population Description |
---|
Intent-to-treat population |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 258 | 258 |
Number [percentage of participants] |
18.6
7.2%
|
20.2
7.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Approximately 255 patients per group were to be enrolled to ensure at least 80% power to demonstrate that the upper bound of the 95% confidence interval (CI) for a treatment difference in favor of the comparator was no larger than 10%. | |
Type of Statistical Test | Non-Inferiority or Equivalence | |
Comments | The upper bound of the 95% CI for the treatment difference was compared to the protocol prespecified non-inferiority margin of 10%. If the upper bound was smaller than 10%, isavuconazole was declared as non-inferior to voriconazole with respect to the primary outcome measure. | |
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -1.0 | |
Confidence Interval |
(2-Sided) 95% -7.759 to 5.683 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The treatment difference (isavuconazole minus voriconazole) was calculated using a stratified Cochran-Mantel-Haenszel (CMH) method. The strata included Geographical Regions, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) |
---|---|
Description | The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified Intent-to-treat (mITT) population consisted of ITT participants who had proven or probable IFD as determined by the DRC. |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 |
35.7
13.8%
|
35.7
13.8%
|
Day 84 |
25.2
9.8%
|
32.6
12.6%
|
End of Treatment |
35.0
13.6%
|
36.4
14.1%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 1.6 | |
Confidence Interval |
(2-Sided) 95% -9.336 to 12.572 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -0.5 | |
Confidence Interval |
(2-Sided) 95% -11.277 to 10.329 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 8.2 | |
Confidence Interval |
(2-Sided) 95% -1.993 to 18.379 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | All-cause Mortality Through Day 84 |
---|---|
Description | All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation. |
Time Frame | Through Day 84 |
Outcome Measure Data
Analysis Population Description |
---|
Intent-to-treat population |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 258 | 258 |
Number [percentage of participants] |
29.1
11.3%
|
31.0
12%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -1.4 | |
Confidence Interval |
(2-Sided) 95% -9.150 to 6.340 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The treatment difference (isavuconazole minus voriconazole) was calculated using a stratified Cochran-Mantel-Haenszel (CMH) method. The strata included Geographical Regions, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator |
---|---|
Description | Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10). |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 0 | 0 |
Title | Percentage of Participants With a Clinical Response Assessed by the DRC |
---|---|
Description | Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. Any visits the DRC assessed as not done were considered as missing and included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n". |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 (n=139, 120) |
64.0
24.8%
|
57.5
22.3%
|
Day 84 (n=141, 124) |
46.1
17.9%
|
44.4
17.2%
|
End of Treatment (n=137, 121) |
62.0
24%
|
60.3
23.4%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment Comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 0.4 | |
Confidence Interval |
(2-Sided) 95% -10.640 to 11.531 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -5.8 | |
Confidence Interval |
(2-Sided) 95% -17.368 to 5.802 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 0.3 | |
Confidence Interval |
(2-Sided) 95% -11.116 to 11.758 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With a Mycological Response Assessed by the DRC |
---|---|
Description | Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable". End of treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. Any visits the DRC assessed as not done were considered as missing and included as a failure; participants with a Not Applicable assessment were excluded. |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 |
39.9
15.5%
|
39.5
15.3%
|
Day 84 |
28.0
10.9%
|
36.4
14.1%
|
End of Treatment |
37.8
14.7%
|
41.1
15.9%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 3.8 | |
Confidence Interval |
(2-Sided) 95% -7.429 to 15.087 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 Comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -0.7 | |
Confidence Interval |
(2-Sided) 95% -11.917 to 10.586 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 Comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 9.1 | |
Confidence Interval |
(2-Sided) 95% -1.624 to 19.830 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With a Radiological Response Assessed by the DRC |
---|---|
Description | Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. A participant with no post-baseline radiology data with evidence of radiologic disease at Baseline was considered a failure. Participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point is indicated by "n". |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 (n=141, 128) |
28.4
11%
|
34.4
13.3%
|
Day 84 (n=141, 128) |
22.0
8.5%
|
29.7
11.5%
|
End of Treatment (n=141, 127) |
29.1
11.3%
|
33.1
12.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 5.7 | |
Confidence Interval |
(2-Sided) 95% -4.936 to 16.268 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 5.3 | |
Confidence Interval |
(2-Sided) 95% -5.338 to 16.032 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 9.0 | |
Confidence Interval |
(2-Sided) 95% -1.231 to 19.186 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With a Clinical Response Assessed by the Investigator |
---|---|
Description | Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n". |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 (n=137, 120) |
64.2
24.9%
|
61.7
23.9%
|
Day 84 (n=140, 122) |
41.4
16%
|
44.3
17.2%
|
End of Treatment (n=137, 121) |
62.0
24%
|
64.5
25%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 5.0 | |
Confidence Interval |
(2-Sided) 95% -6.043 to 16.026 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted treatment Difference |
Estimated Value | 0.2 | |
Confidence Interval |
(2-Sided) 95% -10.873 to 11.220 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted treatment Difference |
Estimated Value | 4.7 | |
Confidence Interval |
(2-Sided) 95% -6.533 to 15.939 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With a Mycological Response Assessed by the Investigator |
---|---|
Description | Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable". End of treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n". |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 (n=109, 100) |
52.3
20.3%
|
50.0
19.4%
|
Day 84 (n=126, 117) |
35.7
13.8%
|
37.6
14.6%
|
End of Treatment (n=107, 100) |
50.5
19.6%
|
55.0
21.3%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 4.4 | |
Confidence Interval |
(2-Sided) 95% -8.429 to 17.218 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | -2.5 | |
Confidence Interval |
(2-Sided) 95% -15.071 to 10.073 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 2.9 | |
Confidence Interval |
(2-Sided) 95% -8.633 to 14.499 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Percentage of Participants With a Radiological Response Assessed by the Investigator |
---|---|
Description | Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration. |
Time Frame | Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure. Participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point is indicated by "n". |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 143 | 129 |
Day 42 (n=142, 128) |
45.1
17.5%
|
51.6
20%
|
Day 84 (n=141, 128) |
38.3
14.8%
|
41.4
16%
|
End of Treatment (n=141, 128) |
43.3
16.8%
|
47.7
18.5%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | End of Treatment comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 6.3 | |
Confidence Interval |
(2-Sided) 95% -5.145 to 17.696 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 42 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 8.0 | |
Confidence Interval |
(2-Sided) 95% -3.335 to 19.356 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Isavuconazole, Voriconazole |
---|---|---|
Comments | Day 84 comparison | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Adjusted Treatment Difference |
Estimated Value | 5.1 | |
Confidence Interval |
(2-Sided) 95% -6.187 to 16.332 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status. |
Title | Number of Participants With Adverse Events, Reported by System Organ Class |
---|---|
Description | |
Time Frame | From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days. |
Outcome Measure Data
Analysis Population Description |
---|
The safety analysis set consists of all randomized patients who received at least one dose of study drug according to the study drug that the participant actually received as the first dose. One participant was randomized to isavuconazole but received voriconazole treatment for the first 7 days and is included in the voriconazole arm for safety. |
Arm/Group Title | Isavuconazole | Voriconazole |
---|---|---|
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. |
Measure Participants | 257 | 259 |
Patients with ≥ 1 TEAE |
247
95.7%
|
255
98.8%
|
Gastrointestinal Disorders |
174
67.4%
|
180
69.8%
|
Infections and Infestations |
152
58.9%
|
158
61.2%
|
General Disorders / Administration Site Conditions |
148
57.4%
|
144
55.8%
|
Respiratory, Thoracic and Mediastinal Disorders |
143
55.4%
|
147
57%
|
Metabolism and Nutrition Disorders |
108
41.9%
|
121
46.9%
|
Nervous System Disorders |
95
36.8%
|
89
34.5%
|
Skin and Subcutaneous Tissue Disorders |
86
33.3%
|
110
42.6%
|
Investigations |
85
32.9%
|
96
37.2%
|
Blood and Lymphatic System Disorders |
77
29.8%
|
82
31.8%
|
Psychiatric Disorders |
70
27.1%
|
86
33.3%
|
Musculoskeletal and Connective Tissue Disorders |
69
26.7%
|
77
29.8%
|
Vascular Disorders |
67
26%
|
77
29.8%
|
Renal and Urinary Disorders |
55
21.3%
|
58
22.5%
|
Cardiac Disorders |
43
16.7%
|
57
22.1%
|
Eye Disorders |
39
15.1%
|
69
26.7%
|
Injury, Poisoning and Procedural Complications |
33
12.8%
|
39
15.1%
|
Hepatobiliary Disorders |
23
8.9%
|
42
16.3%
|
Immune System Disorders |
20
7.8%
|
25
9.7%
|
Neoplasms benign, malignant and unspecified |
19
7.4%
|
31
12%
|
Ear and Labyrinth Disorders |
14
5.4%
|
13
5%
|
Reproductive System and Breast Disorders |
8
3.1%
|
13
5%
|
Endocrine Disorders |
5
1.9%
|
3
1.2%
|
Congenital, Familial and Genetic Disorders |
3
1.2%
|
2
0.8%
|
Social Circumstances |
0
0%
|
1
0.4%
|
Adverse Events
Time Frame | From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days. | |||
---|---|---|---|---|
Adverse Event Reporting Description | The safety analysis set consists of all randomized patients who received at least one dose of study drug according to the study drug that the participant actually received as the first dose. One participant was randomized to isavuconazole but received voriconazole treatment for the first 7 days and is included in the voriconazole arm for safety. | |||
Arm/Group Title | Isavuconazole | Voriconazole | ||
Arm/Group Description | Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. | Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. | ||
All Cause Mortality |
||||
Isavuconazole | Voriconazole | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
Isavuconazole | Voriconazole | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 134/257 (52.1%) | 149/259 (57.5%) | ||
Blood and lymphatic system disorders | ||||
Agranulocytosis | 2/257 (0.8%) | 0/259 (0%) | ||
Anaemia | 1/257 (0.4%) | 2/259 (0.8%) | ||
Febrile neutropenia | 14/257 (5.4%) | 5/259 (1.9%) | ||
Haemorrhagic anaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Haemorrhagic disorder | 1/257 (0.4%) | 0/259 (0%) | ||
Leukocytosis | 1/257 (0.4%) | 0/259 (0%) | ||
Microangiopathic haemolytic anaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Neutropenia | 4/257 (1.6%) | 3/259 (1.2%) | ||
Pancytopenia | 4/257 (1.6%) | 3/259 (1.2%) | ||
Splenic infarction | 1/257 (0.4%) | 0/259 (0%) | ||
Thrombocytopenia | 3/257 (1.2%) | 4/259 (1.5%) | ||
Thrombocytopenic purpura | 0/257 (0%) | 1/259 (0.4%) | ||
Cardiac disorders | ||||
Acute myocardial infarction | 1/257 (0.4%) | 1/259 (0.4%) | ||
Angina pectoris | 0/257 (0%) | 1/259 (0.4%) | ||
Arrhythmia | 1/257 (0.4%) | 0/259 (0%) | ||
Atrial fibrillation | 1/257 (0.4%) | 1/259 (0.4%) | ||
Cardiac arrest | 1/257 (0.4%) | 5/259 (1.9%) | ||
Cardio-respiratory arrest | 2/257 (0.8%) | 2/259 (0.8%) | ||
Cardiogenic shock | 1/257 (0.4%) | 0/259 (0%) | ||
Congestive cardiomyopathy | 1/257 (0.4%) | 0/259 (0%) | ||
Pericarditis | 1/257 (0.4%) | 0/259 (0%) | ||
Sinus bradycardia | 1/257 (0.4%) | 0/259 (0%) | ||
Supraventricular tachycardia | 1/257 (0.4%) | 0/259 (0%) | ||
Ventricular tachycardia | 0/257 (0%) | 2/259 (0.8%) | ||
Eye disorders | ||||
Blindness unilateral | 1/257 (0.4%) | 0/259 (0%) | ||
Eyelid oedema | 0/257 (0%) | 1/259 (0.4%) | ||
Optic neuropathy | 1/257 (0.4%) | 0/259 (0%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 1/257 (0.4%) | 0/259 (0%) | ||
Colitis | 1/257 (0.4%) | 0/259 (0%) | ||
Constipation | 1/257 (0.4%) | 0/259 (0%) | ||
Diarrhoea | 2/257 (0.8%) | 1/259 (0.4%) | ||
Food poisoning | 0/257 (0%) | 1/259 (0.4%) | ||
Gastric perforation | 1/257 (0.4%) | 0/259 (0%) | ||
Gastrointestinal haemorrhage | 0/257 (0%) | 3/259 (1.2%) | ||
Gastrointestinal inflammation | 0/257 (0%) | 1/259 (0.4%) | ||
Ileus paralytic | 0/257 (0%) | 1/259 (0.4%) | ||
Intestinal haemorrhage | 1/257 (0.4%) | 1/259 (0.4%) | ||
Nausea | 1/257 (0.4%) | 1/259 (0.4%) | ||
Oesophageal ulcer | 1/257 (0.4%) | 0/259 (0%) | ||
Peritonitis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Proctalgia | 0/257 (0%) | 1/259 (0.4%) | ||
Rectal haemorrhage | 0/257 (0%) | 1/259 (0.4%) | ||
Small intestinal obstruction | 2/257 (0.8%) | 0/259 (0%) | ||
General disorders | ||||
Asthenia | 1/257 (0.4%) | 0/259 (0%) | ||
Chest pain | 1/257 (0.4%) | 0/259 (0%) | ||
Chills | 1/257 (0.4%) | 1/259 (0.4%) | ||
Death | 1/257 (0.4%) | 1/259 (0.4%) | ||
General physical health deterioration | 1/257 (0.4%) | 0/259 (0%) | ||
Multi-organ failure | 1/257 (0.4%) | 7/259 (2.7%) | ||
Pyrexia | 8/257 (3.1%) | 10/259 (3.9%) | ||
Sudden cardiac death | 0/257 (0%) | 1/259 (0.4%) | ||
Hepatobiliary disorders | ||||
Cholecystitis | 1/257 (0.4%) | 0/259 (0%) | ||
Cholecystitis acute | 0/257 (0%) | 1/259 (0.4%) | ||
Hepatic failure | 0/257 (0%) | 2/259 (0.8%) | ||
Hepatic function abnormal | 0/257 (0%) | 2/259 (0.8%) | ||
Hepatitis | 1/257 (0.4%) | 0/259 (0%) | ||
Hepatitis acute | 1/257 (0.4%) | 0/259 (0%) | ||
Hyperbilirubinaemia | 0/257 (0%) | 2/259 (0.8%) | ||
Immune system disorders | ||||
Acute graft versus host disease | 1/257 (0.4%) | 1/259 (0.4%) | ||
Acute graft versus host disease in intestine | 1/257 (0.4%) | 2/259 (0.8%) | ||
Acute graft versus host disease in liver | 0/257 (0%) | 1/259 (0.4%) | ||
Anaphylactic reaction | 0/257 (0%) | 2/259 (0.8%) | ||
Anaphylactic shock | 1/257 (0.4%) | 0/259 (0%) | ||
Hypersensitivity | 1/257 (0.4%) | 0/259 (0%) | ||
Infections and infestations | ||||
Acinetobacter bacteraemia | 1/257 (0.4%) | 0/259 (0%) | ||
Aspergillosis | 4/257 (1.6%) | 3/259 (1.2%) | ||
Bacteraemia | 0/257 (0%) | 2/259 (0.8%) | ||
Bacterial sepsis | 0/257 (0%) | 4/259 (1.5%) | ||
Bronchitis pneumococcal | 1/257 (0.4%) | 0/259 (0%) | ||
Bronchopneumonia | 1/257 (0.4%) | 0/259 (0%) | ||
Bronchopulmonary aspergillosis | 2/257 (0.8%) | 1/259 (0.4%) | ||
Campylobacter gastroenteritis | 0/257 (0%) | 1/259 (0.4%) | ||
Catheter related infection | 0/257 (0%) | 1/259 (0.4%) | ||
Cellulitis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Cerebral aspergillosis | 1/257 (0.4%) | 0/259 (0%) | ||
Clostridium bacteraemia | 0/257 (0%) | 2/259 (0.8%) | ||
Clostridium difficile colitis | 1/257 (0.4%) | 0/259 (0%) | ||
Cytomegalovirus infection | 2/257 (0.8%) | 2/259 (0.8%) | ||
Cytomegalovirus viraemia | 1/257 (0.4%) | 0/259 (0%) | ||
Diarrhoea infectious | 0/257 (0%) | 1/259 (0.4%) | ||
Empyema | 0/257 (0%) | 1/259 (0.4%) | ||
Encephalitis herpes | 1/257 (0.4%) | 0/259 (0%) | ||
Endocarditis | 1/257 (0.4%) | 0/259 (0%) | ||
Enterococcal bacteraemia | 1/257 (0.4%) | 0/259 (0%) | ||
Escherichia sepsis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Fungal infection | 3/257 (1.2%) | 3/259 (1.2%) | ||
Fusarium infection | 1/257 (0.4%) | 0/259 (0%) | ||
Gastric ulcer helicobacter | 0/257 (0%) | 1/259 (0.4%) | ||
Herpes simplex | 0/257 (0%) | 1/259 (0.4%) | ||
Herpes zoster | 0/257 (0%) | 1/259 (0.4%) | ||
Infection | 1/257 (0.4%) | 0/259 (0%) | ||
Infusion site infection | 1/257 (0.4%) | 0/259 (0%) | ||
Klebsiella bacteraemia | 1/257 (0.4%) | 1/259 (0.4%) | ||
Klebsiella sepsis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Lung abscess | 0/257 (0%) | 1/259 (0.4%) | ||
Meningitis | 0/257 (0%) | 2/259 (0.8%) | ||
Mucormycosis | 1/257 (0.4%) | 0/259 (0%) | ||
Muscle abscess | 1/257 (0.4%) | 0/259 (0%) | ||
Necrotising fasciitis | 0/257 (0%) | 1/259 (0.4%) | ||
Pneumonia | 5/257 (1.9%) | 10/259 (3.9%) | ||
Pneumonia bacterial | 0/257 (0%) | 1/259 (0.4%) | ||
Pneumonia moraxella | 1/257 (0.4%) | 0/259 (0%) | ||
Pneumonia pneumococcal | 0/257 (0%) | 1/259 (0.4%) | ||
Pneumonia staphylococcal | 0/257 (0%) | 1/259 (0.4%) | ||
Pseudomonal bacteraemia | 0/257 (0%) | 1/259 (0.4%) | ||
Pseudomonal sepsis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Pseudomonas infection | 0/257 (0%) | 1/259 (0.4%) | ||
Pyothorax | 0/257 (0%) | 1/259 (0.4%) | ||
Respiratory tract infection | 1/257 (0.4%) | 0/259 (0%) | ||
Sepsis | 7/257 (2.7%) | 8/259 (3.1%) | ||
Sepsis syndrome | 1/257 (0.4%) | 0/259 (0%) | ||
Septic shock | 14/257 (5.4%) | 10/259 (3.9%) | ||
Skin infection | 1/257 (0.4%) | 0/259 (0%) | ||
Staphylococcal bacteraemia | 0/257 (0%) | 3/259 (1.2%) | ||
Staphylococcal infection | 1/257 (0.4%) | 0/259 (0%) | ||
Staphylococcal sepsis | 0/257 (0%) | 2/259 (0.8%) | ||
Stenotrophomonas sepsis | 0/257 (0%) | 1/259 (0.4%) | ||
Systemic candida | 0/257 (0%) | 1/259 (0.4%) | ||
Toxoplasmosis | 0/257 (0%) | 1/259 (0.4%) | ||
Tuberculosis | 0/257 (0%) | 1/259 (0.4%) | ||
Urinary tract infection | 1/257 (0.4%) | 1/259 (0.4%) | ||
Urinary tract infection bacterial | 0/257 (0%) | 1/259 (0.4%) | ||
Injury, poisoning and procedural complications | ||||
Accident at home | 0/257 (0%) | 1/259 (0.4%) | ||
Drug toxicity | 2/257 (0.8%) | 0/259 (0%) | ||
Fall | 1/257 (0.4%) | 0/259 (0%) | ||
Femoral neck fracture | 0/257 (0%) | 1/259 (0.4%) | ||
Radius fracture | 0/257 (0%) | 1/259 (0.4%) | ||
Investigations | ||||
Alanine aminotransferase increased | 0/257 (0%) | 1/259 (0.4%) | ||
Aspartate aminotransferase increased | 0/257 (0%) | 1/259 (0.4%) | ||
Blood alkaline phosphatase increased | 0/257 (0%) | 1/259 (0.4%) | ||
Blood bilirubin increased | 0/257 (0%) | 1/259 (0.4%) | ||
Blood sodium decreased | 1/257 (0.4%) | 0/259 (0%) | ||
Electrocardiogram QT prolonged | 0/257 (0%) | 1/259 (0.4%) | ||
Haemoglobin decreased | 1/257 (0.4%) | 0/259 (0%) | ||
Hepatic enzyme increased | 0/257 (0%) | 1/259 (0.4%) | ||
Liver function test abnormal | 1/257 (0.4%) | 1/259 (0.4%) | ||
Metabolism and nutrition disorders | ||||
Dehydration | 0/257 (0%) | 2/259 (0.8%) | ||
Diabetes mellitus inadequate control | 1/257 (0.4%) | 0/259 (0%) | ||
Failure to thrive | 1/257 (0.4%) | 0/259 (0%) | ||
Hypernatraemia | 0/257 (0%) | 1/259 (0.4%) | ||
Hypoglycaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Hypokalaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Hypophagia | 0/257 (0%) | 1/259 (0.4%) | ||
Metabolic acidosis | 0/257 (0%) | 2/259 (0.8%) | ||
Musculoskeletal and connective tissue disorders | ||||
Muscle haemorrhage | 1/257 (0.4%) | 0/259 (0%) | ||
Musculoskeletal chest pain | 1/257 (0.4%) | 0/259 (0%) | ||
Myositis | 1/257 (0.4%) | 0/259 (0%) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
Acute leukaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Acute lymphocytic leukaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Acute lymphocytic leukaemia recurrent | 1/257 (0.4%) | 1/259 (0.4%) | ||
Acute myeloid leukaemia | 3/257 (1.2%) | 8/259 (3.1%) | ||
Acute myeloid leukaemia recurrent | 0/257 (0%) | 5/259 (1.9%) | ||
B-cell lymphoma | 0/257 (0%) | 1/259 (0.4%) | ||
B-cell lymphoma recurrent | 0/257 (0%) | 1/259 (0.4%) | ||
Blast cell crisis | 1/257 (0.4%) | 1/259 (0.4%) | ||
Burkitt's leukaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Chronic lymphocytic leukaemia | 0/257 (0%) | 2/259 (0.8%) | ||
Chronic lymphocytic leukaemia recurrent | 1/257 (0.4%) | 0/259 (0%) | ||
Endometrial cancer | 1/257 (0.4%) | 0/259 (0%) | ||
Epstein-Barr virus associated lymphoproliferative disorder | 0/257 (0%) | 1/259 (0.4%) | ||
Leukaemia | 0/257 (0%) | 1/259 (0.4%) | ||
Lung neoplasm malignant | 0/257 (0%) | 1/259 (0.4%) | ||
Lymphoma | 2/257 (0.8%) | 1/259 (0.4%) | ||
Malignant neoplasm progression | 1/257 (0.4%) | 1/259 (0.4%) | ||
Metastases to bone | 0/257 (0%) | 1/259 (0.4%) | ||
Metastases to meninges | 1/257 (0.4%) | 0/259 (0%) | ||
Metastatic pain | 0/257 (0%) | 1/259 (0.4%) | ||
Multiple myeloma | 2/257 (0.8%) | 0/259 (0%) | ||
Myelodysplastic syndrome | 1/257 (0.4%) | 0/259 (0%) | ||
Myeloid leukaemia | 1/257 (0.4%) | 1/259 (0.4%) | ||
Neoplasm progression | 1/257 (0.4%) | 1/259 (0.4%) | ||
Non-Hodgkin's lymphoma | 1/257 (0.4%) | 0/259 (0%) | ||
Primary effusion lymphoma | 1/257 (0.4%) | 0/259 (0%) | ||
Nervous system disorders | ||||
Aphasia | 0/257 (0%) | 1/259 (0.4%) | ||
Brain stem stroke | 1/257 (0.4%) | 0/259 (0%) | ||
Central nervous system lesion | 1/257 (0.4%) | 1/259 (0.4%) | ||
Cerebral haemorrhage | 0/257 (0%) | 1/259 (0.4%) | ||
Cerebral ischaemia | 1/257 (0.4%) | 0/259 (0%) | ||
Convulsion | 3/257 (1.2%) | 1/259 (0.4%) | ||
Dizziness | 0/257 (0%) | 1/259 (0.4%) | ||
Encephalitis | 0/257 (0%) | 1/259 (0.4%) | ||
Encephalopathy | 1/257 (0.4%) | 1/259 (0.4%) | ||
Epilepsy | 2/257 (0.8%) | 1/259 (0.4%) | ||
Febrile convulsion | 1/257 (0.4%) | 0/259 (0%) | ||
Grand mal convulsion | 0/257 (0%) | 1/259 (0.4%) | ||
Haemorrhage intracranial | 2/257 (0.8%) | 3/259 (1.2%) | ||
Headache | 1/257 (0.4%) | 0/259 (0%) | ||
Hemiplegia | 0/257 (0%) | 1/259 (0.4%) | ||
Ischaemic stroke | 1/257 (0.4%) | 1/259 (0.4%) | ||
Neurotoxicity | 1/257 (0.4%) | 0/259 (0%) | ||
Paraplegia | 1/257 (0.4%) | 1/259 (0.4%) | ||
Polyneuropathy | 2/257 (0.8%) | 0/259 (0%) | ||
Stupor | 0/257 (0%) | 1/259 (0.4%) | ||
Subarachnoid haemorrhage | 0/257 (0%) | 1/259 (0.4%) | ||
Tremor | 0/257 (0%) | 1/259 (0.4%) | ||
VIIth nerve paralysis | 0/257 (0%) | 1/259 (0.4%) | ||
Psychiatric disorders | ||||
Confusional state | 0/257 (0%) | 1/259 (0.4%) | ||
Depressed mood | 0/257 (0%) | 1/259 (0.4%) | ||
Depression | 1/257 (0.4%) | 0/259 (0%) | ||
Hallucination | 0/257 (0%) | 1/259 (0.4%) | ||
Hallucination, visual | 0/257 (0%) | 2/259 (0.8%) | ||
Mental status changes | 0/257 (0%) | 2/259 (0.8%) | ||
Suicide attempt | 0/257 (0%) | 1/259 (0.4%) | ||
Renal and urinary disorders | ||||
Haematuria | 1/257 (0.4%) | 0/259 (0%) | ||
Renal failure | 3/257 (1.2%) | 2/259 (0.8%) | ||
Renal failure acute | 6/257 (2.3%) | 8/259 (3.1%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Acute lung injury | 0/257 (0%) | 1/259 (0.4%) | ||
Acute respiratory distress syndrome | 0/257 (0%) | 2/259 (0.8%) | ||
Acute respiratory failure | 5/257 (1.9%) | 5/259 (1.9%) | ||
Bronchopleural fistula | 1/257 (0.4%) | 0/259 (0%) | ||
Bronchospasm | 1/257 (0.4%) | 0/259 (0%) | ||
Chronic obstructive pulmonary disease | 0/257 (0%) | 1/259 (0.4%) | ||
Cough | 0/257 (0%) | 1/259 (0.4%) | ||
Dyspnoea | 5/257 (1.9%) | 1/259 (0.4%) | ||
Epistaxis | 0/257 (0%) | 4/259 (1.5%) | ||
Haemoptysis | 2/257 (0.8%) | 2/259 (0.8%) | ||
Haemothorax | 0/257 (0%) | 1/259 (0.4%) | ||
Hydropneumothorax | 1/257 (0.4%) | 0/259 (0%) | ||
Hypoxia | 2/257 (0.8%) | 1/259 (0.4%) | ||
Lung disorder | 1/257 (0.4%) | 1/259 (0.4%) | ||
Lung infiltration | 0/257 (0%) | 3/259 (1.2%) | ||
Pleural effusion | 1/257 (0.4%) | 1/259 (0.4%) | ||
Pleuritic pain | 1/257 (0.4%) | 0/259 (0%) | ||
Pneumonia aspiration | 1/257 (0.4%) | 0/259 (0%) | ||
Pneumothorax | 0/257 (0%) | 1/259 (0.4%) | ||
Productive cough | 0/257 (0%) | 1/259 (0.4%) | ||
Pulmonary embolism | 0/257 (0%) | 3/259 (1.2%) | ||
Pulmonary haemorrhage | 2/257 (0.8%) | 1/259 (0.4%) | ||
Pulmonary hypertension | 0/257 (0%) | 1/259 (0.4%) | ||
Pulmonary oedema | 1/257 (0.4%) | 1/259 (0.4%) | ||
Respiratory acidosis | 1/257 (0.4%) | 0/259 (0%) | ||
Respiratory arrest | 0/257 (0%) | 1/259 (0.4%) | ||
Respiratory depression | 1/257 (0.4%) | 1/259 (0.4%) | ||
Respiratory distress | 4/257 (1.6%) | 3/259 (1.2%) | ||
Respiratory failure | 14/257 (5.4%) | 12/259 (4.6%) | ||
Tachypnoea | 1/257 (0.4%) | 0/259 (0%) | ||
Skin and subcutaneous tissue disorders | ||||
Decubitus ulcer | 1/257 (0.4%) | 0/259 (0%) | ||
Dermatitis | 1/257 (0.4%) | 0/259 (0%) | ||
Panniculitis | 1/257 (0.4%) | 0/259 (0%) | ||
Rash | 0/257 (0%) | 2/259 (0.8%) | ||
Vascular disorders | ||||
Deep vein thrombosis | 0/257 (0%) | 1/259 (0.4%) | ||
Haemorrhage | 1/257 (0.4%) | 1/259 (0.4%) | ||
Hypotension | 1/257 (0.4%) | 2/259 (0.8%) | ||
Hypovolaemic shock | 1/257 (0.4%) | 1/259 (0.4%) | ||
Shock | 0/257 (0%) | 1/259 (0.4%) | ||
Vasculitis | 1/257 (0.4%) | 0/259 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Isavuconazole | Voriconazole | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 227/257 (88.3%) | 228/259 (88%) | ||
Blood and lymphatic system disorders | ||||
Anaemia | 11/257 (4.3%) | 22/259 (8.5%) | ||
Febrile neutropenia | 19/257 (7.4%) | 34/259 (13.1%) | ||
Thrombocytopenia | 10/257 (3.9%) | 22/259 (8.5%) | ||
Cardiac disorders | ||||
Tachycardia | 12/257 (4.7%) | 21/259 (8.1%) | ||
Eye disorders | ||||
Visual impairment | 4/257 (1.6%) | 19/259 (7.3%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 24/257 (9.3%) | 36/259 (13.9%) | ||
Abdominal pain upper | 15/257 (5.8%) | 25/259 (9.7%) | ||
Constipation | 35/257 (13.6%) | 54/259 (20.8%) | ||
Diarrhoea | 59/257 (23%) | 59/259 (22.8%) | ||
Dyspepsia | 15/257 (5.8%) | 13/259 (5%) | ||
Nausea | 70/257 (27.2%) | 78/259 (30.1%) | ||
Vomiting | 64/257 (24.9%) | 73/259 (28.2%) | ||
General disorders | ||||
Asthenia | 15/257 (5.8%) | 20/259 (7.7%) | ||
Chills | 27/257 (10.5%) | 22/259 (8.5%) | ||
Fatigue | 27/257 (10.5%) | 18/259 (6.9%) | ||
Mucosal inflammation | 23/257 (8.9%) | 14/259 (5.4%) | ||
Oedema | 13/257 (5.1%) | 18/259 (6.9%) | ||
Oedema peripheral | 26/257 (10.1%) | 31/259 (12%) | ||
Pyrexia | 53/257 (20.6%) | 72/259 (27.8%) | ||
Infections and infestations | ||||
Cytomegalovirus infection | 15/257 (5.8%) | 21/259 (8.1%) | ||
Oral herpes | 13/257 (5.1%) | 14/259 (5.4%) | ||
Investigations | ||||
Alanine aminotransferase increased | 13/257 (5.1%) | 17/259 (6.6%) | ||
Aspartate aminotransferase increased | 11/257 (4.3%) | 14/259 (5.4%) | ||
Blood alkaline phosphatase increased | 12/257 (4.7%) | 14/259 (5.4%) | ||
Gamma-glutamyltransferase increased | 16/257 (6.2%) | 22/259 (8.5%) | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 22/257 (8.6%) | 28/259 (10.8%) | ||
Hyperglycaemia | 10/257 (3.9%) | 13/259 (5%) | ||
Hypokalaemia | 45/257 (17.5%) | 55/259 (21.2%) | ||
Hypomagnesaemia | 14/257 (5.4%) | 27/259 (10.4%) | ||
Musculoskeletal and connective tissue disorders | ||||
Back pain | 26/257 (10.1%) | 19/259 (7.3%) | ||
Pain in extremity | 11/257 (4.3%) | 15/259 (5.8%) | ||
Nervous system disorders | ||||
Dizziness | 10/257 (3.9%) | 14/259 (5.4%) | ||
Headache | 40/257 (15.6%) | 38/259 (14.7%) | ||
Psychiatric disorders | ||||
Anxiety | 20/257 (7.8%) | 17/259 (6.6%) | ||
Confusional state | 16/257 (6.2%) | 19/259 (7.3%) | ||
Insomnia | 23/257 (8.9%) | 24/259 (9.3%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Cough | 33/257 (12.8%) | 34/259 (13.1%) | ||
Dyspnoea | 30/257 (11.7%) | 28/259 (10.8%) | ||
Epistaxis | 21/257 (8.2%) | 25/259 (9.7%) | ||
Haemoptysis | 14/257 (5.4%) | 16/259 (6.2%) | ||
Oropharyngeal pain | 14/257 (5.4%) | 14/259 (5.4%) | ||
Rales | 5/257 (1.9%) | 14/259 (5.4%) | ||
Skin and subcutaneous tissue disorders | ||||
Erythema | 9/257 (3.5%) | 15/259 (5.8%) | ||
Pruritus | 19/257 (7.4%) | 15/259 (5.8%) | ||
Rash | 17/257 (6.6%) | 26/259 (10%) | ||
Vascular disorders | ||||
Hypertension | 25/257 (9.7%) | 31/259 (12%) | ||
Hypotension | 20/257 (7.8%) | 26/259 (10%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript at least 30 days prior to publication for review and comment. Sponsor may delay the publication for up to 60 days to seek patent protection.
Results Point of Contact
Name/Title | Medical Head Immunology, Transplant and Infectious Disease Therapeutic Area |
---|---|
Organization | Astellas Pharma Global Development, Inc. |
Phone | |
resultsdisclosure@astellas.com |
- 9766-CL-0104
- WSA-CS-004
- 2006-003868-59