9766-CL-0103/WSA-CS-003

Astellas Global Pharma Development, Inc

1 Astellas Way , Northbrook, United States,

Medical Head ID/IM/TX, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com

Medical Head ID/IM/TX, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com

No

No

No

Final

03 Jan 2014

Yes

03 Jan 2014

Yes

03 Jan 2014

No

Main objective of the trial was to describe the safety and efficacy of isavuconazole in the treatment of invasive Aspergillosis in patients with renal impairment (RI) or in patients with invasive fungal disease (IFD) caused by rare moulds, yeasts or dimorphic fungi.

This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

22 Apr 2008

No

Yes

Lebanon: 1

Israel: 21

Belgium: 13

Germany: 4

United States: 57

Russian Federation: 2

Mexico: 8

Brazil: 20

Thailand: 15

Korea, Democratic People's Republic of: 3

India: 5

149

17

0

0

0

0

0

0

119

29

1

Overall Trial (overall period)

Not applicable

isavuconazole/CRESEMBA

BAL8557

isavuconazonium sulfate,(CRESEMBA) as a pro drug of isavuconazole

Capsule, Injection

Intravenous use, Oral use

The IV and oral formulations are 98% bioequivalent and therefore interchangable. A loading regimen of isavuconazole (IV or PO) was used over 2 days, followed by a maintenance regimen from Day 3 to EOT. During Days 1 and 2, three doses of 200 mg isavuconazole were administered every 8 hours for a total of six doses and from Day 3 to End of Treatment (EOT), maintanance dose of 200 mg isavuconazole was administered once daily up to 180 days; with an option for extended treatment under specified criteria.

Isavuconazole

mITT- Aspergillus [Renally Impaired]

Aspergillus - Renally Impaired mITT population consisted of participants who have had proven,probable or possible IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Renal impairment was defined as yes for patients who have a baseline eGFR-MDRD < 60 mL/min/1.73 m^2, no for patients who have a baseline eGFR-MDRD ≥ 60 mL/min/1.73 m^2. Overall there were 24 participants in the mITT-Aspergillus population out of which 20 participants were classified as Renally Impaired (RI).

mITT- Aspergillus [Not Renally Impaired]

Aspergillus - Renally Impaired mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Overall there were 24 participants in the mITT-Aspergillus population out of which 4 participants were classified as Not Renally Impaired (NRI).

mITT- Mucorales [Primary Therapy]

Mucorales – Primary Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 21 participants receiving isavuconazole as a primary therapy.

mITT- Mucorales [Refractory]

Mucorales – Refractory Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis).The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 11 participants whose IFD was refractory to prior AFT.

mITT - Mucorales [Intolerant]

Mucorales – Intolerant mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participant had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 5 participants who were intolerant to prior AFT.

mITT- Other Filamentous Fungi

Other Filamentous Fungi mITT population consisted of 17 participants who have had proven or probable IFD as determined by the DRC caused by other filamentous fungi (4 Fusarium,2 Exophiala,2 Cladosporium,2 Scopulariopsis and 1 each of Acremonium, Alternaria, Curvularia,Exserohilum, Paecilomyces,Pseudallescheria and Scedosporium).

mITT- Mould Species

Other Mould Species mITT population consisted of 7 participants who have had proven or probable IFD as determined by the DRC caused by mould species.

mITT- Dimorphic Fungi

Other Dimorphic Fungi mITT population consisted of 29 participants who have had proven or probable IFD as determined by the DRC caused by dimorphic fungi (10 Paracoccidiodes,9 Coccidiodides, 7 Histoplasma, 3 Blastomyces).

mITT- Non Candida Yeast

Other Non Candida Yeast mITT population consisted of 11 participants who have had proven or probable IFD as determined by the DRC caused by non-Candida yeast (4 Cryptococcus neoformans, 3 Cryptococcus gatii, 2 Cryptococcus NOS and 2 Trichosporon).

mITT-Mixed Infections

Other Mixed Infections mITT population consisted of 15 participants who have had proven or probable IFD as determined by the DRC caused by mixed infections aspergillosis/mucormycosis.

Isavuconazole

mITT- Aspergillus [Renally Impaired]

Aspergillus - Renally Impaired mITT population consisted of participants who have had proven,probable or possible IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Renal impairment was defined as yes for patients who have a baseline eGFR-MDRD < 60 mL/min/1.73 m^2, no for patients who have a baseline eGFR-MDRD ≥ 60 mL/min/1.73 m^2. Overall there were 24 participants in the mITT-Aspergillus population out of which 20 participants were classified as Renally Impaired (RI).

mITT- Aspergillus [Not Renally Impaired]

Aspergillus - Renally Impaired mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Overall there were 24 participants in the mITT-Aspergillus population out of which 4 participants were classified as Not Renally Impaired (NRI).

mITT- Mucorales [Primary Therapy]

Mucorales – Primary Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 21 participants receiving isavuconazole as a primary therapy.

mITT- Mucorales [Refractory]

Mucorales – Refractory Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis).The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 11 participants whose IFD was refractory to prior AFT.

mITT - Mucorales [Intolerant]

Mucorales – Intolerant mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participant had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 5 participants who were intolerant to prior AFT.

mITT- Other Filamentous Fungi

Other Filamentous Fungi mITT population consisted of 17 participants who have had proven or probable IFD as determined by the DRC caused by other filamentous fungi (4 Fusarium,2 Exophiala,2 Cladosporium,2 Scopulariopsis and 1 each of Acremonium, Alternaria, Curvularia,Exserohilum, Paecilomyces,Pseudallescheria and Scedosporium).

mITT- Mould Species

Other Mould Species mITT population consisted of 7 participants who have had proven or probable IFD as determined by the DRC caused by mould species.

mITT- Dimorphic Fungi

Other Dimorphic Fungi mITT population consisted of 29 participants who have had proven or probable IFD as determined by the DRC caused by dimorphic fungi (10 Paracoccidiodes,9 Coccidiodides, 7 Histoplasma, 3 Blastomyces).

mITT- Non Candida Yeast

Other Non Candida Yeast mITT population consisted of 11 participants who have had proven or probable IFD as determined by the DRC caused by non-Candida yeast (4 Cryptococcus neoformans, 3 Cryptococcus gatii, 2 Cryptococcus NOS and 2 Trichosporon).

mITT-Mixed Infections

Other Mixed Infections mITT population consisted of 15 participants who have had proven or probable IFD as determined by the DRC caused by mixed infections aspergillosis/mucormycosis.

The DRC assessed overall response based on individual clinical, mycological and radiological response assessments. Participants with a complete or partial response were considered a success.

Primary

Day 42, Day 84 and End of Treatment [EOT]

All-cause Mortality was assessed through Day 42 and Day 84 and summarized for ITT population.

Secondary

Baseline to End of Treatment (EOT [Day 180]).

The DRC evaluated clinical response to treatment for patients at day 42, day 84 and EOT. The list of possible clinical responses to treatment as assessed by the DRC is as follows; Success [Resolution of all attributable clinical symptoms and physical findings and Partial resolution of attributable clinical symptoms and physical findings], Failure [No resolution of any attributable clinical symptoms and physical findings and/or worsening and Not done or missing] and Not applicable [No attributable signs and symptoms present at baseline and no symptoms attributable to IFD developed post baseline]. Each type of clinical response to treatment evaluated by the DRC at day 42, day 84 and EOT were summarized.

Secondary

Day 42, Day 84 and EOT

The DRC evaluated mycological response to treatment for patients at day 42, day 84 and EOT. The list of possible mycological responses to treatment is as follows, Success [Eradication and Presumed eradication], Failure [Persistence, Presumed persistence and Not done or missing] and Not applicable [No mycological evidence available at baseline]. Each type of mycological response to treatment evaluated by the DRC at day 42, day 84 and EOT was summarized.

Secondary

Day 42, Day 84 and End of Treatment (EOT).

Radiological responses to treatment as assessed by the DRC at different time points are as follows, Day 42-Success [Improvement of at least 25% from baseline for invasive aspergillosis and other filamentous mold infections],Failure [No postbaseline radiology available]; Day 84-Success [Improvement of at least 50% from baseline for invasive aspergillosis and other filamentous mold infections], Failure [No postbaseline radiology available for patient with baseline evidence of radiologic disease]; EOT-Success [Improvement of at least 25% from baseline if EOT occurs prior to day 42 and at least 50% improvement from baseline if EOT occurs after day 42 for invasive aspergillosis and other filamentous mold infections], Failure [No postbasline radiology available].

Secondary

Day 42, Day 84 and EOT

Patients were assessed for the occurrence of AEs on an ongoing basis during the course of the study and up to follow-up visit 1 (28 days after the last administration of study drug).

All adverse events analysis was completed on Safety Analysis Set (SAF) population. Adverse events reported are Treatment Emergent Adverse Events (TEAEs). A treatment- emergent adverse event is any adverse event that starts after the first administration of study medication until 28 days after the last dose of study medication.

12.1

Not Renally Impaired

Renally Impaired